‫لجنة عمداء كليات الصيدلة‬

‫لجنة توحيد منهاج مادة (‪)Clinical Pharmacy II‬‬

‫‪Clinical Pharmacy II‬‬

‫المرحلة الرابعة‬
‫‪2024‬‬

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‫تم اعداد ومراجعة هذا المنهج الموحد لالمتحان التقويمي لكليات الصيدلة للعام الدراسي‬
‫‪ 2024-2023‬من قبل اساتذة متخصصين لديهم خبرة كبيرة في التدريس والعمل االكاديمي ‪.‬‬
‫لقد بذل االساتذة قصارى جهودهم في جمع المعلومات وحرصوا على ترتيبها وتنظيمها لتكون‬
‫واضحة يسيرة على طلبتنا االعزاء ‪ .‬نأمل من طلبتنا االعزاء االستفادة منه في طريقهم الى‬
‫النجاح والتفوق ‪ ،‬وهللا الموفق‬

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 College of Pharmacy
Fourth year. Clinical Pharmacy
Cardiovascular disorders
Hypertension
Introduction
1-Hypertension is defined as persistently elevated arterial blood pressure (BP). (See
Table -1 for the classification of BP in adults).
Table-1: Classification of Blood Pressure in Adults

2-Isolated systolic hypertension is diastolic blood pressure (DBP) <80 mm Hg and

systolic blood pressure (SBP) ≥130 mm Hg.
3-Hypertensive crisis (BP >180/120 mm Hg) is categorized as hypertensive emergency
(extreme BP elevation with acute or progressing end-organ damage) or hypertensive
urgency (extreme BP elevation without acute or progressing end-organ injury).
Pathophysiology
1-Hypertension may result from an unknown etiology (primary or essential hypertension)
or from a specific cause (secondary hypertension).
2-Secondary hypertension (<10% of cases) is usually caused by chronic kidney disease
(CKD) or renovascular disease.
3-Examples of drugs that may increase BP include corticosteroids, estrogens, NSAIDs,
cyclosporine, erythropoietin, and venlafaxine.
4-Major causes of death include cerebrovascular events, cardiovascular (CV) events, and
renal failure.
Clinical presentation
1-Patients with uncomplicated primary hypertension are usually asymptomatic
initially.
2-Patients with secondary hypertension may have symptoms of the underlying disorder.
Diagnosis
1-Elevated BP may be the only sign of primary hypertension on physical examination.
2-Diagnosis should be based on the average of two or more readings taken at each of two
or more clinical encounters.

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3-Signs of end-organ damage occur primarily in the eyes, brain, heart, kidneys, and
peripheral vasculature.
Treatment
1-Goals of Treatment: The overall goal is to reduce morbidity and mortality from CV
events. The 2017 ACC/AHA guideline recommends a goal BP of <130/80 mm Hg for
most patients.
2-For institutionalized older patients and those with a high disease burden or limited
life expectancy, consider a relaxed SBP goal of <150 mm Hg (or <140 mm Hg if
tolerated).
Nonpharmacologic Therapy
A-Implement lifestyle modifications in all patients with elevated BP or stage 1 or 2
hypertension.
B-Lifestyle modifications shown to lower BP include:
(1) weight loss if overweight or obese, (2) the Dietary Approaches to Stop Hypertension
(DASH) eating plan, (3) reduced salt intake, ideally to 1.5 g/day sodium (3.8 g/day
sodium chloride), (4) physical activity (90–150 min/week of aerobic or dynamic resistance
training), and (5) moderation of alcohol intake. Although smoking cessation does not
control BP, it reduces CV disease risk and should be encouraged.
Pharmacologic Therapy
General Approach to Treatment
1-Initial drug selection depends on the degree of BP elevation and presence of compelling
indications for certain drugs.
2-Use a single first-line drug as initial therapy in most patients with newly diagnosed stage
1 hypertension.
3-Start combination drug therapy (preferably with two first-line drugs) as the initial
regimen in patients with newly diagnosed stage 2 hypertension.
4-The four first-line options are angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide
diuretics.
5-β-Blockers should be reserved to treat a specific compelling indication or in
combination with a first-line antihypertensive agent for patients without a compelling
indication.
6-Other antihypertensive drug classes (α1-blockers, direct renin inhibitors, central α2-
agonists, and direct arterial vasodilators) may be used for select patients after
implementing first-line agents.
Compelling Indications
Compelling indications are specific comorbid conditions for which clinical trial data
support using specific antihypertensive drug classes to treat both hypertension and the
compelling indication.

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Notes:
1-β-Blockers (without ISA) are first-line therapy in Stable Ischemic Heart Disease (SIHD).
2-For acute coronary syndromes, first-line therapy includes a β-blocker and ACE
inhibitor (or ARB).
3-Any first-line agent can be used to control hypertension in patients with diabetes in
the absence of albuminuria.
4-In addition to lowering BP, ACE inhibitors and ARBs reduce intraglomerular pressure,
which may further slow chronic kidney disease progression.
5-The threshold for starting antihypertensive drug therapy in patients with a history of
stroke is when BP is >140/90 mm Hg (goal of <130/80 mm Hg).
Angiotensin-Converting Enzyme Inhibitors (captopril, enalapril, fosinopril,
imidapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril)
1-ACE inhibitors block conversion of angiotensin I to angiotensin II, a potent
vasoconstrictor and stimulator of aldosterone secretion.
2-Starting doses should be low with slow dose titration. Acute hypotension may occur at
the onset of therapy.
3-ACE inhibitors decrease aldosterone and can increase serum potassium concentrations.
Hyperkalemia occurs primarily in patients with CKD or those also taking potassium
supplements, potassium-sparing diuretics, mineralocorticoid receptor antagonists, ARBs, or
direct renin inhibitors.
4-AKI is an uncommon but serious side effect; preexisting kidney disease increases risk.
Bilateral renal artery stenosis or unilateral stenosis are particularly susceptible to AKI.
5-Serum creatinine concentrations often increase, but modest elevations (eg, absolute
increases <1 mg/dL) do not warrant treatment changes. Discontinue therapy or reduce
dose if larger increases occur.

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6-Angioedema occurs in <1% of patients. Drug withdrawal is necessary, and some
patients may require drug treatment and/or emergent intubation to support respiration.
7-An ARB can generally be used in patients with a history of ACE inhibitor-induced
angioedema, with careful monitoring.
8-A persistent dry cough occurs in up to 20% of patients and is thought to be due to
inhibition of bradykinin breakdown.
9-ACE inhibitors (as well as ARBs and direct renin inhibitors) are contraindicated in
pregnancy.
Angiotensin II Receptor Blockers (candesartan, eprosartan, irbesartan, losartan,
olmesartan, telmisartan, and valsartan)
1-The ARBs directly block the angiotensin II type 1 receptor that mediates the effects of
angiotensin II.
2-Unlike ACE inhibitors, ARBs do not block bradykinin breakdown and this accounts
for the lack of cough as a side effect.
3-ARBs have a low incidence of side effects. Like ACE inhibitors, they may cause renal
insufficiency, hyperkalemia, and orthostatic hypotension.
Calcium Channel Blockers
1-Dihydropyridine and nondihydropyridine CCBs are first-line antihypertensive therapies
and are also used in addition to or instead of other first-line agents for the compelling
indication of ischemic heart disease.
2-Dihydropyridine CCBs may cause reflex sympathetic activation, and all agents (except
amlodipine and felodipine) may have negative inotropic effects.
3-Verapamil produces a negative inotropic effect that may precipitate HF in patients with
borderline cardiac reserve. Diltiazem decreases heart rate to a lesser extent than
verapamil.
4-Both diltiazem and verapamil can cause peripheral edema and hypotension. Verapamil
causes constipation in about 7% of patients.
5-Dihydropyridines cause a baroreceptor-mediated reflex increase in heart rate because
of potent peripheral vasodilating effects. Other side effects of dihydropyridines are
dizziness, flushing, headache, gingival hyperplasia, and peripheral edema.
Diuretics
1-Thiazides are the preferred type of diuretic and are a first-line option for most
patients with hypertension. Chlorthalidone (thiazide-like) is preferred over
hydrochlorothiazide, especially in resistant hypertension, because it is more potent on a
milligram-per-milligram basis.
2-Loop diuretics (Furosemide, Bumetanide and Torasemide) are more potent for
inducing diuresis but are not ideal antihypertensives unless edema treatment is also

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needed. Loop diuretics are sometimes required over thiazides in patients with severe CKD
when eGFR is <30 mL/min/1.73 m2, especially when edema is present.
3-Potassium-sparing diuretics are weak antihypertensives when used alone. Their
primary use is in combination with another diuretic to counteract potassium-wasting
properties.
4-Mineralocorticoid receptor antagonists (spironolactone and eplerenone) are also
potassium-sparing diuretics that are usually used to treat resistant hypertension because
elevated aldosterone concentrations are prevalent in this setting. They are also used as
add-on agents in patients with HFrEF with or without concomitant hypertension.
5-Acutely, diuretics lower BP by causing diuresis. With chronic therapy, reduced
peripheral vascular resistance is responsible for persistent hypotensive effects.
6-Side effects of thiazides include hypokalemia, hypomagnesemia, hypercalcemia,
hyperuricemia, hyperglycemia, dyslipidemia, and sexual dysfunction.
7-Loop diuretics have less effect on serum lipids and glucose, but hypokalemia is more
pronounced, and hypocalcemia may occur.
8-Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps, and severe
electrolyte abnormalities may result in serious cardiac arrhythmias.
9-Potassium-sparing diuretics may cause hyperkalemia, especially in patients with CKD
or diabetes and in patients receiving concurrent treatment with a mineralocorticoid receptor
antagonist, ACE inhibitor, ARB, direct renin inhibitor, or potassium supplement.
10-Spironolactone may cause gynecomastia in up to 10% of patients; this effect occurs
rarely with eplerenone.
β-Blockers
1-Evidence suggests that β-blockers may not reduce CV events as well as ACE
inhibitors, ARBs, CCBs, or thiazides when used as the initial drug in patients who do
not have a compelling indication for a β-blocker.
2-β-Blockers are appropriate first-line agents when used to treat specific compelling
indications or when an ACE inhibitor, ARB, CCB, or thiazide cannot be used.
3-Atenolol, betaxolol, bisoprolol, metoprolol, and nebivolol are β1-cardioselective at low
dose. As a result, they are less likely to provoke bronchospasm and vasoconstriction and
are safer than nonselective β-blockers in patients with asthma or diabetes. Cardioselectivity
is a dose-dependent phenomenon, and the effect is lost at higher doses.
4-Acebutolol, carteolol, and pindolol possess intrinsic sympathomimetic activity (ISA) or
partial β-receptor agonist activity. Theoretically, these drugs may have advantages in select
patients with HF or sinus bradycardia. Unfortunately, they do not reduce CV events as
well as other β-blockers and may increase CV risk in patients with SIHD. Thus, agents
with ISA are rarely needed and have no role in hypertension management.
5-Atenolol and nadolol have relatively long half-lives and are excreted renally; the
dosage may need to be reduced in patients with renal insufficiency.
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6-Even though the half-lives of other β-blockers are shorter, once-daily administration still
may be effective.
7-Cardiac side effects include bradycardia, AV conduction abnormalities, and acute HF.
Blocking β2-receptors in arteriolar smooth muscle may cause cold extremities and
aggravate intermittent claudication or Raynaud phenomenon because of decreased
peripheral blood flow.
8-Increases in serum lipids and glucose appear to be transient and of little clinical
significance.
9-Abrupt cessation of β-blockers should be avoided. The dose should always be
tapered gradually over 1–2 weeks before discontinuation.
α1-Receptor Blockers
1-Prazosin, terazosin, and doxazosin are selective α1-receptor blockers that inhibit
catecholamine uptake in smooth muscle cells of peripheral vasculature, resulting in
vasodilation and BP lowering.
2-Although they can provide symptomatic benefit in men with benign prostatic hyperplasia,
they should be used to lower BP only in combination with first-line antihypertensive
agents.
Direct Renin Inhibitor
Aliskiren blocks the RAAS at its point of activation, resulting in reduced plasma renin
activity and BP. It is approved for monotherapy or in combination therapy. Its role in the
management of hypertension is limited.
Central α2-Agonists
1-Clonidine, guanfacine, and methyldopa lower BP primarily by stimulating α2-
adrenergic receptors in the brain, which reduces sympathetic outflow from the vasomotor
center.
2-Clonidine is often used in resistant hypertension, and methyldopa is frequently used for
pregnancy-induced hypertension.
Direct Arterial Vasodilators
Hydralazine and minoxidil directly relax arteriolar smooth muscle, resulting in
vasodilation and BP lowering.
Special Populations
Older Persons
1-Older patients may present with either isolated systolic hypertension or elevation in both
SBP and DBP. CV morbidity and mortality are more directly correlated to SBP than
to DBP in patients aged 50 and older.
2-First-line antihypertensives provide significant benefits and can be used safely in older
patients, but smaller-than-usual initial doses must be used for initial therapy.

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Children and Adolescents
1-Because secondary hypertension is more common in children and adolescents than in
adults, an appropriate workup is required if elevated BP is identified.
2-Nonpharmacologic treatment is the cornerstone of therapy for primary
hypertension.
3-ACE inhibitors, ARBs, β-blockers, CCBs, and thiazide diuretics are all acceptable drug
therapy choices.
Pregnancy
1-Preeclampsia (Further reading 1) can lead to life-threatening complications for both
mother and fetus.
2-Eclampsia is the onset of convulsions in preeclampsia and is a medical emergency.
3-Definitive treatment of preeclampsia is delivery, and labor induction is indicated if
eclampsia is imminent or present. Otherwise, management consists of restricting activity,
bed rest, and close monitoring. Salt restriction or other measures that contract blood volume
should be avoided.
4-Antihypertensives are used before induction of labor if DBP is >105 mm Hg, with a
target DBP of 95–105 mm Hg. Intravenous (IV) hydralazine is most commonly used; IV
labetalol is also effective.
5-Chronic hypertension is hypertension that predates pregnancy. Labetalol, long-acting
nifedipine, or methyldopa is recommended as first-line therapy due to favorable safety
profiles. β-Blockers (except atenolol) and CCBs are also reasonable alternatives.
Black Patients
CCBs and thiazides are most effective in African Americans and should be first-line in
the absence of a compelling indication.
Pulmonary Disease and Peripheral Arterial Disease (PAD)
1-Although β-blockers (especially nonselective agents) have generally been avoided in
hypertensive patients with asthma and COPD because of fear of inducing bronchospasm,
cardioselective β-blockers can be used safely.
2-β-Blockers can theoretically be problematic in patients with PAD because of possible
decreased peripheral blood flow secondary to unopposed stimulation of α1-receptors that
results in vasoconstriction. However, available data indicate that β-blockers do not
worsen claudication symptoms or cause functional impairment. Therefore,
antihypertensive treatment for patients with PAD should follow the same general
principles as patients without PAD.
Hypertensive Urgencies and Emergencies
1-Acute administration of a short-acting oral drug (captopril, clonidine, or labetalol) is
an option.
2-Hypertensive emergencies require immediate BP reduction with a parenteral agent
to limit new or progressing end-organ damage.
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Evaluation of therapeutic outcomes
1-Evaluate BP response in the clinic 4 weeks after initiating or making changes in
therapy and compare the results to home BP readings.
2-Once goal BP is obtained, monitor BP every 3–6 months, assuming no signs or
symptoms of acute end-organ damage.
3-Assess patient adherence with the regimen regularly.

Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th
Edition. 2023.

Further reading

1-Preeclampsia is defined as hypertension (elevated BP ≥140/90 mm Hg on more than two

occasions at least 4 hours apart after 20 weeks’ gestation or ≥160/110 mm Hg confirmed
within a short interval) and either proteinuria or new onset hypertension with the onset of
thrombocytopenia, impaired liver function, new onset renal insufficiency, pulmonary
edema, or new onset cerebral or visual disturbances.

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 College of Pharmacy
Fourth year. Clinical Pharmacy
Cardiovascular disorders
Heart Failure
Introduction
1-Heart failure (HF) is a syndrome associated with signs and symptoms due to
abnormalities in cardiac structure or function
2-HF may be caused by an abnormality in systolic function, diastolic function, or both.
3-HF with reduced systolic function (ie, reduced left ventricular ejection fraction, LVEF) is
referred to as HF with reduced ejection fraction (HFrEF).
4-Diastolic dysfunction with normal LVEF is termed HF with preserved ejection
fraction (HFpEF).
Pathophysiology
1-Causes of systolic dysfunction (decreased contractility) include reduced muscle mass
(eg, myocardial infarction [MI])
2-Causes of diastolic dysfunction (restriction in ventricular filling) include increased
ventricular stiffness, and ventricular hypertrophy.
3-The leading causes of HF are coronary artery disease and hypertension.
4-Decreased cardiac output (CO) results in activation of compensatory responses to
maintain circulation:
(A) Tachycardia and increased contractility through sympathetic nervous system
activation, (B) Increased preload (through sodium and water retention) increases
stroke volume, (C) vasoconstriction, and (D) ventricular hypertrophy and
remodeling.
5-Although these compensatory mechanisms initially maintain cardiac function, they are
responsible for the symptoms of HF and contribute to disease progression.
6-Chronic activation of the neurohormonal systems results in a cascade of events that
affect the myocardium.
7-These events lead to changes in ventricular size (left ventricular hypertrophy), shape,
structure, and function known as ventricular remodeling.
Clinical presentation
1-Patient presentation may range from asymptomatic to cardiogenic shock. Primary
symptoms are dyspnea (especially on exertion) and fatigue, which lead to exercise
intolerance.
2-Other pulmonary symptoms include: orthopnea, paroxysmal nocturnal dyspnea (PND),
tachypnea, and cough. Fluid overload can result in pulmonary congestion and peripheral
edema.

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3-Nonspecific symptoms may include fatigue, nocturia, hemoptysis, abdominal pain,
anorexia, nausea, bloating, ascites, poor appetite or early satiety, and weight gain or loss.
Diagnosis
1-Ventricular hypertrophy can be demonstrated on chest radiograph or
electrocardiogram (ECG). Chest radiograph may also show pleural effusions or
pulmonary edema.
2-Echocardiogram can quantify LVEF to determine if systolic or diastolic dysfunction is
present.
3-The New York Heart Association Functional Classification System is intended primarily
to classify symptoms according to the physician’s subjective evaluation.
 Functional class (FC)-I patients have no limitation of physical activity.
 FC-II patients have slight limitation.
 FC-III patients have marked limitation
 FC-IV patients are unable to carry on physical activity without discomfort.
Treatment of chronic heart failure
Goals of Treatment: Improve quality of life, relieve or reduce symptoms, prevent or
minimize hospitalizations, slow disease progression, and prolong survival.
General Approach
1-The first step is to determine the etiology or precipitating factors. Treatment of
underlying disorders (e.g., hyperthyroidism) may obviate the need for treating HF.
2-An international group developed a staging system:

Stage Description Recommendation

Stage At risk for HF (No HF signs Drugs are recommended for HF prevention in
A or symptoms with No select patients
structural heart disease)
Stage PreHF (No HF signs or Drugs are recommended for HF prevention in
B symptoms but with structural select patients
heart disease)
Stage HF (HF signs or symptoms Most patients with HFrEF in stage C should
C with structural heart disease)
receive Guideline directed medical therapy
(GDMT) proven to reduce morbidity and
mortality.
Stage Advanced HF (persistent HF They should be considered for specialized
D symptoms despite maximally interventions, including mechanical circulatory
tolerated GDMT) support, continuous IV positive inotropic therapy,
or cardiac transplantation

Nonpharmacologic Therapy of Chronic Heart Failure

1-Interventions include restriction of fluid intake and dietary sodium intake (<2–3 g of
sodium/day) with daily weight measurements.
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2-In patients with hyponatremia or persistent volume retention despite high diuretic doses
and sodium restriction, limit daily fluid intake to 2 L/day from all sources.
3-Revascularization or anti-ischemic therapy in patients with coronary disease may
reduce HF symptoms. Drugs that can aggravate HF should be discontinued if possible.
Pharmacologic Therapy for Stage C HFrEF
1-In general, patients with stage C HFrEF should receive an ACE inhibitor, ARB, or
ARNI along with β-blocker, Sodium Glucose Cotransporter Type 2 (SGLT2)
Inhibitors (4) plus an aldosterone antagonist.
2-Administer a diuretic if there is evidence of fluid retention. A hydralazine–nitrate
combination, ivabradine, Vericiguat or digoxin may be considered in select patients.
A-Diuretics
1-Diuretic therapy (in addition to sodium restriction) is recommended for all patients with
clinical evidence of fluid retention.
2-However, because they do not alter disease progression or prolong survival, diuretics
are not required for patients without fluid retention.
3-Thiazide diuretics (eg, hydrochlorothiazide) are relatively weak and are infrequently
used alone in HF. However, thiazides or the thiazide-like diuretic metolazone can be used
in combination with a loop diuretic to promote very effective diuresis.
4-Thiazides may be preferred over loop diuretics in patients with only mild fluid retention
and elevated BP because of their more persistent antihypertensive effects.
5-Loop diuretics (furosemide, bumetanide, and torsemide) are usually necessary to restore
and maintain euvolemia in HF.
6-Unlike thiazides, loop diuretics maintain their effectiveness in the presence of
impaired renal function, although higher doses may be necessary.
7-Adverse effects of diuretics include hypovolemia, hypotension, hyponatremia,
hypokalemia, hypomagnesemia, hyperuricemia, and renal dysfunction.
B-Angiotensin-Converting Enzyme Inhibitors
1-ACE inhibitors improve symptoms, slow disease progression, and decrease mortality in
patients with HFrEF.
2-Prior guidelines recommended that all patients with HFrEF, regardless of whether or not
symptoms are present, should receive an ACE inhibitor to reduce morbidity and mortality,
unless there are contraindications. However, recent evidence suggests that
sacubitril/valsartan is preferred over ACE inhibitors (or ARBs) for HFrEF unless
other circumstances (eg, affordability) are present in individual patients .
3-Although symptoms may improve within a few days of starting therapy, it may take
weeks to months before the full benefits are apparent.

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4-The most common adverse effects include hypotension, renal dysfunction, and
hyperkalemia. A dry, nonproductive cough (occurring in 15%–20% of patients) is the most
common reason for discontinuation.
5-Because cough is a bradykinin-mediated effect, replacement with sacubitril/valsartan or
an ARB is reasonable; however, caution is required because crossreactivity has been
reported.
6-Angioedema occurs in approximately 1% of patients and is potentially life threatening;
ACE inhibitors are contraindicated in patients with a history of angioedema.
7-ACE inhibitors are contraindicated in pregnancy due to various congenital defects.
C-Angiotensin Receptor Blockers
1-Because they do not affect the ACE enzyme, ARBs do not affect bradykinin, which is
linked to ACE inhibitor cough and angioedema.

2-Although ARBs are a guideline recommended alternative in patients who are unable to
tolerate an ACE inhibitor due to cough or angioedema, sacubitril/valsartan is preferred
for ACE inhibitor associated cough.
3-Although numerous ARBs are available, only candesartan, valsartan, and losartan are
recommended in the guidelines because efficacy has been demonstrated in clinical trials.
4-ARBs are not suitable alternatives in patients with hypotension, hyperkalemia, or
renal insufficiency due to ACE inhibitors because they are just as likely to cause these
adverse effects.
5-Caution should be exercised when ARBs are used in patients with angioedema from
ACE inhibitors because crossreactivity has been reported. Similar to ACE inhibitors,
ARBs are contraindicated in pregnancy.
D-Angiotensin Receptor–Neprilysin Inhibitor (ARNI)
1-Valsartan/Sacubitril is an ARNI approved for HF. In patients with HFrEF (Further
reading 1), the use of ARNi is recommended to reduce morbidity and mortality (2).
2-Neprilysin is an enzyme that degrades bradykinin and other endogenous vasodilator
and natriuretic peptides. By reducing neprilysin-mediated breakdown of these
compounds, vasodilation, diuresis, and natriuresis are enhanced, and renin and aldosterone
secretion is inhibited.
3-In patients with HFrEF, ARNI is preferred over either ACE inhibitors or ARBs to
improve survival. Patients receiving ACE inhibitors or ARBs can be switched to ARNI or
ARNI can be used as initial treatment in patients with newly detected HFrEF.
4-Discontinue ACE inhibitors 36 hours prior to initiating the ARNI; no waiting period
is needed in patients receiving an ARB.
5-Closely monitor BP, serum potassium, and renal function after the start of therapy and
after each titration step.

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6-The most common adverse effects include hypotension, dizziness, hyperkalemia,
worsening renal function, and cough. Angioedema is most common with
sacubitril/valsartan than with enalapril.
7-Sacubitril/valsartan is contraindicated in patients with a history of angioedema
associated with an ACE inhibitor or ARB. It is also contraindicated in pregnancy and
should not be used concurrently with ACE inhibitors or other ARBs.
E-β-Blockers
1-β-Blockers antagonize the effects of the sympathetic nervous systems in HF and slow
disease progression. β-blockers reduce HF mortality, and hospitalizations.
2-The ACC/AHA guidelines recommend use of β-blockers in all stable patients with
HFrEF in the absence of contraindications or a clear history of β-blocker intolerance.
3-Patients should receive a β-blocker even if symptoms are mild or well controlled with
other GDMT.
4-Carvedilol, metoprolol succinate (CR/XL), and bisoprolol are the only β-blockers
shown to reduce mortality in large HF trials.
5-Initiate β-blockers in stable patients who have no or minimal evidence of fluid
overload. Because of their negative inotropic effects, start β-blockers in very low doses
with slow upward dose titration to avoid symptomatic worsening.
6-Inform patients that HF symptoms may actually worsen during the initiation period.
7-Adverse effects include bradycardia or heart block, hypotension, fatigue, impaired
glycemic control in diabetic patients, bronchospasm in patients with asthma, and worsening
HF.
F-Aldosterone Antagonists
1-Spironolactone and eplerenone block mineralocorticoid receptors, the target for
aldosterone.
2-Current guidelines recommend adding a low-dose aldosterone antagonist to standard
therapy (Further reading 2) provided that serum potassium and renal function can be
carefully monitored.
3-Start with low doses. Avoid aldosterone antagonists in patients with renal impairment,
elevated serum potassium, or history of severe hyperkalemia.
4-Spironolactone also interacts with androgen and progesterone receptors, which may lead
to gynecomastia, impotence, and menstrual irregularities in some patients.
G-Sodium Glucose Cotransporter Type 2 (SGLT2) Inhibitors
1-SLGT2 inhibitors inhibit glucose and sodium reabsorption in the proximal kidney
tubules, which leads to osmotic diuresis and natriuresis, and reduction in arterial
pressure

15
2-In patients with symptomatic chronic HFrEF, SGLT2i (Dapagliflozin or
empagliflozin) are recommended to reduce morbidity and mortality, irrespective of the
presence of type 2 diabetes (with or without diabetes) (2).
3-Patients should be advised to avoid abrupt changes in position as orthostasis may occur
in the setting of overdiuresis.
H-Nitrates and Hydralazine
1-Isosorbide dinitrate (ISDN) is a venodilator that reduces preload, whereas hydralazine
is a direct arterial vasodilator that reduces systemic vascular resistance (SVR) and
increases stroke volume and CO.
2-Guidelines recommend addition of hydralazine/ISDN to black patients with HFrEF
(Further reading 3) who are receiving optimal medical therapy (2).
3-The combination can also be useful in patients unable to tolerate either an ACE inhibitor
or ARB because of renal insufficiency, hyperkalemia, or hypotension.
I-Ivabradine
1-Ivabradine inhibits the If current in the sinoatrial node that is responsible for controlling
HR, thereby slowing the HR. It does not affect AV conduction, BP, or myocardial
contractility.
2-Because of the clear benefits of β-blockers on mortality, clinicians should titrate to the
maximum tolerated doses before considering use of Ivabradine (Patients are either on a
maximally tolerated dose of a β-blocker or have a contraindication to β-blocker use).
J-Digoxin
1-Studies of digoxin in HF showed either neutral effects or reductions in
hospitalizations and either neutral or detrimental effects of digoxin on mortality.
2-So digoxin is not considered a first-line agent in HF. In patients with symptomatic
HFrEF despite GDMT (or who are unable to tolerate GDMT), digoxin might be
considered to improve symptoms and reduce hospitalizations (2).
3-Digoxin may also be considered to help control ventricular rate in patients with HFrEF
and supraventricular arrhythmias.
K-Vericiguat
1-Vericiguat modulates endothelial dysfunction; it is a soluble guanylate cyclase activator
(sGC) that enhances the effect of nitric oxide (NO) and regulate contractility and diastolic
function.
2-In a clinical trial, patients with HFrEF receiving vericiguat demonstrated a significant,
but modest, reduction in cardiovascular death or HF hospitalization.
3-The drug was well tolerated overall, but there was an unexplained greater incidence of
anemia in patients treated with vericiguat.
4-Vericiguat may be considered in addition to optimized HF therapy to reduce
morbidity and mortality in patients at high risk with worsening HFrEF (2).

16
5-It is not indicated in HFpEF due to lack of benefit and safety data.
Pharmacologic Therapy for HFpEF
1-SGLT2i should be initiated in all individuals with HFpEF lacking contraindications (3).
2-Diuretics should be used for symptom relief in volume overload (4).
3-The addition of aldosterone antagonists, ARNIs or ARBs may be considered (further
reading 4) (3).
Reference
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. 2023.
2-Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA
guideline for the management of Heart Failure: A Report of the American College of Cardiology/American
Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Apr 1;145(18).
3-Kittleson MM, Gurusher Panjrath, Kaushik Amancherla, Davis LL, Deswal A, Dixon DL, et al. 2023
ACC Expert Consensus Decision Pathway on Management of Heart Failure with Preserved Ejection
Fraction. Journal of the American College of Cardiology. 2023 Apr 1;81(18).
4-ACCP 2023.

Further reading
1-And NYHA class II to III symptoms (2).
2- in (NYHA class II–IV (2)) patients.
3- (NYHA class III or IV) (2).
4-Treatment Algorithm for Guideline-Directed Medical Therapy in HFpEF (3).

17
 College of Pharmacy
Fourth year. Clinical Pharmacy
Treatment of acute decompensated heart failure (ADHF)
General Approach
1-Acute decompensated heart failure involves patients with new or worsening signs or
symptoms [often resulting from volume overload and/or low cardiac output (CO)]
requiring medical intervention, such as emergency department visit or hospitalization.
2-Admission to an intensive care unit (ICU) may be required for some cases.
3-Signs and symptoms of volume overload include dyspnea, orthopnea, PND, ascites, GI
symptoms (poor appetite, nausea, early satiety), peripheral edema, and weight gain.
4-Low output signs and symptoms include altered mental status tachycardia, hypotension
(more commonly) or hypertension, cool extremities, pallor and decreased urine output.
5-If fluid retention is evident on physical exam, start aggressive diuresis, preferably with
IV diuretics.
6-In the absence of cardiogenic shock or symptomatic hypotension, strive to continue all
GDMT for HF. β-blockers may be temporarily held or dose reduced if recent changes
are responsible for acute decompensation.
7-Other GDMT (ACE inhibitors, ARBs, ARNI, and aldosterone antagonists) may also
need to be temporarily withheld in the presence of renal dysfunction, with close
monitoring of serum potassium.
8-Place all patients with congestive symptoms on sodium restriction (<2 g daily) and
consider fluid restriction for refractory symptoms.
9-Consider noninvasive ventilation for patients in respiratory distress due to acute
pulmonary edema.
10-Provide pharmacologic thromboprophylaxis with unfractionated heparin or low-
molecular-weight heparin for most patients with limited mobility; consider mechanical
thromboprophylaxis with intermittent pneumatic compression devices in patients at high
risk for bleeding.
11-Temporary mechanical circulatory support may be considered for hemodynamic
stabilization until the underlying etiology has been corrected or until definitive therapy
(e.g., cardiac transplantation).
12-Cardiac transplantation is the best option for patients with irreversible advanced HF.
New surgical strategies such myocardial cell transplantation offer additional options for
patients ineligible for device implantation or heart transplantation.
Pharmacologic Therapy for ADHF
A-Loop Diuretics
1-Current guidelines recommend IV loop diuretics (furosemide, bumetanide) as first-line
therapy for ADHF patients with volume overload.
18
2-Bolus administration reduces preload by functional venodilation within 5–15 minutes
and later (>20 minutes) via sodium and water excretion, thereby improving pulmonary
congestion.
3-Diuretic resistance may be improved by administering larger IV bolus doses,
transitioning from IV bolus to continuous IV infusions, or adding a second diuretic with a
different mechanism of action, such as a distal tubule blocker (eg, oral metolazone, oral
hydrochlorothiazide, or IV chlorothiazide).
B-Vasopressin Antagonists
1-Vasopressin receptor antagonists affect one or two AVP (antidiuretic hormone)
receptors, V1A or V2. Stimulation of V1A receptors (located in vascular smooth muscle
cells and myocardium) results in vasoconstriction, and positive inotropic effects. V2
receptors are located in renal tubules, where they regulate water reabsorption.
 Tolvaptan selectively binds to and inhibits the V2 receptor. It is an oral agent
indicated for hypervolemic and euvolemic hyponatremia in patients with HF.

 Conivaptan nonselectively inhibits both the V1A and V2 receptors. It is an IV agent

indicated for hypervolemic and euvolemic hyponatremia due to a variety of causes but
is not indicated for patients with HF.
2-Monitor patients closely to avoid an excessively rapid rise in serum sodium requiring
drug discontinuation.
C-Vasodilators
1-Venodilators reduce preload by increasing venous capacitance, and improve symptoms
of pulmonary congestion. Arterial vasodilators decrease afterload and causing
increased CO. Mixed vasodilators act on both arterial resistance and venous capacitance
vessels, reducing congestive symptoms while increasing CO.
2-IV vasodilators should be considered before positive inotropic therapy in patients with
low CO and elevated systemic vascular resistance (SVR). However, hypotension may
preclude their use in patients with preexisting low BP or SVR.
3-IV nitroglycerin is often preferred for preload reduction in ADHF. Nitroglycerin
displays potent coronary vasodilating properties making it the vasodilator of choice for
patients with severe HF and ischemic heart disease.
4-Sodium nitroprusside is a mixed arteriovenous vasodilator. Hypotension is an
important dose-limiting adverse effect of nitroprusside, and its use should be primarily
reserved for patients with elevated SVR.
D-Inotropes (Dobutamine, Milrinone, Norepinephrine and dopamine)
1-Prompt correction of low CO in patients with hypoperfusion is required to restore
peripheral tissue perfusion and preserve end-organ function.
2-Inotropes should be considered only as a temporizing measure to maintain end-
organ perfusion in patients with cardiogenic shock or severely depressed CO and low
systolic BP (ie, ineligible for IV vasodilators).
19
 Evaluation of therapeutic outcomes
Chronic Heart Failure
1-Ask patients about the presence and severity of symptoms and how symptoms affect
daily activities.
2-Evaluate efficacy of diuretic treatment by disappearance of the signs and symptoms of
excess fluid retention.
3-Body weight is a sensitive marker of fluid loss or retention, and patients should weigh
themselves daily and report changes of (1.4–2.3 kg) to their healthcare provider so
adjustments can be made in diuretic doses.
4-Symptoms may worsen initially on β-blocker therapy, and it may take weeks to
months before patients notice symptomatic improvement.
5-Routine monitoring of serum electrolytes (especially potassium and magnesium) and
renal function (BUN, serum creatinine, eGFR) is mandatory in patients with HF.
Acute Decompensated Heart Failure
1-Assess the efficacy of drug therapy with daily monitoring of weight, strict fluid intake
and output measurements, and HF signs/symptoms.
2-Monitor frequently for electrolyte depletion, symptomatic hypotension, and renal
dysfunction. Assess vital signs frequently throughout the day.
Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th
Edition. 2023.

20
 College of Pharmacy
Fourth year. Clinical Pharmacy
Cardiovascular disorders
Ischemic Heart Disease
Introduction
1-Ischemic heart disease (IHD) is defined as lack of oxygen and decreased or no blood
flow to the myocardium resulting from coronary artery narrowing or obstruction.
2-It may present as acute coronary syndrome (ACS) [which includes unstable angina and
non–ST-segment elevation (NSTE) or ST-segment elevation (STE) myocardial infarction
(MI)], chronic stable exertional angina, ischemia without symptoms, microvascular
angina, or ischemia due to coronary artery vasospasm (variant or Prinzmetal angina).
Pathophysiology
1-Angina pectoris usually results from increased myocardial oxygen demand in the
setting of a fixed decrease in myocardial oxygen supply because of atherosclerotic
plaque.
2-Coronary plaques that occupy less than 50%–70% of the vessel luminal diameter rarely
produce ischemia or angina. However, smaller plaques have a lipid-rich core and thin
fibrous cap and are more prone to rupture and cause acute thrombosis.
3-When the luminal diameter of epicardial vessels is reduced by 70% or more, minimal
physical exertion may result in a flow deficit with myocardial ischemia and often angina.
4-Patients with variant (Prinzmetal) angina usually do not have a coronary flow-
obstructing plaque but instead have significant reduction in myocardial oxygen supply due
to vasospasm in epicardial vessels.
Clinical presentation
1-Patients typically complain of chest pain precipitated by exertion or activities of daily
living that is described as squeezing, crushing, heaviness, or chest tightness. It can also be
more vague and described as a numbness or burning in the chest.
2-The location is often substernal and may radiate to the right or left shoulder or arm
(left more commonly), neck, back, or abdomen. Ischemic symptoms may be associated
with diaphoresis, nausea, vomiting, and dyspnea.
3-Chest pain generally lasts from 5 to 20 minutes and is usually relieved by rest or
sublingual nitroglycerin (SL NTG).
4-Some patients (especially women and older individuals) present with atypical chest
pain. Patients with diabetes mellitus may have decreased pain sensation due to
neuropathy.
5-Patients with variant (Prinzmetal) angina are typically younger and may present with
chest pain at rest, often early in the morning.

21
Diagnosis
1-Obtain the medical history to identify the quality and severity of chest pain, precipitating
factors, location, duration, pain radiation, and response to nitroglycerin or rest.
2-Assess nonmodifiable risk factors for coronary artery disease (CAD): age, sex, and
family history of premature atherosclerotic disease in first degree relatives (male onset
before age 55 or female before age 65).
3-Identify the presence of modifiable CAD risk factors: hypertension, diabetes mellitus,
dyslipidemia, and cigarette smoking.
4-Cardiac troponin concentrations are not typically elevated in stable IHD.
5-Resting ECG is normal in at least half of patients with angina who are not
experiencing acute ischemia. About 50% of patients develop ischemic ECG changes
during an episode of angina, which can be observed on the ECG during an exercise stress
test.
6-Coronary angiography is the most accurate test for confirming CAD but is invasive and
requires arterial access. Myocardial perfusion imaging, cardiac magnetic resonance, and
CT angiography can also be used to detect CAD.
Treatment
Goals of Treatment:
1-A primary goal of therapy is complete (or nearly complete) elimination of anginal chest
pain and return to normal activities.
2-Long-term goals are to slow progression of atherosclerosis and prevent complications
such as MI, heart failure, stroke, and death.
Nonpharmacologic Therapy
1-Lifestyle modifications include daily physical activity, weight management, dietary
therapy (reduced intake of saturated fats, and cholesterol), smoking cessation, psychological
interventions (eg, screening and treatment for depression if appropriate), limitation of
alcohol intake, and avoiding exposure to air pollution.
2-Surgical revascularization options for select patients include coronary artery bypass
grafting (CABG) or percutaneous coronary intervention (PCI) with or without stent
placement.
Pharmacologic Therapy
1-Guideline-directed medical therapy (GDMT) reduces the rates of death and MI
similar to revascularization therapy.
2-Approaches to risk factor modification include the following recommendations:
 Dyslipidemia: Use moderate- or high-dose statin therapy in addition to lifestyle
changes. Addition of ezetimibe (first) or a PCSK9 inhibitor (second) is reasonable
for patients who do not tolerate statins or do not attain a 50% decrease in LDL
cholesterol (or LDL remains above 70–100 mg/dL).
 Blood pressure: If BP is ≥130/80 mm Hg, institute drug therapy in addition to or
after a trial of lifestyle modifications.
22
  Diabetes mellitus: Pharmacotherapy to achieve a target A1C of ≤7% is reasonable
for select patients (eg, short duration of diabetes and long life expectancy). An A1C
goal of <8% is reasonable for other patients, such as those with micro- or
macrovascular complications or coexisting medical conditions.
 Annual influenza vaccinations are recommended.
Antithrombotic Therapy
1-Aspirin reduced platelet activation and aggregation. A small percentage of patients are
nonresponsive to aspirin's antiplatelet effects.
2-The ACC/AHA guidelines contain the following recommendations for stable IHD:
 Aspirin: 75–162 mg daily should be continued indefinitely in the absence of
contraindications.
 Clopidogrel: 75 mg daily is a suitable alternative for patients unable to take aspirin
due to allergy or intolerance.
3-Patient responsiveness to clopidogrel is highly variable, with estimates of
nonresponsiveness ranging from 5% to 44% of patients. The most common cause of
nonresponsiveness is nonadherence, but genetic polymorphisms to CYP2C19 may
contribute in some patients.
4-Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor (clopidogrel,
prasugrel, ticagrelor) is beneficial after PCI with coronary stent placement and after
treatment for ACS. The combination of aspirin (75–162 mg daily) and clopidogrel 75 mg
daily may be reasonable in certain high-risk patients.

5-Rivaroxaban (low-dose), a direct factor Xa inhibitor, has demonstrated benefit

(reduction of major adverse cardiovascular events) in patients with CAD when added
to aspirin therapy (further reading A) (2).
Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin
Receptor Blockers (ARBs)
1-ACE inhibitors have not been shown to improve symptomatic ischemia or reduce
chest pain episodes.
2-The ACC/AHA guidelines for stable IHD recommend the following strategies:
 Use ACE inhibitors in patients who also have hypertension, diabetes, heart failure
with reduced ejection fraction (HFrEF), or chronic kidney disease, unless
contraindicated.
 ARBs are recommended for the same populations if patients are intolerant to ACE
inhibitors.
β-Adrenergic Blockers
1-β-Blockers competitively inhibit the effects catecholamines on β-adrenoceptors. Blockade
of β1-receptors in the heart reduces HR, contractility, and BP, thereby decreasing oxygen
demand.
2-β-Blockers are recommended over calcium channel blockers (CCBs) for initial control
of angina episodes in patients with stable IHD.
23
3-The target is to lower the resting HR to 50–60 beats/min and the exercise HR to <100
beats/min. For patients (eg, elderly) who cannot tolerate these ranges, the target HR should
be as low as can be tolerated above 50 beats/min.
4-β-Blockers may be combined with CCBs or long-acting nitrates when initial treatment
with β-blockers alone is unsuccessful.
5-Only the β-blockers carvedilol, metoprolol succinate, and bisoprolol should be used in
patients with HFrEF.
6-β1-Selective agents are preferred in patients with chronic obstructive pulmonary disease,
peripheral arterial disease (PAD), diabetes, dyslipidemia, and sexual dysfunction.
7-Drugs with combined α1- and β-blockade are effective for IHD, but agents with intrinsic
sympathomimetic activity provide little to no reduction in resting HR and are not
preferred except perhaps in patients with PAD or dyslipidemia.
8-If β-blocker therapy must be discontinued, doses should be tapered over 2–3 weeks
to prevent abrupt withdrawal, which can significantly increase oxygen demand and induce
ischemia and even MI because of up-regulation of β-receptors in the myocardium.

Calcium Channel Blockers

1-All CCBs reduce oxygen demand by reducing wall tension via lowering arterial BP and
(to a minor extent) depressing contractility. CCBs also provide some increase in supply by
inducing coronary vasodilation and preventing vasospasm.
2-CCBs or long-acting nitrates should be prescribed for relief of symptoms when β-
blockers are contraindicated or cause unacceptable side effects.
3-Dihydropyridine CCBs (eg, nifedipine, amlodipine, isradipine, and felodipine) primarily
affect vascular smooth muscle with little effect on the myocardium.
4-Short-acting agents should not be used because of their greater propensity to cause
reflex tachycardia. Other side effects of these CCBs include hypotension, headache,
gingival hyperplasia, and peripheral edema.
5-Although most CCBs are contraindicated in patients with HFrEF, amlodipine and
felodipine are considered safe options in these patients.
6-Nondihydropyridine CCBs (verapamil and diltiazem) mostly affect the myocardium
with minimal effects on vascular smooth muscle. These agents should be avoided in
patients with concomitant HFrEF due to negative inotropic effects.
7-Verapamil may cause constipation in ∼8% of patients.
Colchicine (Further reading B)
Nitrates
1-Nitrates cause vasodilation. Most vasodilation occurs on the venous side, leading to
reduced preload, myocardial wall tension, and oxygen demand.

24
2-All patients should have access to sublingual (SL) NTG tablets or spray to treat acute
angina episodes. Relief typically occurs within 5 minutes of administration.
3-SL nitrates can also be used to prevent acute episodes if given 2–5 minutes before
activities known to produce angina; protection can last for up to 30 minutes with SL NTG
and up to 1 hour with SL isosorbide dinitrate (ISDN).
4-Long-acting nitrates (or CCBs) should be prescribed for relief of symptoms when β-
blockers are contraindicated or cause unacceptable side effects.
5-Transdermal patches and isosorbide mononitrate (ISMN) are most commonly
prescribed for long-term prevention of angina episodes. ISDN is also effective, but the
three times daily regimen requires dosing every 4–5 hours during the day to provide a
nitrate-free interval.
6-Chronic nitrate use should incorporate a 10- to 14-hour nitrate-free interval each
day to reduce nitrate tolerance. Because this approach places the patient at risk for angina
episodes, the nitrate-free interval is usually provided during the nighttime hours when
the patient has a reduced oxygen demand while sleeping.
7-The extended-release ISMN products that are dosed twice daily should be given 7
hours apart (eg, 7:00 AM and 2:00 PM). An extended-release, once daily ISMN product is
available that provides 12 hours of nitrate exposure followed by a 12-hour nitrate-free
interval.
8-Transdermal NTG patches are typically prescribed as “on in the AM and off in the PM”
but patients should be given specific application and removal times (eg, apply at 8:00 AM
and remove at 8:00 PM).
9-Nitrates should not be used routinely as monotherapy for stable IHD because of the
lack of angina coverage during the nitrate-free interval, and potential for reflex
tachycardia.
10-Concomitant β-blocker or diltiazem therapy can prevent rebound ischemia during the
nitrate-free interval.
11-Common nitrate side effects include headache, flushing, nausea, postural hypotension,
and syncope. Headache can be treated with acetaminophen and usually resolves after
about 2 weeks of continued therapy.
12-Transdermal NTG may cause skin erythema and inflammation. Initiating therapy
with smaller doses and/or rotating the application site can minimize transdermal
nitroglycerin side effects.
Ranolazine
1-Ranolazine reduces ischemic episodes by selective inhibition of late sodium current
(INa), which reduces intracellular sodium concentration and improves myocardial function
and perfusion.
2-It does not impact HR, BP, the inotropic state, or increase coronary blood flow.
Ranolazine is effective as monotherapy for relief of angina symptoms but should only be
used if patients cannot tolerate traditional agents.
25
3-Because it does not substantially affect HR and BP, it is recommended as add-on therapy
to traditional antianginal agents for patients who achieve goal HR and BP and still have
exertional angina symptoms, patients who cannot achieve these hemodynamic goals
due to adverse effects, and patients who reach maximum doses of traditional agents
but still have angina symptoms.
Treatment of Variable Threshold Angina and Prinzmetal Angina
1-Patients with variable threshold angina require pharmacotherapy for vasospasm.
Most patients respond well to SL NTG for acute attacks.
2-Both CCBs (Nifedipine, verapamil, and diltiazem) and nitrates are effective for
chronic therapy. CCBs may be preferred because they are dosed less frequently.
3-Patients unresponsive to CCBs alone may have nitrates added. β-Blockers are not
useful for vasospasm because they may induce coronary vasoconstriction and prolong
ischemia.
Evaluation of therapeutic outcomes
1-Assess for symptom improvement by number of angina episodes, weekly SL NTG use,
and increased exercise capacity or duration of exertion needed to induce angina.
2-Once patients have been optimized on medical therapy, symptoms should improve
over 2–4 weeks and remain stable until the disease progresses. Patients may require
evaluation every 1–2 months until target endpoints are achieved; follow-up every 6–12
months thereafter is appropriate.
3-Monitor for adverse drug effects such as headache and dizziness with nitrates; fatigue
and lassitude with β-blockers; and peripheral edema, constipation, and dizziness with
CCBs.
Reference
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. 2023.
2-Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, et al. 2023
AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic
coronary disease: A report of the American Heart Association/American College of Cardiology Joint
Committee on clinical practice guidelines. Circulation. 2023 Jul 20;148(9).

Further reading
A-Addition of low-dose rivaroxaban 2.5 mg twice daily to aspirin 81 mg daily (2).
B-Colchicine:
1-Inflammation is a key component in the development of atherosclerosis. As a result,
using select anti-inflammatory agents may have a role in improving cardiovascular
outcomes (2).
2-Colchicine exhibits anti-inflammatory properties (2).
3-In patients with chronic coronary disease (CCD), the addition of low dose colchicine
(0.5 mg daily) for secondary prevention may be considered to reduce recurrent
atherosclerotic cardiovascular disease (ASCVD) events (myocardial infarction (MI),
stroke, coronary revascularization, and cardiovascular death) (2).

26
 College of Pharmacy
Fourth year. Clinical Pharmacy
Infectious Diseases
Urinary Tract Infections
Introduction
1-Infections of the urinary tract represent a wide variety of clinical syndromes including
urethritis, cystitis, prostatitis, and pyelonephritis.
2-A urinary tract infection (UTI) is defined as the presence of microorganisms in the
urine that cannot be accounted for by contamination.
3-Lower tract infections include cystitis (bladder), urethritis (urethra), prostatitis
(prostate gland), and epididymitis.
4-Upper tract infections involve the kidney and are referred to as pyelonephritis.
5-Uncomplicated UTIs are not associated with structural or functional abnormalities
that may interfere with the normal flow of urine or the voiding mechanism.
6-Complicated UTIs are the result of a predisposing lesion of the urinary tract, such as
an abnormality of the urinary tract, stone, indwelling catheter, prostatic hypertrophy,
obstruction, or neurologic deficit that interferes with the normal flow of urine and urinary
tract defenses.
7-Recurrent UTIs, two or more UTIs occurring within 6 months or three or more
within 1 year, are characterized by multiple symptomatic episodes with asymptomatic
periods occurring between these episodes.
8-These infections are due to reinfection or to relapse. Reinfections are caused by a
different organism and account for the majority of recurrent UTIs. Relapse represents the
development of repeated infections caused by the same initial organism.
Pathophysiology
1-The bacteria causing UTIs usually originate from bowel flora of the host. Organisms
typically gain entry into the urinary tract via three routes: the ascending, hematogenous
(descending), and lymphatic pathways.
2-The most common cause of uncomplicated UTIs is E. coli, accounting for more than
80%–90% of community-acquired infections.
3-Additional causative organisms are Staphylococcus saprophyticus, Klebsiella
pneumoniae, Proteus spp., Pseudomonas aeruginosa, and Enterococcus spp.
4-The urinary pathogens in complicated or nosocomial infections may include E. coli,
which accounts for less than 50% of these infections, Proteus spp., K. pneumoniae,
Enterobacter spp., P. aeruginosa, staphylococci, and enterococci. Enterococci represent
the second most frequently isolated organisms in hospitalized patients.
5-Most UTIs are caused by a single organism; however, in patients with stones,
indwelling urinary catheters, or chronic renal abscesses, multiple organisms may be
isolated.
27
Clinical presentation
1-The typical signs and symptoms of urinary tract infections are:
 Lower UTI: Dysuria, urgency, frequency, nocturia, and suprapubic heaviness, and
gross hematuria.
 Upper UTI: Flank pain, fever, nausea, vomiting, malaise and costovertebral
tenderness.
NOTE: The handbook put the costovertebral tenderness with the lower UTI while the text
put it with the Upper UTI (which is more accurate) .
2-Symptoms alone are unreliable for the diagnosis of bacterial UTIs. The key to the
diagnosis of a UTI is the ability to demonstrate significant numbers of microorganisms
present in urine specimen.
3-Older patients frequently do not experience specific urinary symptoms, but they will
present with altered mental status, change in eating habits, or gastrointestinal (GI)
symptoms.
4-The most reliable method of diagnosing UTIs is by quantitative urine culture.
Treatment
Goals of Treatment:
1-Eradicate the invading organisms, prevent or treat systemic consequences of infection,
prevent recurrence of infection, and decrease the potential for collateral damage with
excessively broad antimicrobial therapy.
2-The initial selection of an antimicrobial agent for the treatment of UTI is primarily based
on the severity of the presenting signs and symptoms, the site of infection, and whether
the infection is determined to be complicated or uncomplicated.
3-Other considerations include antibiotic susceptibility, side-effect potential, cost, current
antimicrobial exposure, and the comparative inconvenience of different therapies.
Pharmacologic Therapy
1-Eradication of bacteria from the urinary tract is directly related to the sensitivity of the
organism and the achievable concentration of the antimicrobial agent in the urine.
2-Most E. coli remain susceptible to trimethoprim–sulfamethoxazole, although resistance is
increasing. In light of rising resistance and in order to decrease the overuse of broad-
spectrum antimicrobials, agents such as nitrofurantoin and fosfomycin are considered
first-line treatments along with trimethoprim–sulfamethoxazole in acute
uncomplicated cystitis.
3-Table 1 presents an overview of various therapeutic options for outpatient therapy for
UTI. Table 2 describes empiric treatment regimens for specific clinical situations .

28
Table 1: Overview of Outpatient Antimicrobial Therapy for Lower Tract Infections in
Adults

a Dosing intervals for normal renal function. DS, double strength; SS, single strength.

Table 2: Evidence-Based Empirical Treatment of UTIs and Prostatitis

29
Acute Uncomplicated Cystitis
1-These infections are predominantly caused by E. coli, and antimicrobial therapy should
be directed against this organism initially.
2-Short-course therapy (3-day therapy) with trimethoprim–sulfamethoxazole or a
fluoroquinolone (eg, ciprofloxacin or levofloxacin, but not moxifloxacin) is superior to
single-dose therapy for uncomplicated infection.
3-Fluoroquinolones should be reserved for patients with suspected or possible
pyelonephritis due to the collateral damage risk. Instead, a 3-day course of
trimethoprim–sulfamethoxazole, a 5-day course of nitrofurantoin, or a one-time dose of
fosfomycin should be considered as first-line therapy.
4-In areas where there is more than 20% resistance of E. coli to trimethoprim–
sulfamethoxazole, nitrofurantoin or fosfomycin should be utilized.

Complicated Urinary Tract Infections

Acute Pyelonephritis
1-The presentation of high-grade fever (>38.3°C) and severe flank pain should be treated
as acute pyelonephritis, and aggressive management is warranted.

30
2-Severely ill patients with pyelonephritis should be hospitalized and IV drugs
administered initially. Milder cases may be managed with oral antibiotics in an
outpatient setting.
3-At the time of presentation, a Gram stain of the urine should be performed, along with
urinalysis, culture, and sensitivities.
4-In the mild to moderately symptomatic patient for whom oral therapy is considered,
an effective agent should be administered for 7–14 days, depending on the agent used.
5-Fluoroquinolones (ciprofloxacin or levofloxacin) orally for 7–10 days are the first-line
choice in mild-tomoderate pyelonephritis. Other options include trimethoprim–
sulfamethoxazole for 14 days.
6-If a Gram stain reveals gram-positive cocci, Streptococcus faecalis should be
considered and treatment directed against this pathogen (ampicillin).
7-In the seriously ill patient, the traditional initial therapy is an IV fluoroquinolone, an
aminoglycoside with or without ampicillin, or an extended spectrum cephalosporin with or
without an aminoglycoside.
8-If the patient has been hospitalized in the last 6 months, has a urinary catheter, or is
in a nursing home, the possibility of P. aeruginosa and enterococci infection, as well as
multiple-resistant organisms, should be considered. In this setting, ceftazidime,
ticarcillin–clavulanic acid, piperacillin, aztreonam, meropenem, or imipenem, in
combination with an aminoglycoside, is recommended.
9-Follow-up urine cultures should be obtained 2 weeks after the completion of therapy
to ensure a satisfactory response and to detect possible relapse.

Urinary Tract Infections in Men

1-Therapy in men requires prolonged treatment. A urine culture should be obtained
before treatment, because the cause of infection in men is not as predictable as in women.
2-If gram-negative bacteria are presumed, trimethoprim–sulfamethoxazole or a
fluoroquinolone is a preferred agent. Initial therapy is for 10–14 days.
3-For recurrent infections in men, cure rates are much higher with a 6-week regimen of
trimethoprim–sulfamethoxazole.

Recurrent Infections
1-Recurrent episodes of UTI (reinfections and relapses) account for a significant portion
of all UTIs.
2-These patients are most commonly women and can be divided into two groups: those
with fewer than two or three episodes per year and those who develop more frequent
infections.
3-In patients with infrequent infections (ie, fewer than three infections per year), each
episode should be treated as a separately occurring infection. Short-course therapy
should be used in symptomatic female patients with lower tract infection.
31
4-In patients who have frequent symptomatic infections, long-term prophylactic
antimicrobial therapy may be instituted. Therapy is generally given for 6 months, with
urine cultures followed monthly.
5-In females who experience symptomatic reinfections in association with sexual
activity, voiding after intercourse may help prevent infection. Also, self-administered,
single-dose prophylactic therapy with trimethoprim–sulfamethoxazole taken after
intercourse significantly reduces the incidence of recurrent infection in these patients.
6-Females who relapse after short-course therapy should receive a 2-week course of
therapy.
7-In patients who relapse after 2 weeks, therapy should be continued for another 2–4
weeks.
8-If relapse occurs after 6 weeks of treatment, urologic examination should be
performed, and therapy for 6 months or even longer may be considered.

Special conditions
Urinary Tract Infection in Pregnancy
1-In females with significant bacteriuria, symptomatic or asymptomatic treatment is
recommended to avoid possible complications during the pregnancy.
2-Therapy should consist of an agent with a relatively low adverse-effect potential
(cephalexin, amoxicillin, or amoxicillin/clavulanate) administered for 7 days.
3-Tetracyclines should be avoided because of teratogenic effects and sulfonamides should
not be administered during the third trimester because of the possible development of
kernicterus and hyperbilirubinemia. Also, the fluoroquinolones should not be given
because of their potential to inhibit cartilage and bone development in the newborn.
Catheterized Patients
1-When bacteriuria occurs in asymptomatic, short-term catheterized patients (<30 days),
the use of systemic antibiotic therapy should be withheld and the catheter removed as
soon as possible. If the patient becomes symptomatic, the catheter should again be
removed, and treatment as described for complicated infections should be started.
2-The use of prophylactic systemic antibiotics in patients with short-term catheterization
reduces the incidence of infection over the first 4–7 days.
3-In long-term catheterized patients, however, antibiotics only postpone the development
of bacteriuria and lead to emergence of resistant organisms.
Reference:
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th
Edition. 2023.

32
 College of Pharmacy
Fourth year. Clinical Pharmacy
Infectious Diseases
Tuberculosis
Introduction
1-Tuberculosis (TB) is a communicable infectious disease caused by Mycobacterium
tuberculosis. It can produce silent, latent infection, as well as progressive, active disease.
2-In 2019, there were about 10 million new cases and 1.2 million deaths from TB reported.

Pathophysiology and etiology

1-M. tuberculosis is transmitted from person to person by coughing or other activities that
cause the organism to be aerosolized. Close contacts of TB patients are most likely to
become infected.
2-Human immunodeficiency virus (HIV) is the most important risk factor for
progressing to active TB. An HIV-infected individual with TB infection is over 100-fold
more likely to develop active disease than an HIV-seronegative patient.
3-Occasionally, a massive inoculum of organisms may be introduced into the
bloodstream, causing widely disseminated disease and granuloma formation known as
miliary TB.
Clinical presentation
1-Patients with TB typically present with cough, weight loss, fatigue, fever, and night
sweats. Symptom onset may be gradual.
2-Frank hemoptysis usually occurs late in the course of disease but may present earlier.
3-Sputum smear is done to detect mycobacteria. Chest radiograph is also important.
4-Clinical features associated with extrapulmonary TB vary depending on the organ
system(s) involved but typically consist of slowly progressive decline of organ function
with low-grade fever and other constitutional symptoms.
5-Patients with HIV may have atypical presentation. HIV-positive patients are less likely
to have positive skin tests, or fever. They have a higher incidence of extrapulmonary
TB and are more likely to present with progressive primary disease.
6-The most widely used screening method for tuberculous infection is the tuberculin
skin test, which uses purified protein derivative (PPD).
7-When active TB is suspected, attempts should be made to isolate M. tuberculosis from
the infected site. Daily sputum collection over 3 consecutive days is recommended.
8-Tests to measure release of interferon-γ in the patient’s blood in response to TB antigens
may provide quick and specific results for identifying M. tuberculosis.
Treatment

33
1-Goals of Treatment: (1) Rapid identification of a new TB case; (2) Initiation of
specific anti-TB treatment; (3) Eradicating M. tuberculosis infection; (4) Achievement of a
noninfectious state in the patient, thus ending isolation; (5) Preventing the development of
resistance; (6) Adherence to the treatment regimen by the patient; and (7) Cure of the
patient as quickly as possible (generally at least 6 months of treatment).
2-Patients with active disease should be isolated to prevent spread of the disease.

3-Drug treatment is the cornerstone of TB management. A minimum of two drugs, and

generally three or four drugs, must be used simultaneously.
4-Directly observed therapy (DOT) by a healthcare worker is a cost-effective way to ensure
completion of treatment and is considered the standard of care.
5-Drug treatment is continued for at least 6 months, and 18–24 months for cases of
multidrug-resistant TB (MDR-TB).
6-Surgery may be needed to remove destroyed lung tissue, space-occupying lesions, and
some extrapulmonary lesions.
Pharmacologic Therapy
Latent Infection
1-Chemoprophylaxis should be initiated in patients to reduce the risk of progression to
active disease.
2-There are three recommended treatment regimens for latent tuberculosis infection
(LTBI): 3 months of once weekly isoniazid plus rifapentine, 4 months of daily
rifampin, or 3 months of daily isoniazid plus rifampin.

3-The Centers for Disease Control and Prevention (CDC) recommends the 12week
isoniazid/rifapentine regimen as an equal alternative to 9 months of daily isoniazid for
treating LTBI in otherwise healthy patients aged 12 years or older who have greater
likelihood of developing active TB.

4-Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid
should receive pyridoxine, 10–50 mg daily, to reduce the incidence of central nervous
system (CNS) effects or peripheral neuropathies.
Treating Active Disease
1-Table 1 lists options for treatment of culture-positive pulmonary TB caused by drug-
susceptible organisms.
2-The standard TB treatment regimen is isoniazid, rifampin, pyrazinamide, and
ethambutol for 2 months, followed by isoniazid and rifampin for 4 months (a total of 6
months of treatment). Ethambutol can be stopped if susceptibility to isoniazid, rifampin,
and pyrazinamide is shown.

34
3-Appropriate samples should be sent for culture and susceptibility testing prior to
initiating therapy for all patients with active TB. The data should guide the initial drug
selection for the new patient.

Table 1: Drug Regimens for Microbiologically Confirmed Pulmonary Tuberculosis

Caused by Drug Susceptible Organisms

DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid;
PZA, pyrazinamide; RIF, rifampin.
aWhen DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted
accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience
indicates this would be an effective practice. DOT should be used when drugs are administered <7
days/week.
bBased on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at
completion of 2 months of therapy should receive a 7month (31week) continuation phase.
cPyridoxine (vitamin B6), 25–50 mg/day, is given with INH to all persons at risk of neuropathy (eg,
pregnant women; breastfeeding infants; persons with HIV; patients with diabetes, alcoholism, malnutrition,
or chronic renal failure; or patients with advanced age). For patients with peripheral neuropathy, experts
recommend increasing pyridoxine dose to 100 mg/day.
dFive‐day‐a‐week administration is always given by DOT.

4-If the patient is being evaluated for the retreatment of TB, it is imperative to know what
drugs were used previously and for how long.
Drug Resistance
1-If the organism is drug resistant, the aim is to introduce two or more active agents that
the patient has not received previously. With MDR-TB, no standard regimen can be
proposed.
35
2-It is critical to avoid monotherapy or adding only a single drug to a failing regimen.
3-Drug resistance should be suspected in the following situations:
 Patients who have received prior therapy for TB
 Patients from geographic areas with a high prevalence of resistance (South Africa,
Mexico, Southeast Asia, the Baltic countries, and the former Soviet states)
 Patients who are homeless, institutionalized, IV drug abusers, and/or infected with
HIV
 Patients who still have acid-fast bacilli–positive sputum smears after 2 months of
therapy
 Patients who still have positive cultures after 2–4 months of therapy
 Patients who fail therapy or relapse after retreatment
 Patients known to be exposed to MDR-TB cases
Special Populations
Tuberculous Meningitis and Extrapulmonary Disease
1-In general, isoniazid, pyrazinamide, ethionamide, cycloserine and linezolid penetrate
the cerebrospinal fluid readily.
2-Patients with CNS TB are often treated for longer periods (9–12 months).
3-Extrapulmonary TB of the soft tissues can be treated with conventional regimens. TB
of the bone is typically treated for 9 months, occasionally with surgical debridement.

Children
1-TB in children may be treated with regimens similar to those used in adults, although
some physicians still prefer to extend treatment to 9 months.
2-Pediatric doses of drugs should be used.
Pregnant Women
1-The usual treatment of pregnant women is isoniazid, rifampin, and ethambutol for 9
months.
2-Women with TB should be cautioned against becoming pregnant, as the disease poses
a risk to the fetus as well as to the mother.

3-Isoniazid or ethambutol is relatively safe when used during pregnancy.

Supplementation with B vitamins is particularly important during pregnancy.
4-Rifampin has been rarely associated with birth defects, but those seen are occasionally
severe, including limb reduction and CNS lesions.
5-Pyrazinamide has not been studied in a large number of pregnant women, but
anecdotal information suggests that it may be safe.
6-Ethionamide may be associated with premature delivery, congenital deformities, and
Down syndrome when used during pregnancy, so it cannot be recommended in pregnancy.

36
7-Cycloserine is not recommended during pregnancy. Fluoroquinolones should be
avoided in pregnancy and during nursing.

Renal Failure
In nearly all patients, isoniazid and rifampin do not require dose modifications in renal
failure. Pyrazinamide and ethambutol typically require a reduction in dosing frequency
from daily to three times weekly.
Evaluation of therapeutic outcomes
1-The most serious problem with TB therapy is nonadherence to the prescribed
regimen. The most effective way to ensure adherence is with DOT.
2-Patients should have blood urea nitrogen, serum creatinine, aspartate transaminase or
alanine transaminase, and a complete blood count determined at baseline and
periodically, depending on the presence of other factors that may increase the likelihood of
toxicity (advanced age, alcohol abuse, and possibly pregnancy).
3-Hepatotoxicity should be suspected in patients whose transaminases exceed five
times the upper limit of normal or whose total bilirubin exceeds 3 mg/dL. At this point,
the offending agent(s) should be discontinued and alternatives selected.
Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.

37
 College of Pharmacy
Fourth year. Clinical Pharmacy
Infectious Diseases
Central Nervous System Infections
Introduction
1-Central nervous system (CNS) infections include a wide variety of clinical conditions
and etiologies: meningitis, meningoencephalitis, encephalitis, brain and meningeal
abscesses, and shunt infections. The focus of this lecture is meningitis.

2-CNS infections may be caused by a variety of bacteria, fungi, viruses, and parasites.
The most common causes of bacterial meningitis are Streptococcus pneumoniae, group
B Streptococcus, Neisseria meningitidis, Haemophilus influenzae, and Listeria
monocytogenes

Pathophysiology
1-The critical first step in the acquisition of acute bacterial meningitis is nasopharyngeal
colonization of the host by the bacterial pathogen.
2-Most cases of acute bacterial meningitis probably occur following bacteremia, but the
high incidence of pneumococcal meningitis in patients with sinusitis and otitis media
suggests that direct spread to the CNS can also occur.
3-The neurologic sequelae of meningitis occur due to the activation of host inflammatory
pathways.
4-These events lead to cerebral edema, elevated intracranial pressure, decreased
cerebral blood flow, cerebral ischemia, and death.
5-Passive and active exposure to cigarette smoke and the presence of a cochlear implant
that includes a positioner both increase the risk of bacterial meningitis.
Clinical presentation
1-Signs and symptoms of acute bacterial meningitis include fever, nuchal rigidity,
altered mental status, chills, vomiting, photophobia, and severe headache.
2-Up to 95% of patients exhibit at least two of the following symptoms: fever, nuchal
rigidity, headache, and altered mental status.

3-Kernig and Brudzinski signs may be present but are poorly sensitive and frequently
absent in children.
4-Clinical signs and symptoms in young children may include bulging fontanelle, apnea,
purpuric rash, and convulsions.
5-Purpuric and petechial skin lesions typically indicate meningococcal involvement,
although the lesions may be present with H. influenza meningitis. Rashes rarely occur with
pneumococcal meningitis.
6-Meningitis causes changes in CSF fluid, and these changes can be used as diagnostic
markers of infection (Table1).
38
7-CSF culture is the gold standard for diagnosis of bacterial meningitis .
8-Gram stain is a rapid, inexpensive, and accurate method to assess the presence of
bacteria in CSF. However, prior antibiotic therapy may cause the Gram stain and CSF
culture to be negative, but the antibiotic therapy rarely affects CSF protein or glucose.
9-Polymerase chain reaction (PCR) techniques can rapidly diagnose CNS infections and
may be particularly useful in patients who have received antimicrobial therapy before
lumbar puncture.
Table 1: Mean Values of the Components of Normal and Abnormal Cerebrospinal
Fluid

aInitial cerebrospinal fluid (CSF), white blood cell (WBC) count may reveal a predominance of
polymorphonuclear neutrophils (PMNs). In CNS infection due to tuberculosis, “therapeutic paradox” may
occur in which a lymphocytic predominance becomes neutrophilic during antituberculous treatment .

Treatment
1-Goals of Treatment: Effective eradication of infection, amelioration of signs and
symptoms, and reduction of morbidity and mortality.
2-Key elements include initiating appropriate antimicrobials, providing supportive care,
and preventing disease through timely introduction of vaccination and chemoprophylaxis.
3-Administration of fluids, electrolytes, antipyretics, and analgesics may be indicated for
patients presenting with a possible CNS infection.
4-Additionally, venous thromboembolism prophylaxis, antiepileptic therapy, and ICP
monitoring may be needed.
Pharmacologic Therapy
1-Empiric antimicrobial therapy should be instituted as soon as possible to eradicate the
causative organism (Table-2). Antimicrobial therapy should last at least 48–72 hours or
until the diagnosis of bacterial meningitis can be ruled out.
2-The time period from suspected diagnosis to initiation of antibiotic treatment should
not exceed 1 hour.
39
Table 2: Bacterial Meningitis: Most Likely Etiologies and Empiric Therapy by Age
Group

3-Once a pathogen is identified, antibiotic therapy should be tailored to the specific

pathogen.
4-With increased meningeal inflammation, there will be greater antibiotic penetration
(Table-3). Problems of CSF penetration can be overcome by direct instillation of
antibiotics intrathecally or intraventricularly.
5-Advantages of direct instillation, however, must be weighed against the risks of invasive
CNS procedures and adverse effects. Intraventricular delivery may be necessary in
patients who have shunt infections that are difficult to eradicate .
6-See (Table-4) for antimicrobial agents of first choice and alternatives for treatment of
meningitis caused by gram-positive and gram-negative microorganisms.
Table 3: Penetration of Anti-infective Agents into the CSF

40
a Using recommended CNS dosing and compared to MIC of target pathogens. b May not achieve
therapeutic levels against organisms with higher MIC, as in P. aeruginosa. Tazobactam does not penetrate
the blood-brain barrier. c Includes clavulanic acid, sulbactam, and tazobactam. d Cefuroxime is an
exception. e Documented effectiveness for B. burgdorferi. f Achieves therapeutic concentrations for
Cryptococcus neoformans therapy.

7-Meningitis caused by S. pneumoniae has been treated successfully with 10–14 days of
antibiotic therapy, while cases caused by N. meningitidis or H. influenzae usually can be
treated with a 7-day course.

8-In contrast, a longer duration (21 days or more) has been recommended for patients with
L. monocytogenes, Gram-negative or pseudomonal meningitis.

Table 4: Antimicrobial Agents of First Choice and Alternative Choice for Treating
Meningitis Caused by Gram-Positive and Gram-Negative Microorganisms

41
Dexamethasone as an Adjunctive Treatment for Meningitis
1-In addition to antibiotics, dexamethasone is a commonly used adjunctive therapy in
the treatment of acute bacterial meningitis to immunomodulate the inflammatory
response.
2-Recommendations call for the use of adjunctive dexamethasone in infants and children
(6 weeks of age and older) with H. influenzae meningitis. The recommended intravenous
dose is 0.15 mg/kg every 6 hours for 2–4 days, initiated 10–20 minutes prior to or
concomitant with the first dose of antibiotics.
3-In infants and children with pneumococcal meningitis, adjunctive dexamethasone may
be considered after weighing the potential benefits and possible risks.
4-If pneumococcal meningitis is suspected or proven, adults should receive
dexamethasone 0.15 mg/kg (up to 10 mg) every 6 hours for 2–4 days with the first dose
administered 10–20 minutes prior to first dose of antibiotics.
42
Neisseria meningitidis (Meningococcus)
1-N. meningitidis is a leading cause of bacterial meningitis among children and young
adults around the world. It is spread by direct person-to-person close contact, including
respiratory droplets and pharyngeal secretions.
2-The presence of petechiae may be the primary clue that the underlying pathogen is N.
meningitidis. Patients may also have disseminated intravascular coagulation (DIC).
3-Deafness unilaterally, or more commonly bilaterally, may develop early or late in the
disease course.
4-Third-generation cephalosporins (ie, cefotaxime and ceftriaxone) are the recommended
empiric treatment for meningococcal meningitis.
5-Penicillin G or ampicillin is recommended for penicillin-susceptible isolates. The
recommended duration of therapy is typically 7 days if there is good clinical response.
6-Antimicrobial chemoprophylaxis of close contacts should be started as soon as possible
(ideally <24 hours after identification of the patient). Ciprofloxacin and rifampin are the
two most used chemoprophylactic agents.

Streptococcus pneumoniae (Pneumococcus or Diplococcus)

1-Streptococcus group B is a leading cause of community acquired bacterial meningitis
in patients 2 months of age or older.

2-Coma, hearing impairment, and seizures are common neurologic complications.

3-The combination of vancomycin and ceftriaxone can be used as empirical treatment

until antimicrobial susceptibility data are available.

Haemophilus influenzae
1-Widespread vaccination of infants and children has effectively decreased the incidence of
bacterial meningitis due to Hib in children between the ages of 1 month and 5 years,
resulting in a significant decline in all cases of bacterial meningitis.
2-Third-generation cephalosporins (cefotaxime and ceftriaxone) are the drugs of choice
for empirical therapy for H. influenzae type b meningitis as they are active against β-
lactamase–producing and non-β-lactamase–producing strains. Cefepime and
fluoroquinolones are suitable alternatives regardless of β-lactamase activity.
3-Recommended duration of treatment is 7 days (adults) or 7–10 days (children).
4-Dexamethasone is beneficial for treatment of infants and children with Hib meningitis
to diminish the risk of hearing loss, if given before or concurrently with the first dose of
antimicrobial agent(s).
5-Chemoprophylaxis with rifampin is indicated to reduce the risk of secondary invasive
Hib disease in close contacts.

43
6-Rifampin should be administered orally, once a day for 4 days (20 mg/kg/dose;
maximum, 600 mg).
Listeria monocytogenes
1-L. monocytogenes is implicated in approximately 10% of meningitis cases in patients
older than 65 years of age and carries a case-fatality rate of approximately 18% in the
United States.
2-Treatment of L. monocytogenes meningitis should consist of penicillin G or ampicillin.
The addition of aminoglycoside is also recommended in proven infection in both
children and adults.
3-Patients should be treated a minimum of 21 days. Trimethoprim–sulfamethoxazole
and meropenem may be effective alternatives because adequate CSF penetration is
achieved with these agents.
Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.

44
 College of Pharmacy
Fourth year. Clinical Pharmacy
Rheumatologic Disorders
Rheumatoid Arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune condition that
primarily affects joints and the synovium but can also have systemic manifestations.
Pathophysiology
1-RA results from a combination of genetic susceptibility, nongenetic factors, and a
triggering event. An unknown infectious process is thought to be the primary trigger.
2-Activated T cells stimulate B cells to produce autoantibodies. Antibodies to
immunoglobulin G (IgG) are known as rheumatoid factor (RF) and have a strong
correlation to the pathogenesis and poor prognosis of RA.
3-B cells also produce proinflammatory cytokines, including tumor necrosis factor (TNF)
and the interleukin (IL) system, which induce further enhance T-cell proliferation and
differentiation, and encouraging cell migration.
4-Overexpression of tumor suppressor gene p53 increased anticitrullinated protein
antibodies (ACPA). ACPA positivity is associated with a worse prognosis in patients with
RA.
5-The inflamed, fibrotic synovium (pannus) invades cartilage and bone around it,
promoting further destruction and dysregulation.

Clinical presentation
1-Nonspecific prodromal symptoms developing over weeks to months include fatigue,
weakness, low-grade fever, anorexia, and joint pain.
2-Joint involvement tends to be symmetric and affects small joints of the hands, feet,
wrists, and ankles; elbows, knees, shoulders, hips, cervical spine, and temporomandibular
joints may also be affected.
3-Joint stiffness is typically worse in the morning, usually exceeds 30 minutes, and
may persist all day. Tissue warm, and may be erythematous.

45
4-If left untreated, long-term joint inflammation may lead to bony erosions and
deformities of joints (swan neck deformity, boutonnière deformity, and ulnar
deviation).

5-Extra-articular involvement may include rheumatoid nodules, interstitial lung disease,

pleural effusions, vasculitis, ocular manifestations, pericarditis, cardiac conduction
abnormalities, bone marrow suppression, and lymphadenopathy.
6-RF is detected in 70%–80% of patients; higher titers generally reflect a more severe
disease course. ACPA antibodies generally predict a more aggressive disease course.
7-Normocytic anemia, thrombocytosis or thrombocytopenia, and leukopenia may also
be present.
Diagnosis
1-The American College of Rheumatology (ACR) and the European League Against
Rheumatism (EULAR) revised criteria for diagnosis of RA in 2010.
2-The criteria use a scoring system with a combined score of 6 or more out of 10
indicating that the patient has definite RA.
Treatment
Goals of Treatment: The ultimate goal is to induce complete remission or low disease
activity. Additional goals are to reduce inflammation and symptoms, maintain ability to
function in daily activities, slow destructive joint changes, and delay disability.
Nonpharmacologic Therapy
1-Patient education about the disease and medications (e.g., potential adverse effects, self-
administration of injectable agents) is important.
2-Physical therapy can reduce pain and inflammation while preserving joint function.
Exercise and physical activity (including aerobic activity and muscle-strengthening
exercises) can improve disease outcomes.
3-Assistive devices and orthoses such as braces and supports are useful to improve pain
and function. Occupational therapy can provide benefits such as appropriate footwear and
splinting.
4-Weight loss can help decrease stress on joints. Surgical options (e.g., joint replacements)
are reserved for patients with more severe disease with significant cartilage loss.
Pharmacologic Therapy
General Approach
1-Therapies to treat RA and slow disease progression include conventional and biologic
disease-modifying antirheumatic drugs (DMARDs) and the small-molecule oral Janus-
kinase (JAK) inhibitors.
 Conventional DMARDs include methotrexate, leflunomide, sulfasalazine, and
hydroxychloroquine.

46
  Biologic DMARDs include TNF inhibitors (adalimumab, certolizumab, etanercept,
golimumab, and infliximab) and non-TNF biologics (abatacept, sarilumab,
tocilizumab, rituximab, and anakinra).
 JAK inhibitors include baricitinib, tofacitinib, and upadacitinib.
2-Current RA treatment guidelines recommend initiating conventional DMARDs
irrespective of disease activity once a diagnosis is established.
3-The preferred conventional DMARD is methotrexate unless a contraindication
exists.
4-For patients with early RA (<6 months duration) and low disease activity, DMARD
monotherapy is recommended. Double or triple DMARD therapy is recommended for
moderate or high disease activity.
5-A biologic agent can be used as monotherapy or with conventional DMARD(s) in
patients with moderate or high disease activity.
6-A JAK inhibitor is an alternate option if disease activity remains moderate or high with
combination conventional DMARDs.
7-If disease activity remains moderate or high despite conventional DMARDs or
biologics, a low-dose glucocorticoid (prednisone ≤10 mg/day or equivalent) can be added
for the shortest duration necessary.
8-If patients achieve remission, DMARDs and biologic agents can be tapered, but
patients should remain on DMARD therapy at some dosage level.
9-Dual biologic therapy should be avoided due to the risk of infection associated with
immunosuppression.
10-Because DMARDs can take weeks to months to take effect, NSAIDs,
glucocorticoids, and other analgesics (eg, acetaminophen) can be used to provide more
rapid symptomatic relief (“bridge therapy”).
11-NSAIDs do not slow disease progression, and glucocorticoids can have serious side
effects, making both drug classes less desirable for long-term use.
Conventional DMARDs
1-Methotrexate inhibits dihydrofolate reductase. Injectable (subcutaneous [SC],
intramuscular [IM]) methotrexate has higher bioavailability than oral methotrexate and
thus provides superior clinical efficacy; it is typically better tolerated with less potential
to cause gastrointestinal (GI) side effects as well.
2-Oral methotrexate doses >15 mg weekly may not have significant added clinical benefit;
changing to SC methotrexate may increase bioavailability and clinical benefit in this
situation.
3-Clinical benefit can be seen 3–6 weeks after starting therapy. Methotrexate has numerous
adverse effects; concomitant folic acid 1–5 mg/day may reduce some adverse effects
without loss of efficacy.

47
4-Methotrexate is teratogenic, and patients should use contraception and discontinue the
drug if conception is planned.
5-Leflunomide *** efficacy for RA is similar to that of methotrexate.
6-Sulfasalazine *** use is limited by GI adverse effects.
7-Hydroxychloroquine ***: Its main advantage is that it does not require frequent,
routine laboratory monitoring because it is not generally associated with infection risk
or hepatic, renal, or blood cell abnormalities. GI side effects can sometimes be mitigated
by taking the medication with food or splitting the dose into two doses. Periodic
ophthalmologic examinations are necessary for early detection of irreversible retinal
toxicity.
***: Can be used alone or in combination with DMARDs

Biologic DMARDs (given i.v or s.c)

1-Biologic agents are genetically engineered . They are categorized as either TNF
inhibitors or non-TNF biologics. They may be effective when conventional DMARDs
fail to achieve adequate disease control but are considerably more expensive.
2-Biologic DMARDs are associated with an increased risk of infection due to
immunosuppressive effects. A tuberculin skin test or interferon gamma release assay
(IGRA) blood test should be obtained before starting a biologic to detect and treat latent
or active tuberculosis.
3-Patients should also be screened for hepatitis B before starting biologic therapy because
of the risk for reactivation.
4-Biologics can be used in combination with conventional DMARDs, but multiple
biologics should not be used concomitantly due to additive immunosuppressive effects.
5-In general, if patients are switched from one biologic to another, the new agent
should be initiated when the patient is due for a dose of the previous biologic.
6-Because of immunosuppressive effects, patients taking biologics should notify their
providers if they are being treated for an infection or plan to undergo major surgery.
Treatment may need to be held until appropriate postsurgical healing and/or resolution
of infection can be confirmed. Live vaccines should not be given to patients taking
biologic agents.
7-Biosimilars are biologic products that have been verified to have no clinically
meaningful differences compared to an FDA-approved reference biologic product.
These agents can increase access to RA treatment because their costs are lower than the
originator products.
A-TNF-α Inhibitors (Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab)
1-They should not be used in patients with moderate-to-severe heart failure (New York
Heart Association [NYHA] class III/IV) because new-onset and worsening heart failure
have been reported.

48
2-These agents increase the risk of serious infection and malignancies (eg, lymphoma,
skin cancers), and new-onset or exacerbation of demyelinating disorders such as multiple
sclerosis has been observed.
3-To prevent formation of an antibody response to Infliximab, methotrexate must be
given orally in doses used to treat RA for as long as the patient continues infliximab.
Premedication with an antihistamine, acetaminophen, and/or a glucocorticoid can
decrease development of infusion-related reactions.
B-Costimulation Modulator
Abatacept *** inhibits the activation of T cells. Abatacept is indicated for moderate-to-
severe RA .
C-IL-6 Receptor Antagonists
1-Sarilumab *** is indicated for treatment of patients with moderate-to-severe RA who
have had an incomplete response or intolerance to one or more DMARDs.
2-Tocilizumab *** can be used for patients with moderate-to-severe RA who have had an
incomplete response to one or more DMARDs.
D-Anti-CD20 Monoclonal Antibody
1-Rituximab is a monoclonal antibody that binds the CD20 antigen on the surface of B
cells. Binding of rituximab to B cells results in nearly complete depletion of peripheral B
cells, with a gradual recovery over several months.
2-Rituximab can be initiated in patients with moderate to-severe RA who have had an
incomplete response to one or more TNF inhibitors. Methotrexate should be given
concurrently in the usual doses for RA to achieve optimal outcomes.
3-Methylprednisolone 100 mg IV is recommended 30 minutes before each infusion as well
as acetaminophen and an antihistamine to reduce the incidence and severity of infusion
reactions.
E-IL-1 Receptor Antagonist
1-Anakinra*** is an IL-1 receptor antagonist; it is less effective than other biologics, is
used infrequently, and is not included in the current ACR treatment recommendations.
2-However, it can be used in patients with moderate-to-severe RA who have failed one or
more DMARDs.
Janus-Kinase Inhibitors
1-Baricitinib, tofacitinib, and upadacitinib are oral, small-molecule, nonbiologic JAK
inhibitors.
2-Baricitinib *** is FDA approved for adults with moderately to severely active RA who
have had an inadequate response to one or more TNF inhibitors.
3-Tofacitinib*** and upadacitinib *** have FDA approval for treatment of adults with
moderately to severely active RA who have had an inadequate response or intolerance to
methotrexate.

49
4-JAK inhibitors should not be given concomitantly with biologic. Labeling for all JAK
inhibitors includes black-box warnings about serious infections, lymphomas, and other
malignancies. Live vaccinations should not be given during treatment.
5-Patients should be tested and treated for latent tuberculosis before starting therapy.
***: Can be used alone or in combination with DMARDs

Nonsteroidal Anti-inflammatory Drugs

1-NSAIDs possess both analgesic and anti-inflammatory properties and reduce stiffness,
but they do not slow disease progression or prevent bony erosions or joint deformity
and should not be used as monotherapy for RA treatment.
2-They have a more rapid onset of action than DMARDs and may be beneficial to “bridge”
patients while DMARDs take effect.

Glucocorticoids
1-Glucocorticoids have anti-inflammatory and immunosuppressive properties; although
they have been shown to slow RA progression, glucocorticoids should not be used as
monotherapy for RA due to the potential for serious, long-term adverse effects.
2-They should be used at the lowest effective dose for the shortest period of time.
According to the ACR, short-term glucocorticoid therapy is defined as <3 months, and
low-dose glucocorticoid is defined as prednisone ≤10 mg/day (or equivalent).
3-Similar to NSAIDs, oral glucocorticoids (eg, prednisone, methylprednisolone) can be
used to “bridge” patients while DMARDs take effect. They can also be used as adjuncts
to DMARDs at the lowest dose possible in patients with refractory disease.
4-High-dose, short-term bursts can be used as needed for acute flares of RA symptoms,
followed by tapering to the lowest effective dose to control symptoms or until
discontinued over several days.
5-The IM route may be useful in nonadherent patients. Depot forms (triamcinolone and
methylprednisolone) provide 2–6 weeks of symptom control. Onset of effect may be
delayed for several days.
6-The depot effect provides a physiologic taper, avoiding hypothalamic–pituitary axis
suppression.
7-Intra-articular injections may be useful when only a few joints are involved.
Injections should not be repeated more often than every 3 months because of the
potential for accelerated loss of joint cartilage.
Evaluation of therapeutic outcomes
1-Assess disease activity at baseline and at each follow-up visit to evaluate therapeutic
response.
2-Laboratory monitoring of acute phase reactants such as CRP and ESR can be useful in
assessing inflammation.

50
3-It is important to monitor and assess for clinical and laboratory adverse effects of the
medications used to treat RA which may include [complete blood count (CBC) with
differential to detect hematological toxicity, SCr to detect renal toxicity, liver function tests
(LFTs): (ALT, AST) to detect hepatic toxicity]and ophthalmologic examination (for
patient taking hydroxychloroquine) to detect ocular toxicity.
Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.

51
 College of Pharmacy
Fourth year. Clinical Pharmacy
Rheumatologic Disorders
Osteoarthritis
Introduction
Osteoarthritis (OA) is a common, progressive disorder affecting primarily weight-
bearing diarthrodial joints, characterized by progressive destruction of articular
cartilage, osteophyte formation, pain, limitation of motion, deformity, and disability.
Pathophysiology
1-Primary (idiopathic) OA, the more common type, has no known cause. Secondary
OA is associated with a known cause such as trauma.
2-OA usually begins with damage to articular cartilage through injury, excessive joint
loading from obesity or other reasons, or joint instability.
3-Cartilage loss causes joint space narrowing and painful, deformed joints. New bone
formations (osteophytes) at joint margins are thought to help stabilize affected joints.
4-Inflammatory changes can occur in the joint capsule and synovium. Inflammatory
changes result in synovial effusions and thickening.
Clinical presentation
1-Risk factors include increasing age, obesity, sex, certain
occupations and sports activities, history of joint injury or
surgery, and genetic predisposition.
2-The predominant symptom is pain in affected joints. Pain
accompanies joint activity and decreases with rest.
3-Joints most commonly affected are the distal interphalangeal
(DIP) and proximal interphalangeal (PIP) joints of the hand, first
carpometacarpal joint, knees, hips, cervical and lumbar spine,
and first metatarsophalangeal (MTP) joint of the toe.
4-Limitation of motion, stiffness, crepitus, and deformities may
occur.
5-Upon arising, joint stiffness typically lasts less than 30 minutes and resolves with
motion. Presence of warm, red, and tender joints suggests inflammatory synovitis.

6-Physical examination of affected joints reveals tenderness, crepitus, and possibly

enlargement. Heberden and Bouchard nodes are bony enlargements (osteophytes) of the
DIP and PIP joints, respectively.
Diagnosis
1-Diagnosis is made through patient history, physician examination, radiologic findings,
and laboratory testing.

52
2-American College of Rheumatology criteria for classification of OA of the hips, knees,
and hands include presence of pain, bony changes on examination, normal erythrocyte
sedimentation rate (ESR), and radiographs showing osteophytes or joint space
narrowing.
Treatment
Goals of Treatment: (1) Educate the patient, family members, and caregivers; (2) relieve
pain and stiffness; (3) maintain or improve joint mobility; (4) limit functional impairment;
and (5) maintain or improve quality of life.
Nonpharmacologic Therapy
1-Educate the patient about the disease process and extent, prognosis, and treatment
options. Promote dietary counseling, exercise, and a weight loss program for overweight
patients.
2-Physical therapy—with heat or cold treatments and an exercise program—helps
maintain range of motion and reduce pain and need for analgesics.
3-Assistive and orthotic devices (canes, walkers, braces, heel cups, and insoles) can be
used during exercise or daily activities.
4-Surgical procedures (e.g., osteotomy, arthroplasty, joint fusion) are indicated for
functional disability and/or severe pain unresponsive to conservative therapy
Pharmacologic Therapy
General Approach
Drug therapy is targeted at relief of pain. Apply an individualized approach (Figs. 1 and
2). Continue appropriate nondrug therapies when initiating drug therapy.
Knee and Hip OA
1-Acetaminophen is a preferred first-line treatment; it may be less effective than oral
NSAIDs but has a lower risk of serious gastrointestinal (GI) and cardiovascular (CV)
events.
2-Acetaminophen is usually well tolerated, but potentially fatal hepatotoxicity with
overdose is well documented. It should be avoided in chronic alcohol users or patients with
liver disease.
3-Nonselective NSAIDs or cyclooxygenase-2 (COX-2) selective inhibitors (eg, celecoxib)
are recommended if a patient fails acetaminophen.

4-Nonselective NSAIDs may cause minor GI complaints such as nausea, dyspepsia,

anorexia, abdominal pain, and diarrhea. They may cause gastric and duodenal ulcers and
bleeding through direct (topical) or indirect (systemic) mechanisms.
5-Risk factors for NSAID-associated ulcers and ulcer complications (perforation, gastric
outlet obstruction, and GI bleeding) include longer duration of NSAID use, higher dosage,
age older than 60 years, past history of peptic ulcer disease of any cause, history of alcohol
use, and concomitant use of glucocorticoids or anticoagulants.

53
Figure 1: Treatment recommendations for knee and hip osteoarthritis.

Figure 2: Treatment recommendations for hand osteoarthritis.

54
6-Options for reducing the GI risk of nonselective NSAIDs include using (1) the lowest
dose possible and only when needed, (2) misoprostol with the NSAID, and (3) a PPI or
H2-receptor antagonist daily with the NSAID.
7-COX-2 inhibitors pose less risk for adverse GI events than nonselective NSAIDs, but
this advantage is substantially reduced for patients taking aspirin. Both nonselective and
selective NSAIDs are associated with an increased risk for CV events (hypertension,
stroke, myocardial infarction, and death).
8-Unlike aspirin, celecoxib and nonspecific NSAIDs inhibit thromboxane formation
reversibly, with normalization of platelet function 1–3 days after drug discontinuation.
Avoid NSAIDs in late pregnancy because of risk of premature closure of the ductus
arteriosus.
9-Topical NSAIDs are recommended for knee OA if acetaminophen fails, and they are
preferred over oral NSAIDs in patients older than 75 years.

10-Topical NSAIDs provide similar pain relief with fewer adverse GI events than oral
NSAIDs but may be associated with adverse events at the application site (e.g., dry skin,
pruritus, and rash).
11-Patients using topical products should avoid oral NSAIDs to minimize the potential
for additive side effects. Use of topical NSAIDs has not been linked with increased risk of
CV events.
12-Intra-articular (IA) corticosteroid injections are recommended for both hip and knee
OA when analgesia with acetaminophen or NSAIDs is suboptimal. They can provide
excellent pain relief, particularly when joint effusion is present.
13-Local anesthetics such as lidocaine or bupivacaine are commonly combined with
corticosteroids to provide rapid pain relief. Injections may also be given with concomitant
oral analgesics for additional pain control. Local adverse effects can include infection,
osteonecrosis, tendon rupture, and skin atrophy at the injection site.
14-Do not administer injections more frequently than once every 3 months to minimize
systemic adverse effects. Systemic corticosteroid therapy is not recommended in OA,
given lack of proven benefit and well-known adverse effects with long-term use.
15-Tramadol is recommended for hip and knee OA in patients who have failed
acetaminophen and topical NSAIDs, who are not appropriate candidates for oral NSAIDs,
and who are not able to receive IA corticosteroids.
16-Tramadol can be added to partially effective acetaminophen or oral NSAID therapy.
Tramadol is associated with opioid-like adverse effects such as nausea, vomiting, dizziness,
constipation, headache, and somnolence.
17-The most serious adverse event is seizures. Tramadol is classified as a Schedule IV
controlled substance due to its potential for dependence, addiction, and diversion.
18-Duloxetine can be used as adjunctive treatment of knee (not hip) OA in patients with
partial response to first-line analgesics (acetaminophen, oral NSAIDs). It may be a
55
preferred second-line medication in patients with both neuropathic and
musculoskeletal OA pain.
19-IA hyaluronic acid (sodium hyaluronate) is not routinely recommended because
injections have shown limited benefit for knee OA and have not been shown to benefit
hip OA.
20-Glucosamine and/or chondroitin and topical rubefacients (e.g, methyl salicylate,
trolamine salicylate) lack uniform improvement in pain control or functional status for hip
and knee pain and are not preferred treatment options.
Hand OA
1-Topical NSAIDs are a first-line option for hand OA. Efficacy with topical NSAIDs
typically occurs with 1–2 weeks.
2-Oral NSAIDs are an alternative first-line treatment for patients who cannot tolerate
the local skin reactions or who received inadequate relief from topical NSAIDs.
3-Capsaicin cream is an alternative first-line treatment. It is a reasonable option for
patients unable to take oral NSAIDs. Capsaicin must be used regularly to be effective, and
it may require up to 2 weeks to take effect. Adverse effects are primarily local.
4-Tramadol is an alternative first-line treatment and is a reasonable option for patients
who do not respond to topical therapy and are not candidates for oral NSAIDs because of
high GI, CV, or renal risks.
5-Tramadol may also be used in combination with partially effective acetaminophen,
topical therapy, or oral NSAIDs.
Evaluation of therapeutic outcomes
1-To monitor efficacy, assess baseline pain with a visual analog scale, and assess range
of motion for affected joints with flexion, or extension.
2-Depending on the joint(s) affected, measurement of grip strength and 50-ft walking
time can help assess hand and hip/knee OA, respectively.

Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th
Edition. 2023.

56
 College of Pharmacy
Fourth year. Clinical Pharmacy
Rheumatologic Disorders
Gout and Hyperuricemia
Introduction
Gout involves an inflammatory response to precipitation of monosodium urate (MSU)
crystals in both articular and nonarticular tissues.

Acute gouty arthritis : pathophysiology

1-An increased urate pool in individuals with gout may result from overproduction or
underexcretion.
2-Overproduction of uric acid may result from abnormalities in enzyme systems that
regulate purine metabolism. Cytotoxic drugs can result in overproduction of uric acid due
to lysis and the breakdown of cellular matter.
3-Dietary purines are insignificant in generating hyperuricemia without some
derangement in purine metabolism or elimination.
4-Two-thirds of uric acid produced daily is excreted in urine. The remainder is
eliminated through gastrointestinal (GI) tract after degradation by colonic bacteria. Decline
in urinary excretion leads to hyperuricemia.
5-Some drugs decrease renal uric acid clearance like diuretics.
6-Deposition of urate crystals in synovial fluid results in inflammation.
7-Uric acid nephrolithiasis occurs in ∼10% of patients with gout. Predisposing factors
include excessive urinary excretion of uric acid, acidic urine (pH <6), and highly
concentrated urine.
8-In acute uric acid nephropathy, acute kidney injury occurs because of blockage of urine
flow from massive precipitation of uric acid crystals in collecting ducts and ureters.
Chronic urate nephropathy is caused by long-term deposition of urate crystals in the renal
parenchyma.
9-Tophi (urate deposits) are uncommon and are a late complication of hyperuricemia.
Clinical presentation
1-Acute gout attacks are characterized by rapid onset of excruciating pain, swelling, and
inflammation. The attack is typically monoarticular, most often affecting the first
metatarsophalangeal joint (podagra), and then, in order of frequency, the insteps, ankles,
heels, knees, wrists, fingers, and elbows.
2-Attacks commonly begin at night, with the patient awakening with excruciating pain.
Affected joints are erythematous, warm, and swollen.
3-Fever and leukocytosis are common. Untreated attacks last from 3 to 14 days before
spontaneous recovery.

57
4-Acute attacks may occur without provocation or be precipitated by stress, trauma,
alcohol ingestion, infection, surgery, rapid lowering of serum uric acid by uric acid-
lowering agents, and ingestion of drugs known to elevate serum uric acid concentrations.
Diagnosis
1-Definitive diagnosis requires aspiration of synovial fluid from the affected joint and
identification of intracellular MSU crystals in synovial fluid leukocytes.
2-When joint aspiration is not feasible, the diagnosis can be made based on presence of
characteristic signs and symptoms as well as the response to treatment.
Treatment
Goals of Treatment: Terminate the acute attack, prevent recurrent attacks, and
prevent complications associated with chronic deposition of urate crystals in tissues.
Nonpharmacologic Therapy
1-Local ice application is the most effective adjunctive treatment.
2-Dietary supplements (eg, flaxseed, cherry, celery root) are not recommended.
Pharmacologic Therapy
Most patients are treated successfully with NSAIDs, corticosteroids, or colchicine.
Treatment should begin as soon as possible after the onset of an attack.
A-NSAIDS
1-NSAIDs have excellent efficacy and minimal toxicity with short-term use.
Indomethacin, naproxen, and sulindac have FDA approval for gout, but others are likely
to be effective.
2-Start therapy within 24 hours of attack onset and continue until complete resolution
(usually 5–8 days). Tapering may be considered after resolution.
3-Selective cyclooxygenase-2 inhibitors (e.g., celecoxib) may be an option for patients
unable to take nonselective NSAIDs, but the cardiovascular risk must be considered.
B-Corticosteroids
1-Corticosteroid efficacy is equivalent to NSAIDs; they can be used systemically or by
intra-articular (IA) injection. If only one or two joints are involved, either IA or oral
corticosteroids are recommended. Systemic therapy is necessary for polyarticular
attacks.
2-Tapering is often used to reduce the hypothetical risk of a rebound attack upon steroid
withdrawal.
3-IA corticosteroids should be used with an oral NSAID, colchicine, or corticosteroid
therapy. Alternatively, IM corticosteroid monotherapy may be considered in patients
with multiple affected joints who cannot take oral therapy.
4-Avoid long-term use because of risk for osteoporosis, hypothalamic–pituitary–adrenal
axis suppression, cataracts, and muscle deconditioning.

58
C-Colchicine
1-Colchicine is highly effective in relieving acute gout attacks; when it is started within
the first 24 hours of onset, about two-thirds of patients respond within hours.
2-Colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea).
Non-GI effects include neutropenia and axonal neuromyopathy, which may be worsened in
patients taking other myopathic drugs (e.g., statins) or with impaired kidney function.
3-Use colchicine with caution in patients taking P-glycoprotein or strong CYP450 3A4
inhibitors (e.g., clarithromycin) due to increased plasma colchicine levels and potential
toxicity; colchicine dose reductions may be required.
Hyperuricemia in gout
Recurrent gout attacks can be prevented by maintaining low uric acid levels, but
nonadherence with nonpharmacologic and pharmacologic therapies is common.

Nonpharmacologic Therapy
1-Promote weight loss through caloric restriction and exercise in all patients to enhance
renal urate excretion.
2-Alcohol restriction is important because increased consumption has been associated with
an increased risk of gout attacks.
3-Dietary recommendations include limiting consumption of high-fructose corn syrup and
purine-rich foods (organ meats and some seafood) which have been linked to uric acid
elevation.
4-Evaluate the medication list for potentially unnecessary drugs that may elevate uric
acid levels. Low-dose aspirin for cardiovascular prevention should be continued
because aspirin has a negligible effect on elevating serum uric acid.
Pharmacologic Therapy
1-After the first attack of acute gout, prophylactic pharmacotherapy is recommended if
patients have two or more attacks per year, even if serum uric acid is normal or only
minimally elevated.
2-Other indications include presence of tophi, and radiographic evidence of damage
attributable to gout.
3-Urate-lowering therapy can be started during an acute attack if anti-inflammatory
prophylaxis has been initiated.
4-Xanthine oxidase inhibitors are recommended first-line therapy, with uricosurics
reserved for patients with a contraindication or intolerance to xanthine oxidase inhibitors.
5-In refractory cases, combination therapy with a xanthine oxidase inhibitor plus a
drug with uricosuric properties (probenecid, losartan, or fenofibrate) is suggested.
6-Pegloticase may be used in severe cases in which the patient cannot tolerate or is not
responding to other therapies.

59
7-The ACR guideline goal of urate-lowering therapy is to achieve and maintain serum uric
acid <6 mg/Dl. Urate lowering should be prescribed for long-term use.
A-Xanthine Oxidase Inhibitors
1-Xanthine oxidase inhibitors reduce uric acid by impairing conversion of hypoxanthine to
xanthine and xanthine to uric acid.
2-Because they are effective in both overproducers and underexcretors of uric acid, they
are the most widely prescribed agents for long-term prevention of recurrent gout
attacks.
3-Mild adverse effects of allopurinol include skin rash, leukopenia, GI problems,
headache, and urticaria. A more severe adverse reaction known as allopurinol
hypersensitivity syndrome, which includes severe rash (toxic epidermal necrolysis,
erythema multiforme, or exfoliative dermatitis), occurs rarely but is associated with a 20%–
25% mortality rate.
4-Febuxostat: also lowers serum uric acid in a dose dependent manner. Clinical trial
evidence demonstrated an increase in all cause and cardiovascular mortality compared
to allopurinol, resulting in a warning that febuxostat should be reserved for patients unable
to take allopurinol.

B-Uricosurics
1-Uricosuric drugs increase renal clearance of uric acid by inhibiting renal tubular
reabsorption of uric acid.
2-Patients with a history of urolithiasis should not receive uricosurics. Maintaining
adequate urine flow and urine alkalinization during the first several days of therapy may
also decrease likelihood of uric acid stone formation.
C-Pegloticase
1-Pegloticase is a pegylated recombinant uricase that reduces serum uric acid by converting
uric acid to allantoin, which is water soluble.
2-Pegloticase is indicated for antihyperuricemic therapy in adults refractory to
conventional therapy.
3-Because of potential infusion-related allergic reactions, patients must be pretreated with
antihistamines and corticosteroids.
4-Pegloticase is substantially more expensive than first-line urate-lowering therapies.
The ideal duration of pegloticase therapy is unknown. Patients may develop pegloticase
antibodies that result in loss of efficacy after several months.
5-Because of its limitations, reserve pegloticase for patients with refractory gout who are
unable to take or have failed all other urate-lowering therapies.
D-Miscellaneous Urate-Lowering Agents
1-Fenofibrate is thought to increase clearance of hypoxanthine and xanthine, leading to a
susained reduction in serum urate concentrations of 20%–30%. However, ACR guidelines

60
recommend against changing cholesterol lowering agents to fenofibrate because it is
not a preferred therapy in current lipid guidelines.
3-Losartan inhibits renal tubular reabsorption of uric acid and increases urinary
excretion, properties that are not shared with other angiotensin II receptor blockers. It also
alkalinizes the urine, which helps reduce the risk for stone formation. Guidelines
recommend choosing losartan preferentially as antihypertensive therapy in patients
with gout when feasible.
Anti-Inflammatory Prophylaxis During Initiation of Urate-Lowering Therapy
1-Initiation of urate-lowering therapy can precipitate an acute gout attack due to
remodeling of urate crystal deposits in joints after rapid lowering of urate
concentrations.
2-Prophylactic anti-inflammatory therapy is recommended to prevent such gout
attacks.

3-The ACR guidelines strongly recommend low dose oral colchicine, low dose NSAIDs,
or prednisone 10 mg daily during the first 3 to 6 months of urate lowering therapy
initiation, and longer as needed if gout flares persist.
Evaluation of therapeutic outcomes
1-Check the serum uric acid level in patients suspected of having an acute gout attack,
however, acute gout can occur with normal serum uric acid concentrations.
2-Monitor patients with acute gout for symptomatic relief of joint pain.

3-Because of the high rates of comorbidities associated with gout (diabetes, chronic
kidney disease, hypertension, obesity, myocardial infarction, heart failure, and stroke),
elevated serum uric acid concentrations or gout should prompt evaluation for
cardiovascular disease and the need for appropriate risk reduction measures.
Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.

61
 College of Pharmacy
Fourth year. Clinical Pharmacy
Rheumatologic Disorders
Osteoporosis
Introduction
Osteoporosis is a bone disorder characterized by low bone density, impaired bone
architecture, and compromised bone strength predisposing to fracture.
Pathophysiology
1-Bone loss occurs when resorption exceeds formation (when the bone resorption greatly
exceeds the ability of osteoblasts to form new bone).
2-Men and women begin to lose bone mass starting in the third or fourth decade
because of reduced bone formation. Estrogen deficiency during menopause increases
osteoclast activity, increasing bone resorption more than formation.
3-Men are at a lower risk for developing osteoporosis and osteoporotic fractures. Male
osteoporosis results from aging or secondary causes.
4-Age-related osteoporosis results from hormone, calcium, and vitamin D deficiencies;
less exercise; and other factors.
5-Drug-induced osteoporosis may result from systemic corticosteroids, excessive thyroid
hormone replacement, antiepileptic drugs (eg, phenytoin, phenobarbital), depot
medroxyprogesterone acetate, and other agents.
Clinical presentation
1-Many patients are unaware that they have osteoporosis and only present after
fracture. Fractures can occur after bending, lifting, or falling or independent of any
activity.
2-The most common fractures involve vertebrae, proximal femur, and distal radius
(wrist or Colles fracture).
3-Multiple vertebral fractures decrease height and sometimes curve the spine (kyphosis or
lordosis).
4-Patients with a nonvertebral fracture frequently present with severe pain, swelling,
and reduced function and mobility at the fracture site.
Diagnosis
1-Physical examination findings may include bone pain, postural changes (ie, kyphosis),
and loss of height (>1.5 in [3.8 cm]).
2-Bone mineral density (BMD) is measured by dual-energy x-ray absorptiometry (DXA)
scan.

Treatment
Goals of Treatment:
1-The primary goal of osteoporosis care is prevention.
62
2-After low bone mass or osteoporosis develops, the objective is to stabilize or improve
bone mass and strength and prevent fractures.
3-Goals in patients with osteoporotic fractures include reducing pain and deformity, and
improving quality of life
Nonpharmacologic Therapy
1-All individuals should have a balanced diet with adequate intake of calcium and
vitamin D. Protein is required for bone formation.
2-Smoking cessation, and reduced alcohol and caffeine consumption are recommended.
3-Weight-bearing aerobic and strengthening exercises can decrease risk of falls and
fractures by improving muscle strength.
4-Fall prevention programs can decrease falls and fractures.
5-Vertebroplasty and kyphoplasty involve injection of cement into fractured vertebra(e)
for patients with debilitating pain from compression fractures. Research demonstrated only
short term benefit with no major pain relief and the potential for post-procedure
complications.
Pharmacologic Therapy
General Approach
1-Alendronate, risedronate, zoledronic acid, and denosumab reduce both hip and vertebral
fracture risks.
2-Abaloparatide, calcitonin, ibandronate, raloxifene, romosozumab, and teriparatide reduce
vertebral but not hip fracture risks.
3-Calcitonin is last-line therapy. Estrogen and testosterone are not used for
osteoporosis treatment but can have a positive bone effect when prescribed for other
conditions.
Antiresorptive Therapy
Calcium Supplementation
1-There are insufficient data to support using calcium and vitamin D supplementation to
reduce fracture incidence.
2-Because the fraction of calcium absorbed decreases with increasing dose, maximum
single doses of 600 mg or less of elemental calcium are recommended.
3-Calcium carbonate is the salt of choice because it contains the highest concentration of
elemental calcium (40%) and is typically least expensive. It should be ingested with meals
to enhance absorption in an acidic environment.
4-Calcium citrate (21% calcium) has acid-independent absorption and need not be
taken with meals. It may have fewer GI side effects than calcium carbonate.
5-Tricalcium phosphate contains 38% calcium. It may be useful in patients with
hypophosphatemia that cannot be resolved with increased dietary intake.

63
6-Constipation is the most common calcium-related adverse reaction; treat with
increased water intake, dietary fiber , and exercise.
7-Calcium carbonate can sometimes cause flatulence or upset stomach. Calcium causes
kidney stones rarely.
8-Calcium can decrease the oral absorption of some drugs including iron, tetracyclines,
quinolones, bisphosphonates, and thyroid supplements.
Vitamin D Supplementation
1-Supplementation is usually provided with daily nonprescription cholecalciferol (vitamin
D3) products. Higher-dose prescription ergocalciferol (vitamin D2) regimens given
weekly, monthly, or quarterly may be used for replacement and maintenance therapy.
2-Current guidelines recommend treating patients with osteoporosis to a 25-hydroxyvitamin
D concentration of at least 20 ng/mL or 30–50 ng/mL.
3-Because the half-life of vitamin D is about 1 month, recheck the vitamin D
concentration after about 3 months of therapy.
Bisphosphonates
1-Bisphosphonates mimic pyrophosphate, an endogenous bone resorption inhibitor.
Therapy leads to decreased osteoclast maturation, number, recruitment, and life span.
2-Incorporation into bone gives bisphosphonates long biologic half-lives of up to 10 years.
3-Ibandronate is not a first-line therapy because of the lack of hip fracture reduction
data.
4-BMD increases are dose dependent and greatest in the first 12 months of therapy.
After discontinuation, the increased BMD is sustained for a prolonged period that varies per
bisphosphonate.
5-Oral bisphosphonates must be administered correctly to optimize clinical benefit and
minimize adverse GI effects.
A-Each oral tablet should be taken in the morning with at least (180 mL) of plain
water (not coffee, juice, mineral water, or milk) at least 30 minutes (60 minutes for oral
ibandronate) before consuming any food, supplements, or medications.
B-An exception is delayed-release risedronate, which is administered immediately
after breakfast with at least (120 mL) of plain water.
C-The patient should remain upright (sitting or standing) for at least 30 minutes after
alendronate and risedronate and 1 hour after ibandronate to prevent esophageal
irritation and ulceration.
D-If a patient misses a weekly dose, it can be taken the next day. If more than 1 day has
elapsed, that dose is skipped. If a patient misses a monthly dose, it can be taken up to 7
days before the next scheduled dose.

64
6-The most common bisphosphonate adverse effects include nausea, abdominal pain, and
dyspepsia. Esophageal, gastric, or duodenal irritation, perforation, ulceration, or
bleeding may occur.
7-The most common adverse effects of IV bisphosphonates include fever, flu-like
symptoms, and local injection-site reactions.
8-The optimal duration of bisphosphonate therapy is unknown.
Denosumab
1-Denosumab is a RANK ligand inhibitor that inhibits osteoclast formation and increases
osteoclast apoptosis. It is indicated for treatment of osteoporosis in women and men.
2-Denosumab is contraindicated in patients with hypocalcemia until the condition is
corrected.
Mixed Estrogen Agonists/Antagonists and Tissue-Selective Estrogen
Complexes
1-Raloxifene is an estrogen agonist/antagonist that is an estrogen agonist on bone
receptors but an antagonist at breast receptors, with minimal effects on the uterus.
2-It is approved for prevention and treatment of postmenopausal osteoporosis .
3-Bazedoxifene is an estrogen agonist/antagonist that is an agonist at bone and antagonist
at the uterus and breast; however, reduction in breast cancer risk has not yet been
demonstrated. The proprietary product Duavee is combined with conjugated equine
estrogens (CEE), making it a tissue-selective estrogen complex. It is approved for
prevention of postmenopausal osteoporosis and vasomotor menstrual symptoms.
Calcitonin
Calcitonin is FDA approved for osteoporosis treatment for women at least 5 years past
menopause. Calcitonin is considered as a last line therapy because there are more
effective treatment options.
Hormone Therapies
1-Estrogen therapy is FDA approved for prevention of postmenopausal osteoporosis but not
for treatment. Estrogen therapy can be a good choice for women going through early
menopause when protection against bone loss is needed in addition to reduction of
vasomotor symptoms.
2-Testosterone is used to treat hypogonadism in men, but an osteoporosis medication
should be added when risk for osteoporotic fracture is high.
Formation Medications
Parathyroid Hormone Analogs
1-Abaloparatide is an analog of parathyroid hormone-related peptide (PTHrP), and
teriparatide is an analogs of parathyroid hormone (PTH); these agents are indicated for the
treatment of postmenopausal women with osteoporosis at high risk for fracture.
2-Transient hypercalcemia can occur. PTH analogs should not be used in patients with
hypercalcemia.
65
Formation and Antiresorptive Medication
Romosozumab
1-Romosozumab prevent inhibition of bone formation and decrease bone resorption, an
activity that differentiates this medication from other anabolic therapies.
2-It indicated for postmenopausal women at high risk for fracture.
Sequential and Combination Therapy
1-In sequential therapy, an anabolic agent is given first to increase bone mass, followed
by an antiresorptive agent.
2-Combination therapy is rarely used because of no documented fracture benefit,
increased cost, and potential for more adverse effects.
Glucocorticoid-induced osteoporosis
1-Glucocorticoids decrease bone formation through decreased proliferation and
differentiation as well as enhanced apoptosis of osteoblasts. They also increase the number
of osteoclasts, increase bone resorption, decrease calcium absorption, and increase renal
calcium excretion.
2-All glucocorticoid doses and formulations have been associated with increased bone loss
and fractures; however, risk is much greater with oral prednisone doses ≥5 mg daily (or
equivalent) and oral therapy compared to inhaler or intranasal therapy.
3-All patients starting or receiving systemic glucocorticoid therapy (any dose or
duration) should practice a bone-healthy lifestyle and ingest 1000–1200 mg elemental
calcium and 600–800 units of vitamin D daily to achieve therapeutic 25-hydroxyvitamin
D concentrations.
4-Use the lowest possible corticosteroid dose and duration.
5-Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide are FDA
approved for glucocorticoid-induced osteoporosis.
6-Oral bisphosphonates are recommended first-line, although IV bisphosphonates can
be used in nonadherent patients or those unable to take the oral preparations.
7-Teriparatide is recommended for patients who cannot use a bisphosphonate, and
denosumab is recommended if neither a bisphosphonate nor teriparatide can be used.
8-Denosumab is not recommended as first-line therapy due to limited safety data in this
population.

Evaluation of therapeutic outcomes

1-Assess medication adherence and tolerability at each visit.
2-Ask patients about possible fracture symptoms (eg, bone pain, disability) at each visit.
3-Obtain a central DXA BMD measurement after 1–2 years or 3–5 years after initiating a
medication therapy to monitor response.

66
4-Repeat a central DXA every 2 years until BMD is stable, at which time the reassessment
interval can be lengthened.

Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.

67
 College of Pharmacy
Fourth year. Clinical Pharmacy
Hematologic Disorders
Anemias
Introduction
1-Anemia is a group of diseases characterized by a decrease in either hemoglobin (Hb) or
the volume of red blood cells (RBCs), resulting in decreased oxygen-carrying capacity
of blood.
2-The World Health Organization defines anemia as Hb less than 13 g/dL in men or less
than 12 g/dL in women.
Pathophysiology
1-The functional classification of anemias is found in Fig. -1.

Figure -1. Functional classification of anemia.

2- Morphologic classifications are based on cell size.
A-Macrocytic cells are larger than normal and are associated with deficiencies of
vitamin B12 or folic acid.
B-Microcytic cells are smaller than normal and are associated with iron deficiency,
whereas normocytic anemia may be associated with recent blood loss or chronic
disease.
3-Iron-deficiency anemia (IDA), characterized by decreased levels of ferritin (most
sensitive marker) and serum iron, and decreased transferrin saturation, can be caused by
inadequate dietary intake, inadequate gastrointestinal (GI) absorption, increased iron
demand (eg, pregnancy), blood loss, and chronic diseases.
4-Vitamin B12– and folic acid–deficiency anemias, macrocytic in nature, can be caused
by inadequate dietary intake, malabsorption syndromes, and inadequate utilization.

68
 A-Deficiency of intrinsic factor causes decreased absorption of vitamin B12 (ie,
pernicious anemia).
B-Folic acid–deficiency anemia can be caused by hyperutilization due to pregnancy,
hemolytic anemia, malignancy, chronic inflammatory disorders, long-term dialysis, or
growth spurt.
C-Drugs can cause anemia by reducing absorption of folate (eg, phenytoin) or through
folate antagonism (eg, methotrexate).
5-Anemia of inflammation (AI) is a newer term used to describe both anemia of chronic
disease and anemia of critical illness.
A-AI is an anemia that traditionally has been associated with malignant, infectious, or
inflammatory processes, tissue injury, and conditions associated with release of
proinflammatory cytokines.
B-Serum iron is decreased but in contrast to IDA, the serum ferritin concentration is
normal or increased.
Clinical presentation
1-Acute-onset anemia is characterized by cardiorespiratory symptoms such as
palpitations, angina, orthostatic light-headedness, and breathlessness.
2-Chronic anemia is characterized by weakness, fatigue, headache, orthopnea, dyspnea on
exertion, vertigo, faintness, cold sensitivity, and pallor.
3-IDA is characterized by glossal pain, smooth tongue, reduced salivary flow, pica
(compulsive eating of nonfood items), and pagophagia (compulsive eating of ice).
4-Neurologic effects (eg, numbness and paraesthesisas) of vitamin B12 deficiency may
precede hematologic changes. Psychiatric findings, including irritability, depression, and
memory impairment, may also occur with vitamin B12 deficiency. Anemia with folate
deficiency is not associated with neurologic symptoms.
Diagnosis
1-Rapid diagnosis is essential because anemia is often a sign of underlying pathology.
Severity of symptoms does not always correlate with the degree of anemia.
2-Initial evaluation of anemia involves a complete blood cell count (CBC), reticulocyte
index, and examination of the stool for occult blood.
3-The earliest and most sensitive laboratory change for IDA is decreased serum ferritin
(storage iron).
4-In macrocytic anemias, mean corpuscular volume is usually elevated. Vitamin B12 and
folate concentrations can be measured to differentiate between the two deficiency
anemias.
5-In AI, serum iron is usually decreased, but, unlike IDA, serum ferritin is normal or
increased. The peripheral smear reveals normocytic anemia.

69
Treatment
Goals of Treatment: The goals are to return hematologic parameters to normal, restore
normal function and quality of life, and prevent long-term complications.
Iron-deficiency anemia
1-Oral iron therapy with soluble ferrous iron salts, which are not enteric coated and not
slow or sustained release, is recommended at a daily dosage of 150–200 mg elemental iron
in two or three divided doses.
2-Iron is best absorbed from meat, fish, and poultry. Administer iron at least 1 hour
before meals because food interferes with absorption, but administration with food may be
needed to improve tolerability.
3-Consider parenteral iron for patients with iron malabsorption, intolerance of oral iron
therapy, or nonadherence.
4-Iron dextran, sodium ferric gluconate, iron sucrose, ferumoxytol, and ferric
carboxymaltose are available parenteral iron preparations with similar efficacy but
different pharmacokinetics, bioavailability, and adverse effect profiles.

Vitamin B12–deficiency anemia

1-Oral vitamin B12 supplementation is as effective as parenteral, even in patients with
pernicious anemia, because the alternate vitamin B12 absorption pathway is independent of
intrinsic factor.
2-Parenteral therapy acts more rapidly than oral therapy and is recommended if neurologic
symptoms are present. Initiate daily oral cobalamin administration after symptoms
resolve.
3-Continue vitamin B12 for life in patients with pernicious anemia.
Folate-deficiency anemia
1-Oral folic acid, 1 mg daily for 4 months, is usually sufficient for treatment of folic acid–
deficiency anemia, unless the etiology cannot be corrected.
2-If malabsorption is present, a dose of 1–5 mg daily may be necessary. Parenteral folic
acid is available but rarely necessary.
Anemia of inflammation
1-Treatment of AI is less specific than that of other anemias and should focus on
correcting reversible causes. Reserve iron therapy for an established IDA; iron is not
effective when inflammation is present. RBC transfusions are effective but should be
limited to Hb of 7–8 g/dL.
2-Erythropoiesis-stimulating agents (ESAs) can be considered, but response can be
impaired in patients with AI. Iron, cobalamin, and folic acid supplementation may improve
response to ESA treatment.
3-Potential toxicities of exogenous ESA administration include increases in blood
pressure, nausea, headache, fever, bone pain, and fatigue. Hb must be monitored during
ESA therapy. An increase in Hb greater than 12 g/dL with treatment or a rise of
70
greater than 1 g/dL every 2 weeks has been associated with increased mortality and
cardiovascular events.
4-In patients with anemia of critical illness, parenteral iron is often used but is associated
with a theoretical risk of infection.
Anemia in pediatric populations
1-Infants aged 9–12 months: Administer ferrous sulfate 3–6 mg/kg/day (elemental iron)
divided once or twice daily between meals for 4 weeks. Continue for two additional months
in responders to replace storage iron pools.
2-The dose and schedule of vitamin B12 should be titrated according to clinical and
laboratory response. The daily dose of folic acid is 1 mg.
Evaluation of therapeutic outcomes
1-IDA: Positive response to oral iron therapy is characterized by an increase in Hb seen at 2
weeks. Hb should return to normal after 2 months; continue iron therapy until iron stores
are replenished and serum ferritin normalized (up to 12 months).
2-Megaloblastic anemia: Signs and symptoms usually improve within a few days after
starting vitamin B12 or folic acid therapy.

Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12th
Edition. 2023.

71
 College of Pharmacy
Fourth year. Clinical Pharmacy
Respiratory disorders
Asthma
Asthma is defined by the Global Initiative for Asthma (GINA) as a heterogeneous disease
usually characterized by chronic airway inflammation. It is defined by a history of
respiratory symptoms such as wheezing, shortness of breath, chest tightness, and
cough that vary over time and in intensity, together with variable expiratory airflow
limitation.
Pathophysiology
1-There is a variable degree of airflow obstruction. In acute inflammation, inhaled
allergens in allergic patients cause activation of inflammatory cells (mast cells,
neutrophils and macrophages)
2-After rapid activation, inflammatory cells release proinflammatory mediators such as
histamine and eicosanoids that induce contraction of airway smooth muscle
(bronchospasm), mucus secretion, edema, and exudation of plasma in the airways.
Clinical presentation
A-Chronic asthma
Signs and symptoms include episodes of shortness of breath, chest tightness, dry
coughing (particularly at night), wheezing, or a whistling sound when breathing. These
often occur with exercise but may occur spontaneously or in association with known
allergens.
B-Acute severe asthma
1-Uncontrolled asthma can progress to an acute state. Patients may be anxious in acute
distress and complain of severe dyspnea, shortness of breath, chest tightness, or
burning. They may be able to say only a few words with each breath. Symptoms are
unresponsive to usual measures (ie, SABAs).
2-Signs include dry, hacking cough; tachypnea; tachycardia; pallor or cyanosis; and
hyperinflated chest with intercostal and supraclavicular retractions.
Diagnosis
A-Chronic asthma
1-Diagnosis is made primarily by history and confirmatory spirometry.
2-Spirometry demonstrates obstruction (forced expiratory volume in 1 second
[FEV1]/forced vital capacity [FVC] <80%) with reversibility after inhaled β2-agonist
administration.
B-Acute severe asthma
1-Peak expiratory flows (PEF) and FEV1 are <40% of normal predicted values. Pulse
oximetry reveals decreased arterial oxygen and O2 saturations.
2-Arterial blood gases may reveal metabolic acidosis and low partial pressure of oxygen
(PaO2).
72
Treatment
Goals of Treatment: The GINA long-term goals for asthma management include:
(1) achieve good control of symptoms and maintain normal activity levels.
(2) minimize future risk of exacerbations, and side effects.
For acute severe asthma, the primary goal is prevention of life-threatening asthma by early
recognition of signs of deterioration and providing rapid treatment.
Nonpharmacologic Therapy
1-Patient education is mandatory to improve medication adherence, self-management
skills, and use of healthcare services.
2-Routine PEF monitoring is generally recommended only for patients with severe
asthma or poor symptom perception.
3-Avoidance of known allergenic triggers can improve symptoms, and reduce medication
use. Smokers should be encouraged to quit.
4-In acute asthma exacerbations, initiate oxygen therapy.
5-Correct dehydration if present.
Pharmacologic Therapy
General Approach
1-Figure 1 summarizes GINA recommendations for initial treatment in adults and
adolescents with asthma (further reading).

Figure 1: GINA recommendations for initial treatment in adults and adolescents

73
2-Despite the addition of inhaled corticosteroid-short acting β2 agonist (ICS-SABA)
reliever in track 2, GINA track 1 with as-needed ICS- formoterol remains the preferred
treatment for adults and adolescents (2).
[Single Maintenance and Reliever Therapy (SMART) also called Maintenance and
Reliever Therapy (MART) in GINA guidelines: SMART therapy with ICS-formoterol
significantly reduces the risk of severe exacerbation compared with using a SABA
reliever, with similar symptom control] (2).
3-Depending on the inflammatory phenotype (e.g. allergic asthma, eosinophilic asthma) and
other clinical features, add-on treatment for severe asthma include long acting muscarinic
antagonist (LAMA), leukotriene receptor antagonists (LTRA), and biologic agents (2).
4-Low-dose maintenance oral corticosteroid (OCS) should be considered only as a last
resort if no other options are available, because of their long-term side effects (2).

5-Once good asthma control has been achieved and maintained for 2-3 months, consider
stepping down gradually to find the patient's lowest treatment that controls both symptoms
and exacerbations (2).
6-The primary therapy of acute exacerbations includes inhaled SABAs and (depending
on severity) systemic corticosteroids, inhaled ipratropium, intravenous (IV) magnesium
sulfate, and oxygen. Treatments are typically administered concurrently to facilitate rapid
improvement.
β2-Agonists
1- SABAs (eg, albuterol) are the treatment of first choice for managing acute severe
asthma. A SABA is also indicated for as needed treatment of intermittent episodes of
bronchospasm (e.g., exercise induced bronchospasm).
2-Aerosol administration enhances bronchoselectivity and provides more rapid response
than systemic administration.
3-Two long-acting β2-agonists (LABAs), formoterol and salmeterol, provide
bronchodilation for 12 hours or longer and are dosed twice daily. When combined with
an ICS, formoterol may be dosed on a daily and as needed basis (thus, more frequently
than twice daily).
Corticosteroids
1-ICS are the preferred long-term control therapy for persistent asthma because of
potency and consistent effectiveness; they are the only therapy shown to reduce risk of
dying from asthma.
2-Response to ICS is delayed.
3-Systemic toxicity of ICS is minimal with low-to-moderate doses, but risk of systemic
effects increases with high doses (e.g., growth suppression in children, osteoporosis,
cataracts, dermal thinning, adrenal insufficiency).
4-Local adverse effects include dose-dependent oropharyngeal candidiasis and dysphonia,
which can be reduced by using a spacer device.
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5-Systemic corticosteroids are indicated in all patients with acute severe asthma not
responding completely to initial inhaled β2-agonist administration and should be
administered within 1 hour of presentation.
6-IV therapy offers no advantage over oral administration except in patients unable to
take oral medications.
Anticholinergics
1-Anticholinergics reverse cholinergic mediated bronchoconstriction and are effective
bronchodilators in asthma.
2-Ipratropium bromide is useful as adjunctive therapy in acute severe asthma not
completely responsive to SABA alone.
3-Patients with persistent asthma who are intolerant to short acting β2agonists may be
prescribed ipratropium for rescue inhaler use.
4-Tiotropium bromide is a long acting inhaled anticholinergics with a duration of 24
hours. Tiotropium may be considered an add on therapy in patients whose asthma is not
well controlled with ICS and LABA combination therapy.
Leukotriene Modifiers
1-Zafirlukast and montelukast are oral leukotriene receptor antagonists (LTRA) that
reduce the proinflammatory and bronchoconstriction effects of leukotriene D4.
2-They are less effective than ICS, and they are less effective than LABAs when added
to ICS. They are not used to treat acute exacerbations and must be taken on a regular basis,
even during symptom-free periods.
3-Use of montelukast and zafirlukast has fallen out of favor due to increased
observance of unusual adverse effects and modest therapeutic efficacy.
4-Because of reports of adverse neuropsychiatric events especially within a few weeks of
starting therapy, monitor patients for signs of irritability, aggressiveness, and sleep
disturbances; suicidality has also been reported rarely.
5-There have been reports of fatal hepatic failure associated with zafirlukast.
6-Zileuton is a 5-lipoxygenase inhibitor; its use is limited due to potential for elevated
hepatic enzymes and inhibition of metabolism of drugs metabolized by CYP3A4 (eg,
theophylline, warfarin).
Biologic Agents
1-These agents target the IgE pathway (Omalizumab) or (IL-4, IL-13) (Dupilumab),
and IL-5 pathways (Mepolizumab, Benralizumab and reslizumab).
A-Omalizumab is approved for treatment of allergic asthma.
B-Mepolizumab, Benralizumab, Dupilumab and reslizumab are indicated for
patients with an “eosinophilic phenotype”.

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Magnesium Sulfate
1-Magnesium sulfate is a moderately potent bronchodilator, producing relaxation of
smooth muscle by blocking calcium ion influx into smooth muscles; it may also have anti-
inflammatory effects.
2-For patients with severe asthma exacerbations, a single 2 g IV infusion may reduce
hospital admissions
3-Adverse effects include hypotension, facial flushing, sweating, depressed deep tendon
reflexes, hypothermia, and CNS and respiratory depression.
Methylxanthines
1-Methylxanthines are rarely used today because of the high risk of severe life-threatening
toxicity, numerous drug interactions, and decreased efficacy compared with ICS, LABAs,
and biologics.
2-Theophylline is available for oral and IV administration. Theophylline dosing requires
monitoring of serum concentrations for both efficacy and toxicity, including seizures and
death.
3-In addition, theophylline is eliminated primarily by metabolism via the hepatic CYP P450
microsomal enzymes, and drug interactions affecting metabolism significantly affect
blood concentrations.
Evaluation of therapeutic outcomes
1-All patients on inhaled drugs should have their inhalation technique evaluated monthly
initially and then every 3–6 months.
2-After initiation of anti-inflammatory therapy or increase in dosage, most patients should
experience decreased symptoms within 1–2 weeks and achieve maximum
improvement within 4–8 weeks.

Reference
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.
2-GINA guideline. 2023.

76
 Further reading

Table 1: Initial asthma-treatment recommended options for adults and adolescents (2).

77
 College of Pharmacy
Fourth year. Clinical Pharmacy
Respiratory disorders
Chronic Obstructive Pulmonary Disease
Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition
characterized by chronic respiratory symptoms (dyspnea, cough, sputum production
and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or
alveoli (emphysema) that cause persistent, often progressive, airflow obstruction (3).
It includes two principal conditions:
A-Chronic bronchitis: Chronic or recurrent excess mucus secretion with cough that
occurs on most days for at least 3 months of the year for at least 2 consecutive years.
B-Emphysema: Abnormal, permanent enlargement of the airspaces distal to the
terminal bronchioles, accompanied by destruction of their walls, without fibrosis.
Pathophysiology
1-The most common cause of COPD is exposure to tobacco smoke.
2-Inhalation of noxious particles and gases activates inflammatory cells to release
inflammatory mediators. Inflammatory cells and mediators lead to widespread
destructive changes in airways resulting in chronic airflow limitation.
3-Chronic hypoxemia and changes in pulmonary vasculature lead to increases in pulmonary
pressures. Sustained elevated pulmonary pressures can lead to right-sided heart failure
(cor pulmonale) characterized by right ventricle hypertrophy in response to increased
pulmonary vascular resistance.
Clinical presentation
1-Initial symptoms include chronic cough and sputum production; patients may
experience cough for several years before dyspnea develops.
2-Dyspnea (described by patients as “increased effort to breathe” or “air hunger”)
(2)
is worse with exercise and progressive over time, with decreased exercise tolerance or
decline in physical activity. Chest tightness or wheezing may be present.
3-When airflow limitation progresses, patients may have shallow breathing, increased
resting respiratory rate, “barrel chest” due to lung hyperinflation, pursed lips during
expiration, use of accessory respiratory muscles, and cyanosis of mucosal membranes.
Diagnosis
1-Diagnosis is based on patient symptoms, history of exposure to risk factors such as
tobacco smoke and occupational substances, and confirmation by pulmonary function
testing, such as spirometry (Spirometry assesses lung volumes and capacities. Forced
vital capacity (FVC) is the total volume of air exhaled after maximal inhalation, and FEV1
is the total volume of air exhaled in 1 second).

78
2-The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines suggest a
four-grade classification of airflow limitation: mild (GOLD 1), moderate (GOLD 2),
severe (GOLD 3), or very severe (GOLD 4).
Treatment
Goals of Treatment: Prevent or slow disease progression, relieve symptoms, improve
exercise tolerance, improve overall health status, prevent and treat exacerbations, prevent
and treat complications, and reduce morbidity and mortality (Further reading 1).
Nonpharmacologic Therapy
1-Smoking cessation is the most important intervention to prevent development and
progression of COPD.
2-Reducing exposure to occupational dust and fumes as well as other environmental
toxins is also important.
3-Pulmonary rehabilitation programs include exercise training, breathing exercises, and
psychosocial support.
4-Administer the influenza vaccine annually during each influenza season. Vaccination
against pneumococcal infection is recommended for all adults with COPD.
5-Some patients with severe COPD required long-term O2 therapy (by nasal cannula).
Pharmacologic Therapy
1-Bronchodilators are the mainstay of drug therapy; classes include short- and long-
acting β2-agonists, short- and long-acting muscarinic antagonists (anticholinergics), and
methylxanthines.
2-Short-acting inhaled bronchodilators relieve symptoms (e.g., dyspnea). Long acting
inhaled bronchodilators relieve symptoms and reduce exacerbation frequency.
Patient assessment and selection of therapy
GOLD guidelines combine symptoms (by questionnaires) and frequency of
exacerbations in the previous 12 months to determine patient risk group and recommend
initial treatment (Figure 1 and 2) (2).

79
 Figure 1. GOLD guidelines: refined assessment of COPD severity and risk (2).

Initial pharmacological management

1-Rescue short-acting bronchodilators should be prescribed to all patients for
immediate symptom relief (3).
2-Group A: All Group A patients
should be offered bronchodilator
treatment based on its effect on
breathlessness. This can be either a
short- or a long-acting
(3)
bronchodilator .
3-Group B: Treatment should be
initiated with a LABA+LAMA
combination.
Figure 2: Initial pharmacological management (3).
4-Group E (“E” for “Exacerbations”):
A-LABA+LAMA is the preferred choice for initial therapy in group E patients.
B-Consider LABA+LAMA+ICS in group E if eosinophil count ≥ 300 cells/μL.
Maintenance therapy
Maintenance therapy adjustments are recommended according to the predominant
treatable trait of dyspnea (Figure 3 left column); or exacerbations (Figure 3 right
column). If both exacerbations and dyspnea need to be targeted, the exacerbation
pathway should be followed (2, 3).

80
 Figure 3: Maintenance therapy of COPD (3).

Dyspnea (patients with persistent dyspnea)

For patients with persistent breathlessness or exercise limitation on bronchodilator
monotherapy, the use of two long acting bronchodilators is recommended (3).
Exacerbations [patients continuing to have exacerbations (with or without persistent
dyspnea)]
1-For patients with persistent exacerbations on bronchodilator monotherapy:
A-Escalation to LABA+LAMA+ICS may be considered if blood eosinophil count ≥
300 cells/μL(3).
B-If blood eosinophil count < 300 cells/μL escalation to LABA+LAMA is
recommended (3).
2-In patients on LABA+LAMA and still have exacerbations, Escalation to
LABA+LAMA+ICS if eosinophil counts ≥ 100 cells/ml may be considered (3).
3-In patients on LABA+LAMA and eosinophil counts < 100 cells/ μL who still have
exacerbations, or patient treated with LABA+LAMA+ICS and still have exacerbations, the
following options may be considered (3):
A-Add roflumilast. This may be considered in patients with an FEV1 < 50%
predicted and chronic bronchitis (3).
B-Add azithromycin (especially in those who are not current smokers) (3).

81
Short-Acting Bronchodilators
1-Either a short- or long-acting bronchodilator is recommended initially for patients
with occasional symptoms (category A).
2-Short acting bronchodilators are also recommended for all patients (categories A–E) as
rescue or as-needed therapy to manage symptoms.
3-Choices among short-acting bronchodilators include short-acting β2-agonists (SABAs)
or short-acting muscarinic antagonists (SAMAs). Both drug classes have a relatively
rapid onset of action, relieve symptoms to a similar degree, and improve exercise
tolerance and lung function.
4-Short-acting bronchodilators do not reduce the frequency or severity of COPD
exacerbations.
5-If a patient does not achieve adequate symptom control with one agent, combining a
SABA with a SAMA is reasonable.
6-The SABA choices include albuterol and levalbuterol. Inhalation is the preferred route
for SABAs, and administration via metered-dose or dry powder inhalers (MDIs, DPIs) is at
least as effective as nebulization therapy and is more convenient and less costly.
7-Inhaled SABAs are generally well tolerated; they can cause sinus tachycardia and
rhythm disturbances rarely in predisposed patients. Skeletal muscle tremors can occur
initially but generally subside as tolerance develops. Older patients may be more sensitive
and experience palpitations, tremors, and “jittery” feelings.
8-Ipratropium bromide is the most commonly prescribed SAMA. Improvements in
pulmonary function are similar to inhaled SABAs, although ipratropium has a slower
onset of action (15–20 minutes vs. 5 minutes for albuterol) and more prolonged effect.
9-Because of its slower onset, ipratropium may be less suitable for as needed use but is
often prescribed in this manner.
10-The most frequent patient complaints are dry mouth, nausea, and occasionally metallic
taste.
Long-Acting Bronchodilators
1-Therapy can be administered as an inhaled long-acting β2-agonist (LABA) or
muscarinic antagonist (LAMA). There is no dose titration for any of these agents; the
starting dose is the effective and recommended dose for all patients.
2-The available LABA formoterol, has an onset of action similar to albuterol (<5 minutes),
whereas salmeterol has a slower onset (15–20 minutes); however, none of these agents
are recommended for acute relief of COPD symptoms.
3-The available LAMA: tiotropium has an onset of action (80 minutes) and is not
recommended for acute relief of symptoms.

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Methylxanthines (Theophylline and aminophylline)
1-Methylxanthines have a limited role in COPD therapy because of the availability of
LABAs and LAMAs as well as significant methylxanthine drug interactions and
interpatient variability in dosage requirements.
2-Theophylline may be considered in patients intolerant of or unable to use inhaled
bronchodilators.
3-Sustained-release theophylline preparations are most appropriate for long-term COPD
management. Caution should be used in switching from one sustained-release
preparation to another because of variability in sustained-release characteristics.
4-Common theophylline side effects include dyspepsia, nausea, vomiting, diarrhea,
headache, dizziness, and tachycardia. Arrhythmias and seizures may occur, especially at
toxic concentrations.
Corticosteroids
1-The clinical benefits of ICS therapy have been observed with combination therapy.
ICS monotherapy is not recommended for patients with COPD.
2-Short-term systemic corticosteroids may also be considered for acute exacerbations.
Chronic systemic corticosteroids should be avoided in COPD because of questionable
benefits and high risk of toxicity.
Roflumilast
1-Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor that relaxes airway smooth
muscle.
2-Roflumilast is recommended for patients with recurrent exacerbations despite treatment
with triple inhalation therapy (LAMA/LABA/ICS) or [dual therapy (LAMA/LABA)
who are not candidates for ICS (eosinophil count <100 cells/ μL)].
3-Because theophylline and roflumilast have similar mechanisms of action, they should
not be used together.
Azithromycin
1-Chronic azithromycin was associated with a lower rate of COPD exacerbation but
also with colonization with macrolide resistant bacteria and hearing deficits.
2-In addition, the azithromycin product labeling includes a precaution about QT
prolongation.
3-Current guidelines recommend to consider adding chronic azithromycin only for
patients with recurrent exacerbations despite optimal therapy (especially in those who
are not current smokers) (3).
COPD exacerbations
1-A COPD exacerbation is defined as a change in the patient’s baseline symptoms
(dyspnea, cough, or sputum production) (worsening dyspnea, increased sputum volume,
or increased sputum purulence) sufficient to warrant a change in management.
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2- Classification (2):
A. Mild: SA bronchodilators only
B. Moderate: SA bronchodilators plus antibiotics and/or oral corticosteroids
C. Severe: hospitalization or emergency department (ED) visits
3-Goals of Treatment: (1) Minimize the negative consequences of the acute exacerbation
(i.e., reduce symptoms, prevent hospitalization, shorten hospital stay, prevent acute
respiratory failure or death) and (2) prevent future exacerbations.
Nonpharmacologic therapy
1-Provide oxygen therapy for patients with significant hypoxemia.
2-Noninvasive positive-pressure ventilation (NPPV) provides ventilatory support with
oxygen using a face or nasal mask without endotracheal intubation.
3-Intubation and mechanical ventilation may be needed in patients failing NPPV or who
are poor candidates for NPPV.
Pharmacologic Therapy
The three classes of medications most commonly used for COPD exacerbations are
bronchodilators, corticosteroids, and antibiotics (3).
A-Bronchodilators
1-It is recommended that inhaled SABAs are the initial bronchodilators for acute treatment
of a COPD exacerbation (3). SABAs are preferred because of rapid onset of action.
Muscarinic antagonists may be added if symptoms persist despite increased doses of β2-
agonists.
2-Bronchodilators may be administered via MDI, DPI, or nebulization with equal efficacy.
Nebulization may be considered for patients with severe dyspnea who are unable to hold
their breath after actuation of an MDI.
3-Methylxanthines are not recommended due to increased side effect profiles. [I.V
methylxanthines (theophylline or aminophylline) are not recommended due to
significant side effects] (3).
B-Corticosteroids
Although the optimal corticosteroid dose and duration are unknown, prednisone 40 mg
orally daily (or equivalent) for 5 days is effective for many patients.
C-Antimicrobial Therapy
1-In order to limit unnecessary use, antibiotics should be initiated in any of these clinical
situations:
(1) patients presenting with three cardinal symptoms of acute exacerbation
(worsening dyspnea, increased sputum volume, or increased sputum purulence).
(2) patients presenting with two cardinal symptoms as long as one is increased
sputum purulence.
(3) patients requiring mechanical ventilation regardless of symptoms.

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2-The most common pathogens in COPD exacerbations are Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis (2).
3-The choice of the antibiotic should be based on the local bacterial resistance pattern.
Usually, initial empirical treatment is an aminopenicillin with clavulanic acid, macrolide,
tetracycline or, in selected patients, quinolone (3).
3-Continue antimicrobial therapy for at least 5–7 days. If the patient deteriorates or does
not improve as anticipated, hospitalization may be necessary, and more aggressive attempts
should be made to identify potential pathogens responsible for the exacerbation.
Evaluation of therapeutic outcomes
1-In chronic stable COPD, assess pulmonary function tests annually and with any
treatment additions or discontinuations.
2-In acute exacerbations of COPD, assess white blood cell count, vital signs, chest x-ray,
and changes in frequency of dyspnea, sputum volume, and sputum purulence at the onset
and throughout treatment of the exacerbation.
3-In more severe exacerbations, ABG and SaO2 should also be monitored.
Reference
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.
2-ACCP 2023
3-Global Initiative for Chronic Obstructive Lung Disease. GLOBAL STRATEGY
FOR PREVENTION, DIAGNOSIS AND MANAGEMENT OF COPD: 2023 Report.
Global Initiative for Chronic Obstructive Lung Disease - GOLD. 2023.

Further reading

Pharmacological and non-pharmacological therapies with evidence of efficacy in reducing

the mortality of COPD patients include [Triple combinations (LABA+LAMA+ICS),
Smoking cessation, Pulmonary rehabilitation, Long term oxygen therapy, Non-invasive
positive pressure ventilation, Lung transplantation and lung volume reduction surgery] (3).

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 College of Pharmacy
Fourth year. Clinical Pharmacy
Gastrointestinal disorders
Peptic Ulcer Disease
Introduction
1-Peptic ulcer disease (PUD) refers to ulcerative disorders of the upper gastrointestinal
(GI) tract that require acid and pepsin for their formation.
2-The three common etiologies include (1) Helicobacter pylori infection, (2) nonsteroidal
anti-inflammatory drug (NSAID) use, and (3) stress-related mucosal damage (SRMD).
Pathophysiology
1-Most duodenal ulcers occur in the first part of the duodenum (duodenal bulb).
2-Pathophysiology is determined by the balance between aggressive factors (gastric acid
and pepsin) and protective factors (Mucus and bicarbonate secretion, mucosal blood flow
normally).
3-Increased acid secretion may be involved in duodenal ulcers, but patients with gastric
ulcers usually have normal or reduced acid secretion (hypochlorhydria).
4-Nonselective NSAIDs (including aspirin) cause gastric mucosal damage by two
mechanisms: (1) direct or topical irritation of the gastric epithelium, and (2) systemic
inhibition of endogenous mucosal PG synthesis (the primary mechanism).
5-COX-2 selective inhibitors have a lower risk of ulcers and related GI complications than
nonselective NSAIDs. Addition of aspirin to a selective COX-2 inhibitor reduces its
ulcer-sparing benefit and increases ulcer risk.
6-Use of corticosteroids alone does not increase risk of ulcer or complications, but ulcer
risk is doubled in corticosteroid users taking NSAIDs concurrently.
7-Cigarette smoking has been linked to PUD, impaired ulcer healing, and ulcer recurrence.
Risk is proportional to amount smoked per day.
8-Psychological stress has not been shown to cause PUD, but ulcer patients may be
adversely affected by stressful life events.
9-Carbonated beverages, coffee, tea, beer, milk, and spices may cause dyspepsia but
do not appear to increase PUD risk. Ethanol ingestion in high concentrations is associated
with acute gastric mucosal damage and upper GI bleeding but is not clearly the cause of
ulcers.
Clinical presentation
1-Abdominal pain is the most frequent PUD symptom. Pain is often epigastric and
described as burning but can present as vague discomfort, abdominal fullness, or cramping.
2-Nocturnal pain may awaken patients from sleep, especially between 12 AM and 3 AM.

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3-Pain from duodenal ulcers often occurs 1–3 hours after meals and is usually relieved
by food, whereas food may precipitate or accentuate ulcer pain in gastric ulcers.
Antacids provide rapid pain relief in most ulcer patients.
4-Presence or absence of epigastric pain does not define an ulcer, and ulcer healing does
not necessarily render the patient asymptomatic. Conversely, absence of pain does not
preclude an ulcer diagnosis, especially in older persons, who may present with a “silent”
ulcer complication.
5-Ulcer complications include upper GI bleeding, perforation into the peritoneal cavity,
penetration into an adjacent structure (eg, pancreas, biliary tract, or liver), and gastric
outlet obstruction.
6-Bleeding may be occult or present as melena or hematemesis. Perforation is
associated with sudden, sharp, severe pain.
7-Symptoms of gastric outlet obstruction typically occur over several months and
include early satiety, bloating, anorexia, nausea, vomiting, and weight loss.
Diagnosis
1-Routine blood tests are not helpful in establishing a diagnosis of PUD. Hematocrit,
hemoglobin, and stool guaiac tests are used to detect bleeding.
2-Diagnosis of PUD depends on visualizing the ulcer crater; upper GI endoscopy has
replaced radiography as the procedure of choice because it provides a more accurate
diagnosis and permits direct visualization of the ulcer.
3-Diagnosis of H. pylori infection can be made using endoscopic or nonendoscopic (urea
breath test [UBT], serologic antibody detection, and fecal antigen) tests.
4-Endoscopic biopsy-based tests, UBT, and fecal antigen tests are the recommended
tests to verify H. pylori eradication but must be delayed until at least 4 weeks after
completion of antibiotic treatment and after proton pump inhibitor (PPI) therapy has
been discontinued for 2 weeks to avoid confusing bacterial suppression with
eradication.
Treatment
1-Goals of Treatment: Overall goals are to relieve ulcer pain, heal the ulcer, prevent ulcer
recurrence, and reduce ulcer-related complications.
2-In H. pylori-positive patients with an ulcer, goals are to eradicate H. pylori, heal the
ulcer, and cure the disease with a cost-effective drug regimen.
3-The primary goal for a patient with an NSAID-induced ulcer is to heal the ulcer as
rapidly as possible.
Nonpharmacologic Therapy
1-Lifestyle modifications including stress reduction and smoking cessation should be
implemented. NSAIDs should be avoided if possible, and alternative agents such as
acetaminophen should be used for pain relief when feasible.

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2-There is no specific recommended diet, but patients should avoid foods and beverages
that cause dyspepsia or exacerbate ulcer symptoms (e.g., spicy foods, caffeine, and alcohol).
3-Emergent surgery may be required for patients with ulcer related complications (e.g.,
bleeding, perforation, or obstruction).

Pharmacologic Therapy
1-Treatment of H. pylori infection should be effective, well tolerated, convenient, and
cost-effective. Drug regimens to eradicate H. pylori are shown in Table 1.
2-Clarithromycin triple therapy (PPI, clarithromycin, amoxicillin) is no longer
recommended in areas where H. pylori resistance exceeds 15%. This regimen given for
14 days remains an option in regions where clarithromycin resistance is <15% and no prior
macrolide exposure is documented.
3-Bismuth quadruple therapy (PPI or H2RA, bismuth subsalicylate, metronidazole,
tetracycline) for 10–14 days is the preferred first-line therapy to eradicate H. pylori
infection. PPIs generally produce higher H. pylori eradication rates and are preferred over
H2RA. All medications except the PPI should be taken with meals and at bedtime. The
PPI should be taken 30–60 minutes before a meal. The mean eradication rate for a 10-day
course is ∼90%, but limitations include the need for four-times-daily therapy (which can
impair adherence), and frequent minor side effects.
4-Non-bismuth quadruple (or “concomitant”) therapy (PPI, clarithromycin, amoxicillin,
metronidazole) for 10–14 days is another recommended first-line therapy. “Concomitant”
therapy means that all four drugs are given at the same time twice daily for the entire
duration of therapy.

5-Sequential therapy involves a PPI plus antibiotics given in sequence rather than
together. The rationale is to treat initially with antibiotics that rarely promote resistance
(eg, amoxicillin) to reduce bacterial load and preexisting resistant organisms and then to
follow with different antibiotics (eg, clarithromycin and metronidazole) to kill any
remaining organisms.
6-Hybrid therapy combines the strategies of concomitant and sequential therapy; it
involves 7 days of dual therapy (PPI and amoxicillin) followed by 7 days of quadruple
therapy (PPI, amoxicillin, clarithromycin, metronidazole).
7-Levofloxacin-based regimens include (1) triple therapy with amoxicillin and a PPI, (2)
modified sequential therapy with 5–7 days of amoxicillin plus a PPI followed by 5–7 days
of levofloxacin, and (3) quadruple therapy with levofloxacin, omeprazole or another PPI,
nitazoxanide (Alinia), and doxycycline (“LOAD” therapy).

8-The LOAD regimen is not currently recommended due to high cost and lack of
efficacy data. In addition, concerns with fluoroquinolone use include development of
resistance and adverse effects (eg, tendonitis, hepatotoxicity).

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 Table 1:Drug Regimens Used to Eradicate Helicobacter pylori

aAlthough treatment is minimally effective if used for 7 days, 10−14 days is recommended. The
antisecretory drug may be continued beyond antimicrobial treatment for patients with a history of a
complicated ulcer, for example, bleeding, or in heavy smokers.
bStandard PPI peptic ulcer healing dosages given once or twice daily.
cStandard H2RA peptic ulcer healing dosages may be used in place of a PPI.
dBismuth subcitrate potassium (biskalcitrate) 140 mg, as the bismuth salt, is contained in a prepackaged
capsule (Pylera), along with metronidazole 125 mg and tetracycline 125 mg; three capsules are taken with
each meal and at bedtime; a standard PPI dosage is added to the regimen and taken twice daily. All
medications are taken for 10 days.
e Requires validation as first-line therapy in the United States.
H2RA, H2>-receptor antagonist; PPI, proton pump inhibitor.

9-If initial treatment fails to eradicate H. pylori, second-line (salvage) treatment

should: (1) use antibiotics that were NOT included in the initial regimen, (2) be
guided by region-specific or individual antibiotic resistance testing, and (3) use an
extended treatment duration of 10–14 days.
10-Patients failing clarithromycin triple therapy can be treated with either bismuth
quadruple therapy or the levofloxacin triple regimen for 14 days.
11-Other salvage regimens may also be successful. Penicillin allergy testing is
recommended for patients who report penicillin allergy because many patients are not
truly allergic.
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12-Patients with NSAID-induced ulcers should be tested to determine H. pylori status. If
they are H. pylori positive, start treatment with a recommended first-line regimen. If
patients are H. pylori negative, discontinue the NSAID and treat with a PPI, H2RA, or
sucralfate. PPIs are generally preferred due to more rapid symptom relief and ulcer
healing.
13-If the NSAID must be continued, implement cotherapy with a PPI or misoprostol.
Patients at highest risk of recurrent ulcers or ulcer-related complications should be switched
to a COX-2 inhibitor.
14-Limit maintenance therapy with a PPI or H2RA to high-risk patients with ulcer
complications, patients who fail H. pylori eradication, and those with H. pylori-negative
ulcers.
15-Patients with ulcers refractory to treatment should undergo upper endoscopy to
confirm a nonhealing ulcer, exclude malignancy, and assess H. pylori status.
H. pylori-positive patients should receive eradication therapy. Refractory ulcers despite a
complete standard PPI course should be retreated with double-dose of PPI, or
consideration can be given to using a different PPI.
Evaluation of therapeutic outcomes
1-Monitor patients for symptomatic relief of ulcer pain, potential adverse drug effects,
and drug interactions.
2-Ulcer pain typically resolves in a few days when NSAIDs are discontinued and
within 7 days upon initiation of antiulcer therapy. Patients with uncomplicated PUD are
usually symptom free after treatment with any of the recommended antiulcer regimens.
3-Persistent or recurrent symptoms within 14 days after the end of treatment suggests
failure of ulcer healing or H. pylori eradication or presence of an alternative diagnosis
such as gastroesophageal reflux disease.
4-Eradication of H. pylori should be confirmed after treatment in all patients, particularly
those who are at risk for complications.

Reference: Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic

Approach, 12th Edition. 2023.

90
 College of Pharmacy
Fourth year. Clinical Pharmacy
Endocrine disorders:
Diabetes Mellitus Part I
Introduction
1-Diabetes mellitus (DM) is a group of metabolic disorders characterized by
chronically elevated blood glucose (BG) and abnormal carbohydrate, fat, and protein
metabolism.
2-Without effective treatment, DM can lead to acute complications such as diabetic
ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS).
3-Chronic hyperglycemia can cause microvascular, macrovascular, and neuropathic
complications.
Pathophysiology
1-Type 1 DM (5%–10% of cases) usually results from autoimmune destruction of
pancreatic β-cells (islet cell antibody), leading to absolute deficiency of insulin.
2-It usually presents in children and adolescents but can occur at any age.
3-Type 2 DM (90%–95% of cases) is characterized by multiple defects:
 Impaired insulin secretion:
 Reduced incretin effect: Normally, the gut incretin hormones glucagon-like peptide-
1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and
stimulate insulin secretion in response to a meal. Patients with type 2 DM have a
reduced incretin effect.
 Insulin resistance: This is manifested by excessive hepatic glucose production,
decreased skeletal muscle uptake of glucose, and increased lipolysis and free fatty
acid production.
 Excess glucagon secretion.
 Sodium-glucose cotransporter-2 (SGLT-2) upregulation in the kidney: This
increases reabsorption of glucose, which further contributes to hyperglycemia.
4-Gestational diabetes (GDM) is DM that occurs in women during pregnancy.
5-Microvascular complications include retinopathy, neuropathy, and nephropathy.
6-Macrovascular complications include coronary heart disease (CHD), stroke, and
peripheral vascular disease.
Clinical presentation
Type 1 Diabetes Mellitus
1-Patients often have symptoms in the days or weeks preceding the diagnosis. The most
common initial symptoms are polyuria, polydipsia, polyphagia, weight loss, fatigue, and
lethargy.

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2-Individuals are often thin and are prone to develop DKA in the absence of an adequate
insulin supply; many patients initially present with DKA.
3-Symptom onset can be triggered by infection, trauma, or psychological stress.
Type 2 Diabetes Mellitus
1-Most patients are asymptomatic or have only mild fatigue at the time of diagnosis.
Many patients are incidentally found to have type 2 DM after routine laboratory testing
(eg, plasma glucose or A1C) or development of complications (eg, myocardial infarction,
stroke).
2-Because mild hyperglycemia may exist for years prior to the diagnosis, microvascular
and macrovascular complications are often present at the time of diagnosis.
3-Most patients are overweight or obese.
Diagnosis
1-Criteria for diagnosis of DM include any one of the following:
1. A1C ≥6.5% 2. Fasting (no caloric intake for at least 8 hours) plasma glucose (FPG)
≥126 mg/dL 3. Oral glucose tolerance test (OGTT) ≥200 mg/dL 4. Random plasma
glucose ≥200 mg/dL with classic symptoms of hyperglycemia or hyperglycemic crisis.
2-Prediabetes is a condition of abnormal BG that is not sufficiently high to meet the
thresholds that define DM but often progresses to the diagnosis.
3-Screening for type 1 DM in asymptomatic children or adults is not recommended
due to low disease prevalence and the acute onset of symptoms.
4-Screening for type 2 DM is recommended for asymptomatic adults who are
overweight (BMI ≥25 kg/m2) and have at least one other risk factor for developing type
2 DM.

5-All adults, even those without risk factors, should be screened every 3 years starting
at 45 years old. Children at risk for developing type 2 DM should undergo screening every
3 years starting at age 10 years.
Treatment
1-Goals of Treatment: The primary goal is to prevent or delay progression of long-term
microvascular and macrovascular complications.
2-Additional goals are to alleviate symptoms of hyperglycemia, minimize hypoglycemia
and other adverse effects.
3-General glycemic targets for most nonpregnant adults with DM are listed in Table-1.
Table-1: Glycemic Target Recommendations for Most Nonpregnant Adults with
Diabetes

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4-Glycemic targets should be individualized. More stringent or less stringent goals may be
appropriate for some patients.
Nonpharmacologic Therapy
1-Medical nutrition therapy (MNT): Implement a healthy meal plan that is moderate in
calories and carbohydrates and low in saturated fat with all of the essential vitamins and
minerals. Target an initial weight loss goal of at least 5% in all type 2 DM patients who are
overweight or obese through calorie restriction.
2-Aerobic exercise: Physical activity goals include at least 150 min/week of moderate
intensity exercise spread over at least 3 days/week with no more than 2 days between
activity. Resistance/strength training is recommended at least 2 times/week for patients
without proliferative diabetic retinopathy.
3-Patients must be involved in decision making and have strong knowledge of the
disease and associated complications.
Pharmacologic Therapy
Insulin
1-The main advantage of insulin over other antihyperglycemic agents is that the dose can
be individualized based on glycemic levels.
2-Disadvantages include the risk of hypoglycemia, need for injections, and weight gain.
3-Most insulin products are administered subcutaneously (SC) for chronic diabetes
management, except for inhaled human insulin, which is a dry powder of regular insulin
that is inhaled and absorbed through pulmonary tissue.
4-The pharmacokinetics of insulin products is characterized by their onset, peak, and
duration of action (Table-2).

5-Basal insulin (or background insulin) refers to longer-acting insulins that regulate BG
levels in between meals. Options include the following insulins:
 NPH is the least ideal product because it has a distinct peak and usually requires
twice daily dosing.
 Detemir also has a peak and often lasts <24 hours; it can be given once daily in
some patients but should be dosed twice daily at low doses.
 Glargine and degludec are longer acting-agents that have no peak and are given
once daily.

6-The longer-acting products have a lower risk of hypoglycemia (particularly nocturnal

hypoglycemia). However, they are more expensive.
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7-Bolus insulin refers to short- or rapid-acting insulins that cover meals (also called
prandial insulin) or glycemic excursions (also called correction insulin).

8-Basal insulin is the preferred and most convenient initial insulin formulation for
patients with type 2 DM, whereas patients with type 1 DM require a combination of
basal and bolus insulin to achieve adequate glycemic control.
Table-2: Pharmacokinetics of Select Insulins Administered Subcutaneously

9-Bolus insulin options include:

 Aspart, lispro, and glulisine, the rapid-onset, short-duration insulins

94
  Inhaled human insulin, fast-acting insulin aspart (Fiasp®), and insulin lispro
(Lyumjev®): the ultrarapid onset insulins
10-Rapid-acting insulins offer a faster onset and shorter duration of action than regular
insulin, and ultra-rapid acting insulins offer an even faster onset; this may more closely
mimic prandial endogenous insulin release.

11-Rapid-acting insulins have a modestly lower risk of hypoglycemia than regular insulin.
12-Various premixed insulin products containing both a basal and a prandial component
are also available (Table-2). However, these products are limited by fixed mixed
formulations, which can make it challenging to tailor the dosing regimen.
13-The insulin dose must be individualized. In type 1 DM, the average daily
requirement is 0.5–0.6 units/kg, with approximately 50% given as basal insulin and the
remaining 50% dedicated to meal coverage.
14-Hypoglycemia is the most common adverse effects of insulin therapy. Insulin also
causes dose-dependent weight gain.
15-SC administration can result in lipoatrophy or lipohypertrophy, which can be
prevented by routinely rotating injection sites.
Biguanides
1-Metformin decreases hepatic glucose production and enhances insulin sensitivity in
peripheral (muscle) tissues, allowing for increased glucose uptake into muscle cells.
2-Metformin is recommended as first-line pharmacotherapy in patients with type 2 DM
(unless a contraindication or intolerability exists).
3-It does not cause weight gain and may lead to a modest (2–3 kg) weight loss.
4-It has a low risk of hypoglycemia because it does not directly increase pancreatic insulin
secretion.
5-Metformin decreases plasma triglycerides and low-density lipoprotein cholesterol
(LDL-C) and modestly increases high-density lipoprotein cholesterol (HDL-C).
6-Metformin frequently causes GI side effects (diarrhea, abdominal discomfort, stomach
upset); these effects are usually dose-dependent, transient, mild, and can be minimized
with slow dose titration and taking metformin with or immediately after meals.
7-Extended-release metformin may lessen some of the GI side effects.
8-Metformin may cause a metallic taste and may lower vitamin B12 concentrations;
B12 levels or methylmalonic acid should be measured annually or if a deficiency is
suspected, with vitamin B12 supplementation given if indicated.
9-Lactic acidosis occurs rarely, usually in the setting of severe illness or acute kidney
injury. Because symptoms are often nonspecific, the diagnosis must be confirmed by
laboratory measurement of high lactic acid levels and acidosis.

95
10-Metformin is renally excreted and accumulates in renal insufficiency; Due to the risk of
acute renal failure with use of IV contrast dye, withhold metformin therapy starting
the day of the procedure and resume it 2–3 days later if normal renal function has been
documented.
11-Metformin can be used in combination with any other antihyperglycemic therapy
and is often continued when insulin therapy is initiated.

Sodium-Glucose Cotransporter-2 Inhibitors

1-Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin reduce plasma glucose by
preventing the kidneys from reabsorbing glucose back into the bloodstream, leading to
increased glucose excretion in the urine.
2-SGLT-2 inhibitors lower both FPG and postprandial glucose (PPG).
3-SGLT-2 inhibitors can be added to metformin or other second-line agents. They can be
used as monotherapy in patients who cannot tolerate or take metformin ..
4-They are recommended for patients at high risk for or with established ASCVD, heart
failure, or CKD.
5-They are unlikely to cause hypoglycemia unless combined with medications such as
sulfonylureas, meglitinides, or insulin.
6-The most common adverse effect is genital mycotic infections, which are more
common in women and uncircumcised men. There is also a slightly increased risk of
urinary tract infections. Polyuria, dehydration, dizziness, or hypotension may occur
because of the osmotic diuresis effects.
Glucagon-like Peptide 1 Receptor Agonists (GLP1-RAs)
1-Dulaglutide, exenatide, exenatide XR, lixisenatide, liraglutide, and semaglutide stimulate
insulin secretion and suppress inappropriately high postprandial glucagon secretion,
decreasing hepatic glucose output. They also slow gastric emptying, increase satiety, and
cause weight loss (average 1–3 kg).
2-Short-acting agents (exenatide, lixisenatide) predominantly lower PPG levels, whereas
long-acting agents (dulaglutide, liraglutide, exenatide XR, semaglutide) lower both FPG
and PPG, but with larger effects on FPG.
3-Dulaglutide, liraglutide, and semaglutide are FDA approved to reduce the risk of major
adverse CV events in adults with type 2 DM and established ASCVD
4-GLP1RAs can be used as monotherapy in patients who cannot tolerate or take first line
therapy. Six GLP1RAs are administered SC. Semaglutide is available as SC and oral
preparations.
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
1-Alogliptin, linagliptin, saxagliptin, and sitagliptin prolong the half-life of endogenously
produced GLP-1 and GIP, thereby increasing glucose-dependent insulin secretion from the
96
pancreas and reducing inappropriate postprandial glucagon secretion, resulting in lower
glucose levels without an increase in hypoglycemia when used as monotherapy.
2-They do not alter gastric emptying, or cause weight gain/loss.
3-DPP-4 inhibitors are considered second- or third-line therapy.
4-Advantages include once-daily dosing, oral administration, weight neutrality, low risk
of hypoglycemia, and good tolerability.

Thiazolidinediones (TZDs)
1-TZDs bind to the peroxisome proliferator activator receptor-γ (PPAR-γ) located primarily
on fat and vascular cells, enhancing insulin sensitivity in muscle, liver, and fat tissues.
2-Maximum effects may not be seen until 3–4 months of therapy.
3-TZDs are considered second- or third-line agents and can be used in combination with
metformin and other commonly prescribed medications for type 2 DM.
4-Fluid retention may occur. This may result in peripheral edema, HF, hemodilution of
hemoglobin and hematocrit, and weight gain.
5-TZDs are contraindicated in patients with New York Heart Association Class III or
IV HF and should be used with caution in patients with Class I or II HF.
6-Weight gain is dose related and results from both fluid retention and fat accumulation.
Sulfonylureas (e.g. glyburide, glipizide, and glimepiride)
1-Sulfonylureas enhance insulin secretion by binding to the sulfonylurea receptor SUR1 on
pancreatic β-cells.
2-Sulfonylureas are widely used because they have an extensive record of safety and
effectiveness, are given orally, and are inexpensive. However, current treatment
guidelines either discourage their use or suggest caution due to the risk of
hypoglycemia and weight gain. In addition, tachyphylaxis to the insulin secretion effect
occurs, leading to poor long-term durability of response in most patients.
3-The most common side effect is hypoglycemia.
4-Weight gain is common (typically 1–2 kg). Patients with sulfa allergy rarely
experience crossreactivity with sulfonylureas.

Reference
Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach,
12th Edition. 2023.

97
 College of Pharmacy
Fourth year. Clinical Pharmacy
Endocrine disorders
Diabetes Mellitus Part II
α-Glucosidase Inhibitors
1-Acarbose and miglitol delay the breakdown of sucrose and complex carbohydrates in
the small intestine, prolonging carbohydrate absorption.
2-Good candidates for these drugs are patients who are near target A1C levels with near-
normal FPG but high PPG levels.
3-The most common side effects are flatulence, abdominal pain, and diarrhea, which
can be reduced by slow dosage titration.
Meglitinides
1-Nateglinide and repaglinide stimulate insulin secretion from pancreatic β-cells by
binding to a site adjacent to the sulfonylurea receptor.
2-They are similar to sulfonylureas except that they have a faster onset and shorter
duration of action.
3-Similar to sulfonylureas, the main side effects are hypoglycemia and weight gain.
4-They may be a good option for patients with erratic meal schedules. However, multiple
daily dosing may decrease adherence.
5-Meglitinides should be taken by mouth with each meal.
Bile Acid Sequestrants
Colesevelam. Its mechanism in lowering plasma glucose levels is unknown, and its role in
therapy is unclear.
Dopamine Agonists
1-Bromocriptine mesylate is FDA approved for treatment of type 2 DM. The mechanisms
by which it improves glycemic control are unknown .
2-Its role in the treatment of type 2 DM is unclear.
Amylin Analogs
1-Pramlintide is a synthetic amylin analog that reduces glucagon secretion, slows gastric
emptying, and increases satiety. It was the first noninsulin agent approved for patients
with type 1 DM.
2-It is used primarily in type 1 DM as adjunctive therapy for patients who are not
achieving PPG goals despite maximizing mealtime insulin doses.
3-It can also decrease weight and may allow for lower mealtime insulin doses.
Treatment of Type 2 Diabetes

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1-Upon diagnosis, set a patient-specific A1C target. Implement comprehensive lifestyle
modifications .
2-Initiate with metformin [or agent(s), including combination therapy, that provide
adequate efficacy to achieve and maintain treatment goals] (Unless there is a comorbidity
in which other agents are preferred). Recommendations based on patient-specific
comorbidities include:
✔High risk or established ASCVD: SGLT2 inhibitor or GLP1RA.
✔Heart Failure (HF): SGLT2 inhibitor. Avoid TZDs in patients with HF.
✔CKD (with or without ASCVD): SGLT2 inhibitor.
3-If the initial A1C is close to goal (eg, ≤7.5%) consider initial treatment with lifestyle
modifications alone if the patient is motivated.
4-Consider starting two medications (e.g. metformin plus a second agent) if the initial
A1C is >1.5% higher than the target A1C.
5-Consider early introduction of basal insulin in patients with very high A1C levels
(>10%), or symptoms of hyperglycemia.
6-See patients at least every 3 months if they are not meeting their goals and at least
every 6 months if they are meeting goals. Add additional therapy if glucose targets have
not been met.
7-Most patients eventually require combination therapy.
8-If the A1C target is not achieved after 3 months of dual therapy or if the patient did not
tolerate the selected drug(s), then triple therapy is warranted, adding a drug from another
class.
9-People with type 2 DM can often be managed with oral medications for years before
injectable medications are needed.
10-Insulin is recommended for extreme (A1C >10%) or symptomatic hyperglycemia.
Otherwise, GLP-1 RAs are preferred over basal insulin because they have equal or
superior A1C lowering efficacy and lead to weight loss instead of weight gain with a low
risk of hypoglycemia.
11-Basal insulin can be initiated if additional glucose lowering is needed after the GLP-1
RA dose has been maximized.
12-If the A1C target is not reached by maximally titrating basal insulin, PPG levels are
likely elevated and a GLP1-RA or SGLT-2 inhibitor should be considered if the patient
is not already taking one.
13-Prandial insulin is also an option. Titrate the dose over time to achieve target PPG
levels <180 mg/dL. A second or third injection can be added to the other meals if needed.
Treatment of Hyperglycemia in Type 1 Diabetes
1-All patients with type 1 DM require exogenous insulin. Achieving adequate glycemic
control usually requires intensive insulin regimens designed to provide insulin in a
manner that mimics normal physiologic insulin secretion, with consistent secretion of
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insulin throughout the day to manage glucose levels overnight and in between meals (ie,
basal insulin), and bursts of insulin in response to glucose rises after ingestion of
carbohydrates (ie, prandial insulin).
2-Intensive insulin regimens can be given with either multiple daily injections (MDI) or
use of continuous subcutaneous insulin infusion (CSII) via an insulin pump.
3-A common MDI approach is one injection of long-acting insulin (eg, insulin glargine)
for the basal component and three injections of rapid acting insulin (eg, insulin lispro) for
the prandial component.
4-A less expensive option consists of two injections of intermediate-acting insulin (eg,
NPH insulin) and two injections of short-acting insulin (eg, regular insulin). However,
the ADA Standards of Care recommend that most patients should use rapid-acting insulins
rather than regular insulin to reduce the risk of hypoglycemia.
5-Insulin pump therapy or CSII infuses rapid-acting insulin to cover both the basal
and prandial insulin needs . The pump infuses a basal rate constantly throughout the day
and allows the patient to give bolus doses using a bolus dose calculator based on current
glucose levels, carbohydrate intake, and insulin on board.
6-The total daily insulin dose is divided to give 50% as basal insulin and 50% as
prandial insulin (distributed across meals). The insulin doses would then be adjusted
based on self-monitoring of blood glucose (SMBG) data. Ideally, patients should learn to
count carbohydrates so they can match their prandial insulin doses to their carbohydrate
intake.
7-Patients should also SMBG before each meal or use continuous glucose monitoring
(CGM) to evaluate the insulin regimen and make treatment decisions. Bolus insulin
doses can be better individualized by using carbohydrate-to-insulin ratios (C:I ratios) and
correction factors (CF).
8-Pramlintide is indicated as adjunctive treatment in patients with type 1 DM who are
not achieving glycemic targets despite optimization of mealtime insulin.
9-Assess patients every 3 months if uncontrolled and every 6 months if controlled.
Patients on intensive insulin therapy should SMBG at least four times daily, before meals
and at bedtime.
10-Patients should also test before exercise, prior to critical tasks such as driving, and
if symptoms of hypoglycemia occur. SMBG is crucial during times of intercurrent illness
or stresses for early detection and prevention of DKA.
11-Current guidelines recommend CGM in patients with type 1 DM who are not
meeting glycemic goals. They are also recommended in patients with hypoglycemia
unawareness to better detect and prevent hypoglycemic events.
Common insulin regimens.
(A) Multiple-component insulin regimen consisting of one injection of long-acting insulin
(detemir, glargine degludec) to provide basal glycemic coverage and three injections of
rapid-acting insulin (aspart, lispro, glulisine) to provide glycemic coverage for each meal.
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(B) Insulin regimen consisting of two injections of intermediate-acting insulin (NPH) and
rapid-acting insulin (aspart, lispro, glulisine), or short-acting regular insulin.
(C) Insulin administration by insulin infusion device. The basal insulin rate is decreased
during the evening and increased slightly prior to the patient awakening in the morning.
Rapid-acting insulin (aspart, lispro, or glulisine) is used in the insulin pump.
Hypoglycemia
1-Hypoglycemia is a common complication of some diabetes medications.
2-The severity of hypoglycemia is classified as follows:
 Level 1 (hypoglycemia alert value; ≤70 mg/dL: May not cause symptoms but should
be treated with a fast-acting carbohydrate and may need medication dose
adjustment.
 Level 2 (clinically significant hypoglycemia; <54 mg/dL: Serious, clinically
important hypoglycemia
 Level 3 (severe hypoglycemia): Associated with cognitive impairment requiring
external assistance for recovery and can be life threatening.
3-Initial autonomic symptoms include tachycardia, palpitations, sweating, tremors, and
hunger. Neuroglycopenic symptoms often occur with BG <60 mg/dL and can include
cognitive impairment, confusion, behavioral changes, anger, irritability, blurred vision,
headaches, seizures, and loss of consciousness.
4-Some patients have hypoglycemia unawareness and are unable to detect the early
warning symptoms of hypoglycemia; they are at increased risk for the serious sequelae
associated with severe hypoglycemia.
5-SMBG and CGM can be useful in preventing hypoglycemia. Patients must be
educated to understand situations that increase risk of hypoglycemia (eg, delaying meals,
during or after exercising, or fasting).
6-Treatment of hypoglycemia requires ingestion of carbohydrates, preferably glucose.
Patients should carry a source of fast-acting glucose with them at all times and use the “rule
of 15” for proper treatment:

 First use SMBG to confirm BG <70 mg/dL and then ingest 15 g of fast-acting
carbohydrates such as 1/2 cup (4 oz or 125 mL) of milk, juice, or soda; 1 tablespoon
of honey; hard candy; jelly beans; or glucose tablets.
 Repeat SMBG in 15 minutes; if the BG is <70 mg/dL, repeat the process.
 Once the BG is normalized, eat a snack or meal that includes complex
carbohydrates and protein to prevent further hypoglycemic episodes.
7-If the patient is unconscious, give IV glucose or glucagon injection. Glucagon increases
glycogenolysis in the liver and may be given in any situation in which IV glucose cannot be
rapidly administered.
8-A glucagon kit should be prescribed and readily available to all patients on insulin
who have a history of or high risk for severe hypoglycemia. It can take 10–15 minutes
before glucose levels start to rise, and patients often vomit.
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9-Position the patient on the side with the head tilted slightly downward to avoid
aspiration.
10-Clinicians should monitor hypoglycemia at every visit.
11-Reevaluate the treatment regimen of patients with frequent or severe hypoglycemia to
minimize future episodes.
Complications and Comorbidities
Macrovascular Complications
1-Macrovascular complications (eg, CHD, stroke) are the leading causes of death in
people with diabetes.
2-The ADA recommends low-dose aspirin therapy (75–162 mg daily) in all patients with
established ASCVD. Clopidogrel may be used in patients allergic to aspirin.
3-The role of antiplatelet therapy for primary CV prevention is unclear because the benefits
may be offset by a higher risk of bleeding; some practice guidelines recommend aspirin
if the 10-year risk of a CV event is >20%.
4-In patients with established ASCVD, use of a GLP1-RA or an SGLT-2 inhibitor
should be strongly considered.

5-For all patients whose BP exceeds 120/80 mm Hg, the ADA recommends dietary
changes, physical activity, and weight loss in overweight or obese patients.
6-Drug therapy using agents proven to reduce CV events should be started for BP >140/90
mm Hg. A combination of two medications should be used for BP >160/100 mm Hg.
7-Initiate high-intensity statin therapy in all patients with diabetes and preexisting ASCVD
regardless of baseline lipid levels. In the absence of ASCVD, prescribe a moderate-
intensity statin to all patients with type 1 or type 2 DM over the age of 40.
8-In patients <40 years of age, a moderate intensity statin may be appropriate for patients
with multiple CV risk factors.
9-A fibrate (e.g., fenofibrate), omega-3 fatty acid, or niacin can be added for patients with
marked hypertriglyceridemia.

10-Peripheral arterial disease can lead to claudication, nonhealing foot ulcers, and limb
amputation. Smoking cessation, statin therapy, good glycemic control, and antiplatelet
therapy are important strategies. Cilostazol may be useful in select patients to reduce
symptoms. Revascularization surgery can be considered in some situations.
Microvascular Complications
Efforts to improve glucose control significantly reduce the risk of developing microvascular
complications and slow their progression.
Nephropathy:
1-Albuminuria is a marker of renal damage. The ADA recommends screening for
albuminuria upon diagnosis and annually thereafter in persons with type 2 DM.
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2-Screening with type 1 DM should begin with puberty and after 5-years’ disease
duration.
3-Glucose and BP control are important for preventing and slowing progression of
nephropathy.
4-The SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin significantly
reduce the decline in kidney function in patients with CKD, with or without diabetes.
5-ACE inhibitors and ARBs can slow the progression of renal disease in patients with
diabetes.
6-Diuretics are often necessary due to volume expanded states and are recommended
second-line therapy.
7-The ADA recommends a BP goal <140/90 mm Hg in patients with nephropathy but a
lower target (e.g., <130/80 mm Hg) if it can be achieved without undue burden or side
effects. Three or more antihypertensives are often needed to reach goal BP.
Retinopathy:
1-Patients with diabetes should have routine eye examinations to fully evaluate the
retina.
2-Early retinopathy may reverse with improved glycemic control and optimal BP
control. More advanced retinopathy will not fully regress with improved glycemia.
3-Laser photocoagulation has markedly improved sight preservation. Intravitreal
antivascular endothelial growth factor (VEGF) therapy is also highly effective for sight
preservation.
4-Bevacizumab (used off-label) and ranibizumab are anti-VEGF monoclonal
antibodies, and aflibercept is a VEGF decoy receptor.
Neuropathy:
 Peripheral neuropathy is the most common complication in patients with type 2
DM. Paresthesias, numbness, or pain are the predominant symptoms. The feet are
involved far more often than the hands. Improved glycemic control is the primary
treatment and may alleviate some symptoms. Pharmacologic therapy is
symptomatic and includes low-dose tricyclic antidepressants (nortriptyline or
desipramine), duloxetine, gabapentin, pregabalin, venlafaxine, topical capsaicin,
and tramadol.
 Gastroparesis. Improved glycemic control and use of metoclopramide or low-dose
erythromycin may be helpful.
 Diabetic diarrhea is often nocturnal and frequently responds to a 10- to 14-day
course of an antibiotic such as doxycycline or metronidazole. Octreotide may be
useful in unresponsive cases.
 Orthostatic hypotension may require mineralocorticoids (eg, fludrocortisone) or
adrenergic agonists (midodrine).
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  Erectile dysfunction is common, and initial therapy should include a trial of an oral
phosphodiesterase-5 inhibitor (eg, sildenafil, vardenafil, or tadalafil).
Evaluation of therapeutic outcomes
1-Measure A1C every 3–6 months to follow long-term glycemic control for the
previous 2–3 months.
2-For patients with type 1 DM, SMBG is typically performed 4–6 times per day—prior
to food intake and physical activity and at bedtime.
3-The optimal frequency of SMBG in patients with type 2 DM on oral agents is
controversial.
4-At each visit, ask patients with type 1 DM about the frequency and severity of
hypoglycemia.
5-Screen for complications (eye exams, assess BP, examine the feet, screen for
albuminuria, check fasting lipid panel)
6-Administer an annual influenza vaccine and assess for administration of the
pneumococcal vaccine and hepatitis B vaccine series along with management of other
CV risk factors (e.g., smoking).
Reference: Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic
Approach, 12th Edition. 2023.

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