CARDIOVASCULAR

SYSTEM DRUGS

SEMUKUNZI HERVE
BPHARM,
MPHARM(SCIENCES OF
PHARMACOLOGY)
I. CARDIOVASCULAR SYTEM
Body

Lungs
Venous system

Artery system
Heart

Kidney
 GENERAL INTRODUCTION
 THE KIDNEY FILTERS AT 180L/DAY,
A. DIURETICS MOST COMPONENTS ARE
REABSORBED
 MOST DIURETICS ACT ON THE
LUMEN SIDE EXCEPT ALDOSTERONE
ANTAGONIST ACTING ON
BASOLATERAL IN THE COLLECTING
TUBULE
 THE KIDNEY CONTAINS ADENOSINE
AND PROSTANGLANDIN RECEPTORS
WHICH MAY ALTER DIURETICS
FUNCTION THROUGH THEIR
AGONISTS AND ANTAGONISTS.
 THE EFFICACY OF MOST DIURETICS IS
INHIBITED BY NSAID,
PROSTAGLANDINS ARE IMPORTANT
IN GLOMERULAR FILTRATION
Lumen Side:
• Location: The inner surface of the kidney tubules and collecting
ducts.
• Function: Active transport of substances from the tubular fluid back
into the bloodstream.
• Structure: Lined with microvilli, specialized finger-like projections that
increase the surface area for transport.

Basolateral Side:
• Location: The outer surface of the kidney tubules and collecting
ducts.
• Function: Exchange of substances between the tubular fluid and the
interstitial space, the space surrounding the tubules.
• Structure: Lined with tight junctions, specialized cell junctions that
prevent leakage of substances between the cells.
Physiology: nephron functions
 Prototypical Diuretics per class
1. CA Inhibitors 4. Potassium sparing
Acetazolamide Aldosterone antagonists
Diclofenamide Spironolactone
Canrenone 5. Osmotics
2. Loop diuretics Mannitol
Furosemide Blockers of channels Na+ Isosorbide
Bumetanide Amiloride Glucose
Acid ethacrynic Triamterene
3. Thiazides
Hydrochlorthiazide Combinations
Chlorothiazide H.chlorthiazide +amiloride
Chlorotalidone Altizide +spironolactone
Bendrofluazide
Metolazone
Indapamide
 1. Inhibitors of carbonic anhydrase
• They act by reducing
bicarbonate reabsorption
in the proximal
convoluted tubule cell.
• Na+/H+ ion exchanger
• Na+/K+ ATPase balances Na
and K balance
• H+ + HCO3- H2CO3
• H2CO3 H2O + CO2
• CA
Use of CAI diuretics

• Edema monotherapy
• Glaucoma
• The reduction of aqueous humor formation by carbonic anhydrase inhibitors
decreases the intraocular pressure. Topically active carbonic anhydrase
inhibitors (dorzolamide, brinzolamide) are also available.
• Urinary Alkalinization
• Uric acid, cystine, and some other weak acids are relatively insoluble in, and
easily reabsorbed from, acidic urine. Renal excretion of these compounds can
be enhanced by increasing urinary pH with carbonic anhydrase inhibitors
• Metabolic Alkalosis
• Acetazolamide has also been used to rapidly correct the metabolic alkalosis
that may develop in the setting of respiratory acidosis.
Use of CAI diuretics

• Acute Mountain Sickness

• Weakness, dizziness, insomnia, headache, and nausea can occur in mountain
travelers who rapidly ascend above 3000 m. The symptoms are usually mild
and last for a few days. In more serious cases, rapidly progressing pulmonary
or cerebral edema can be life-threatening. By decreasing cerebrospinal fluid
formation and by decreasing the pH of the cerebrospinal fluid and brain,
acetazolamide can enhance performance status and diminish symptoms of
mountain sickness.
• Epilepsy
• Carbonic anhydrase inhibitors have been used as adjuvants for the treatment
of epilepsy, in some forms of hypokalemic periodic paralysis, and to increase
urinary phosphate excretion during severe hyperphosphatemia.
2. Loop of Henle Diuretics
• The NaCl transport system in
the luminal membrane of the
thick ascending limb is a
Na+/K+/2Cl cotransporter.
• This transporter is selectively
blocked by diuretic agents
known as "loop" diuretics.
Thus, inhibition of salt
transport in the thick
ascending limb by loop
diuretics causes an increase in
urinary excretion of divalent
cations (Mg++ ; Ca++ )in
addition to NaCl.
3. Thiazide Diuretics

• Only about 10% of the filtered

NaCl is reabsorbed in the distal
convoluted tubule. Like the
thick ascending limb, this
segment is relatively
impermeable to water, and the
NaCl reabsorption therefore
further dilutes the tubular
fluid.
• The mechanism of NaCl
transport in the distal
convoluted tubule is electrically
neutral: Na+ and Cl-
cotransport.
• This NaCl transporter is blocked
by diuretics of the thiazide
class.
Uses of loop & thiazide diuretics

Loop diuretics Trade name Indications

Furosemide Lasix® Acute pulmonary, cardiac,
Bumetanide Burinex® hepatic or renal edema ;
Acid ethacrynic Edecrin® Rebel hypertension ;
Forced diuresis (in
intoxications).
Thiazides
Hydrochlorthiazide Esidrex® Hypertension;
Chlorothiazide Diuril® Edema associated with
Chlorotalidone Hygroton® congestive heart failure, chronic
Bendrofluazide Naturine-Leo® hepatic and renal diseases;
Metolazone Zaroxolyne® Calcic lithiases)
Indapamide Fludex 2.5 mg
4. Potassium sparing diuretics
• The aldosterone receptor and the sodium channels
are sites of action of the potassium-sparing diuretics
• The collecting tubule is responsible for only 2–5% of
NaCl reabsorption by the kidney.
• As the final site of NaCl reabsorption, the collecting
tubule is responsible for volume regulation and for
determining the final Na+ concentration of the urine.
Furthermore, the collecting tubule is a site at which
mineralocorticoids exert a significant influence.
• Lastly, the collecting tubule is the major site of
potassium secretion by the kidney and the site at
which virtually all diuretic-induced changes in
potassium balance occur.
• Inward diffusion of Na+ leaves a lumen-negative
potential, which drives reabsorption of Cl- and efflux
of K+ and H+. (R-aldosterone or ADH receptor)
 Use of potassium sparing agents

Prototypes Trade name Indications

Aldosterone antagonists Hypertension (in combination)

Spironolactone Aldactone® These agents are most
Canrenone Saldactone® useful in states of
Blockers of channels Na+
mineralocorticoid excess.
Amiloride Midamor®
Triamterene Dytac®

Combinations
H.chlorthiazide +amiloride Modiuretic®
Altizide +spironolactone Aldactazine®
5. Osmotic Diuretics
• The proximal tubule and
descending limb of Henle's loop
are freely permeable to water. An
osmotic agent that is not
reabsorbed causes water to be
retained in these segments and
promotes a water diuresis.
• Such agents can be used to reduce
increased intracranial pressure and
to promote prompt removal of
renal toxins. The prototypic
osmotic diuretic is mannitol.
 Mechanisms of Action
Inhibitors of carbonic anhydrase Thiazides

Na+
K+ Na+
CA
CoSymports
HCO3- + H+ →H2CO3 →H2O + CO2 →
Cl- Na+
Ca++

Potassium sparing Loop diuretics

Aldosterone
Receptor
Na+ Na+
K+ Channel K+
ADH Symports
H+ 2Cl- Na+
H2O
Receptor Cl-
Diuretic Combinations

• Loop Agents & Thiazides

• Some patients are refractory to the usual dose of loop diuretics or become
refractory after an initial response. Since these agents have a short half-life,
refractoriness may be due to an excessively long interval between doses.
Renal Na+ retention is enhanced during the time period when the drug is no
longer active. After the dosing interval for loop agents is minimized or the
dose is maximized, the use of two drugs acting at different nephron sites
may exhibit synergy.
• Potassium-Sparing Diuretics & Loop Agents or Thiazides
• Hypokalemia eventually develops in many patients who are placed on loop
diuretics or thiazides. This can often be managed with dietary NaCl
restriction. When hypokalemia cannot be managed in this way, or with
dietary KCl supplements, the addition of a potassium-sparing diuretic can
significantly lower potassium excretion. While this approach is generally
safe, it should be avoided in patients with renal insufficiency in whom life-
threatening hyperkalemia can develop in response to potassium-sparing
diuretics.
CLINICAL USES OF DIURETICS

Product Characteristics Indications

Osmotic Poor oral absorption Reduction of Intracranial
 Mannitol Powerful diuretic and Intraocular Pressure
Edema
(osmitrolR)
 Isosorbide Good oral absorption Poor diuresis
(IsmoticR)
 Glucose To be infused i.v. (>180 mg%).

ICA Glaucoma open-angle ;

Acetazolamide Alkalize urine in Reduction of epilepsy
episodes ; Acute
DiamoxR intoxication with symptoms in « Mountain
Diclofenamide acidic products sickness syndrome ».
Oratrol®
Toxicity-Cautions on the use of diuretics

• Overzealous use of any diuretic is dangerous in hepatic cirrhosis,

borderline renal failure, or heart failure.
• Furosemide, bumetanide, and torsemide may demonstrate cross-
reactivity in patients who are sensitive to other sulfonamides.
• Potassium sparing agents can cause severe, even fatal hyperkalemia
in susceptible patients. Oral K+ administration should be
discontinued if aldosterone antagonists are administered. Patients
with chronic renal insufficiency are especially vulnerable and should
rarely be treated with aldosterone antagonists.
• Concomitant use of other agents that blunt the renin-angiotensin
system (β-blockers or ACE inhibitors) increases the likelihood of
hyperkalemia. Patients with liver disease may have impaired
metabolism of triamterene and spironolactone, and dosing must be
carefully adjusted.
Toxicity-Cautions on the use of diuretics

• Ototoxicity
• Loop diuretics can cause dose-related hearing loss that is usually
reversible. It is most common in patients who have diminished
renal function or who are also receiving other ototoxic agents
such as aminoglycoside antibiotics.
• Hyperuricemia
• Loop diuretics can cause hyperuricemia and precipitate attacks of
gout. This is caused by hypovolemia-associated enhancement of
uric acid reabsorption in the proximal tubule. It may be avoided
by using lower doses.
• Hypomagnesemia
• Magnesium depletion is a predictable consequence of the chronic
use of loop agents and occurs most often in patients with dietary
magnesium deficiency. It can be reversed by administration of oral
magnesium preparations.
Toxicity-Cautions on the use of diuretics

• Electrolytes losses
• Even more than other diuretics, loop agents can cause severe dehydration.
Hyponatremia is less common than with the thiazides, but patients who
increase water intake in response to hypovolemia-induced thirst can become
severely hyponatremic with loop agents. Loop agents are known for their
calciuric effect, but hypercalcemia can occur in patients who have another—
previously occult—cause for hypercalcemia, such as an oat cell carcinoma of
the lung if they become severely volume-depleted.
• Allergic Reactions
• Skin rash, eosinophilia and, less often, interstitial nephritis are occasional
side effects of furosemide, bumetanide, and torsemide therapy. These
usually resolve rapidly after drug withdrawal. Allergic reactions are much less
common with ethacrynic acid.
 Acid-base balance

GROUP AMOUNT IN URINE AMOUNT IN BLOOD

NaCl NaHCO3 K+ Cl- pH
IAC ↑ ↑↑↑ ↑ ↑ Acidosis
hyperchloremic

Thiazides ↑↑ ↑ ↑ ↓ Alcalosis
- hypochloremic

Loop diuretics ↑↑↑↑ - ↑ ↓ Alcalosis

hypochloremic

Potassium sparing ↑ - ↓ ↓ Acidosis

- hyperkaliemic
Preparations available
• Chlorthalidone(generic, Thalitone, combination • Hydrochlorothiazide (generic, Microzide, Hydro-
drugs) DIURIL, combination drugs)
• Oral: 15, 25, 50, 100 mg tablets • Oral: 12.5 mg capsules; 25, 50, 100 mg tablets; 10
mg/mL solution
• Demeclocycline(Declomycin)
• Hydroflumethiazide (generic, Diucardin)
• Oral: 150 mg tablets and capsules; 300 mg tablets
• Oral: 50 mg tablets
• Dichlorphenamide (Daranide)
• Indapamide(generic, Lozol)
• Oral: 50 mg tablets
• Oral: 1.25, 2.5 mg tablets
• Dorzolamide(Trusopt)
• Mannitol(generic, Osmitrol)
• Ophthalmic: 2% solution
• Parenteral: 5, 10, 15, 20, 25% for injection
• Eplerenone (Inspra)
• Methazolamide (generic, Neptazane)
• Oral: 25, 50, 100 mg tablets
• Oral: 25, 50 mg tablets
• Ethacrynic acid(Edecrin)
• Methyclothiazide (generic, Aquatensen)
• Oral: 25, 50 mg tablets
• Oral: 2.5, 5 mg tablets
• Parenteral: 50 mg IV injection
• Furosemide(generic, Lasix, others)
• Oral: 20, 40, 80 mg tablets; 8 mg/mL solutions
• Parenteral: 10 mg/mL for IM or IV injection
Preparations available
• Amiloride(generic, Midamor, combination drugs) • Metolazone (Mykrox, Zaroxolyn) note:
Bioavailability of Mykrox is greater than that of
• Oral: 5 mg tablets Zaroxolyn.)
• Bendroflumethiazide (Naturetin) • Oral: 0.5 (Mykrox); 2.5, 5, 10 mg (Zaroxolyn) tablets
• Oral: 5, 10 mg tablets • Polythiazide (Renese)
• Benzthiazide (Exna, combination drugs) • Oral: 1, 2, 4 mg tablets
• Oral: 50 mg tablets • Quinethazone (Hydromox)
• Brinzolamide(Azopt) • Oral: 50 mg tablets
• Ophthalmic: 1% suspension • Spironolactone(generic, Aldactone)
• Bumetanide(generic, Bumex) • Oral: 25, 50, 100 mg tablets
• Oral: 0.5, 1, 2 mg tablets • Torsemide(Demadex)
• Parenteral: 0.5 mg/2 mL ampule for IV or IM • Oral: 5, 10, 20, 100 mg tablets
injection
• Parenteral: 10 mg/mL for injection
• Chlorothiazide (generic, Diuril, others)
• Triamterene(Dyrenium)
• Oral: 250, 500 mg tablets; 250 mg/5 mL oral
suspension • Oral: 50, 100 mg capsules
• Parenteral: 500 mg for injection • Trichlormethiazide (generic, Diurese, others)
• Oral: 2, 4 mg tablets
B. Antihypertensive Agents

• PATHOPHYSIOLOGY
• Normal tension :110 - 140 mm Hg in systole, and 70 - 90 mm
Hg in diastole.
• HIGH BLOOD PRESSURE-HYPERTENSION
• Permanent BP >140 mm Hg in systole and > 90 mm Hg diastole
• LOW BLOOD PRESSURE-HYPOTENSION
• Permanent BP <110 mm Hg in systole and < 70 mm Hg diastole

• BP=CO x PVR
• According to the hydraulic equation, arterial
blood pressure (BP) is directly proportionate to
the product of the blood flow (cardiac output,
CO) and the resistance to passage of blood
through precapillary arterioles (peripheral
vascular resistance, PVR).
• Physiologically, in both normal and
hypertensive individuals, blood pressure is
maintained by moment-to-moment regulation
of cardiac output and peripheral vascular
resistance, exerted at three anatomic sites:
arterioles, postcapillary venules (capacitance
vessels), and heart.
• Kidney is the fourth site – volume of
intravascular fluid
• Baroreflex, humoral mechanism and renin-
angiotensin- aldosterone system regulates the
above 4 sites
• In hypertensives – Baroreflex and renal blood-
volume control system – set at higher level
• All antihypertensives act via interfering with
normal mechanisms
• BARORECEPTOR REFLEX
IS A MECHANISM USED BY THE BODY TO MAINTAIN STABLE
BP MEASURES OR HOMEOSTASIS, IN HIGH BP
BARORECEPTOR REFLEX CAUSES HEART RATE TO DECREASE
AND VICE VERSA, IT HAPPENS THROUGH STRETCH
RECEPTORS(BARORECEPTORS) IN AORTIC ARCH AND
CAROTID SINUS, STRETCH CAUSES A HIGH THAN NORMAL
RATE ACTION POTENTIAL FROM BAROR, THROUGH
IX(GLOSSOPHAREANGEAL NERVE) & X(VAGUS NERVE) TO
THE NTS WHICH ACTIVATES PNS & INACTIVATES SNS, PNS
ACTIVATION RELEASE ACH AND REDUCE HEART RATE
THROUGH SA NODE PACEMAKER , SNS INHIBITION
DECREASE HR, STROKE VOLUME & CAUSES VASODILATION.
IN A REVERSE SITUATION, LIKE WHEN STANDING UP, BP
DROPS & SNS IS ACTIVATED AND PNS IS INHIBITED, SNS
ACTIVATION RELEASES NOREPINEPHRINE ACTING ON SA
NODE TO INCREASE HR, ON MYOCYTE TO INCREASE STROKE
VOLUME, ON VESSELS SMOOTH MUSCLE TO CAUSE
VASOCONSTRICTION
• BARORECEPTOR REFLEX CONT….
LIVER RELEASES ANGIOTENSINOGEN INTO
CIRCULATION(LOW BP & ADV CHANGES IN NA CONC.),
KIDNEY RELEASE RENIN WHICH CLEAVES
ANGIOTENSINOGEN TO ANGIOTENSIN I, LUNG AND
VASCULAR ENDOTHELIUM RELEASE ACE, ACE CONVERT
ANGIOTENSIN I INTO ANGIOTENSIN II, (TONIN, CATHEPSIN
D, TISSUE PLASMINOGEN TPA BYPASS ACE), ACE DEGRADE
BRADYKININ WHICH HELP IN PRODUCTION OF NITRIC
OXIDE( HENCE LESS NO), ANGIOTENSIN II ACTIVATES AT1
RECEPTOR FURTHER IMPAIRS NO CAUSING
VASOCONSTRICTION, AT1-R ACTIVATION CAUSES THE
ADRENAL GLAND TO RELEASE ALDOSTERONE THAT
CAUSES NA RETENTION, VASOCONSTRICTION AND NA
RETENTION MEANS HIGH BP, HIGH BP CAUSES KIDNEY TO
REDUCE RENIN IN NEGATIVE FEEDBACK. AT2-R
COUNTERACTS AT1-R, AT4-R INCREASE TPA INHIBITOR PAI1
Causes of Hypertension

• A specific cause of hypertension can be established in only

10–15% of patients. It is important to consider specific
causes in each case, because some of them are amenable to
definitive surgical treatment:
• renal artery constriction,
• coarctation of the aorta,
• pheochromocytoma,
• Cushing's disease, and
• primary aldosteronism.
• Patients in whom no specific cause of hypertension can be
found are said to have essential hypertension.
Management of Hypertension

DIETARY SODIUM
RESTRICTION ANTIHYPERTENSIVE AGENTS
• Dietary sodium restriction 1. DIURETICS
has been known for many 2. SYMPATHOPLEGIC
years to decrease blood AGENTS
pressure in hypertensive
patients. 3. AGENTS THAT BLOCK
PRODUCTION OR ACTION
• Several studies have shown OF ANGIOTENSIN
that even modest dietary
sodium restriction lowers 4. VASODILATORS
blood pressure (although to
varying extents) in many
hypertensive individuals.
1. DIURETICS

• DIURETICS LOWER BLOOD PRESSURE PRIMARILY BY

DEPLETING BODY SODIUM STORES. INITIALLY, DIURETICS
REDUCE BLOOD PRESSURE BY REDUCING BLOOD VOLUME
AND CARDIAC OUTPUT; PERIPHERAL VASCULAR RESISTANCE
MAY INCREASE. AFTER 6–8 WEEKS, CARDIAC OUTPUT
RETURNS TOWARD NORMAL WHILE PERIPHERAL VASCULAR
RESISTANCE DECLINES. SODIUM IS BELIEVED TO
CONTRIBUTE TO VASCULAR RESISTANCE BY INCREASING
VESSEL STIFFNESS AND NEURAL REACTIVITY, POSSIBLY
RELATED TO INCREASED SODIUM-CALCIUM EXCHANGE WITH
A RESULTANT INCREASE IN INTRACELLULAR CALCIUM. THESE
EFFECTS ARE REVERSED BY DIURETICS OR SODIUM
RESTRICTION.
DIURETICS
• THIAZIDE DIURETICS ARE APPROPRIATE FOR MOST PATIENTS
WITH MILD OR MODERATE HYPERTENSION AND NORMAL
RENAL AND CARDIAC FUNCTION.
• MORE POWERFUL DIURETICS (EG, THOSE ACTING ON THE
LOOP OF HENLE) ARE NECESSARY IN SEVERE
HYPERTENSION, WHEN MULTIPLE DRUGS WITH SODIUM-
RETAINING PROPERTIES ARE USED; IN RENAL INSUFFICIENCY,
WHEN GLOMERULAR FILTRATION RATE IS LESS THAN 30 OR
40 ML/MIN; AND IN CARDIAC FAILURE OR CIRRHOSIS,
WHERE SODIUM RETENTION IS MARKED.
• POTASSIUM-SPARING DIURETICS ARE USEFUL BOTH TO
AVOID EXCESSIVE POTASSIUM DEPLETION, PARTICULARLY IN
PATIENTS TAKING DIGITALIS, AND TO ENHANCE THE
NATRIURETIC EFFECTS OF OTHER DIURETICS.
2. SYMPATHOPLEGICS

Prototypes Activity Indications

Dibenamine Inhibition 1 = 2 Hypertension
Dihydroergotamine
Phentolamine
Azapetine Inhibition 1  2 Pheochromocytoma
Phenoxybenzamine
Doxazosin Hypertenson
Prazosin Inhibition 1 selective
Alfuzosin Prostatic hypertrophy
Clonidine Agonists 2 Hypertension

Propranolol (21 ) blocker Hypertension

Atenolol (1) blocker
Metoprolol (1) blocker
2.1. Alpha (adrenoceptor) blockers
2.2. Beta blockers
2.3. Sympathoplegics That Act in the Central
Nervous System
3. ANGIOTENSIN ANTAGONISTS
& A RENIN INHIBITOR
4.VASODILATORS
4.1 Calcium Channel-Blocking Agents
 4.2. Hydralazine and Minoxidil
THESE OLDER VASODILATORS HAVE MORE EFFECT ON ARTERIOLES
THAN ON VEINS. THEY ARE ORALLY ACTIVE AND SUITABLE FOR
CHRONIC THERAPY.
HYDRALAZINE APPARENTLY ACTS THROUGH THE RELEASE OF NITRIC
OXIDE FROM ENDOTHELIAL CELLS AND CAUSES SIGNIFICANT
BARORECEPTOR HOMEOSTATIC RESPONSES AND MUST BE COMBINED
WITH EITHER DIURETICS OR Β BLOCKERS. HYDRALAZINE CAN CAUSE
LUPUS ERYTHEMATOSUS WHICH IS REVERSIBLE UPON STOPPING THE
DRUG.
MINOXIDIL IS A PRODRUG; ITS METABOLITE, MINOXIDIL SULFATE, IS A
POTASSIUM CHANNEL OPENER THAT HYPERPOLARIZES AND RELAXES
VASCULAR SMOOTH MUSCLE. THE COMPENSATORY RESPONSES TO
MINOXIDIL REQUIRE THE CONCOMITANT USE OF DIURETICS AND Β
BLOCKERS, BCZ IT CAN CAUSE HIRSUTISM, MINOXIDIL IS ALSO
AVAILABLE AS A TOPICAL AGENT FOR THE TREATMENT OF BALDNESS.
 4.3. Nitroprusside, Diazoxide, and Fenoldopam
THESE PARENTERAL VASODILATORS ARE USED IN HYPERTENSIVE
EMERGENCIES. NITROPRUSSIDE IS A LIGHT-SENSITIVE, SHORT-ACTING AGENT
(DURATION OF ACTION IS A FEW MINUTES) THAT MUST BE INFUSED
CONTINUOUSLY. THE RELEASE OF NITRIC OXIDE (FROM THE DRUG MOLECULE
ITSELF) STIMULATES GUANYLYL CYCLASE AND INCREASES CYCLIC GUANINE
MONOPHOSPHATE (CGMP) CONCENTRATION AND RELAXATION IN VASCULAR
SMOOTH MUSCLE.
DIAZOXIDE IS A THIAZIDE DERIVATIVE THAT LACKS DIURETIC PROPERTIES
WHICH IS GIVEN AS INTRAVENOUS BOLUSES OR AS AN INFUSION AND HAS
SEVERAL HOURS’ DURATION OF ACTION. DIAZOXIDE OPENS POTASSIUM
CHANNELS, THUS HYPERPOLARIZING AND RELAXING SMOOTH MUSCLE CELLS.
THIS DRUG ALSO REDUCES INSULIN RELEASE AND CAN BE USED TO TREAT
HYPOGLYCEMIA
CAUSED BY INSULIN-PRODUCING TUMORS.
DOPAMINE D1 RECEPTOR ACTIVATION BY FENOLDOPAM CAUSES PROMPT,
MARKED ARTERIOLAR VASODILATION. THIS DRUG IS GIVEN BY INTRA-VENOUS
INFUSION. IT HAS A SHORT DURATION OF ACTION (10 MIN) AND, LIKE
NITROPRUSSIDE AND DIAZOXIDE, IS USED FOR HYPERTENSIVE EMERGENCIES
Preparations available

• Benazepril(Lotensin) • Ramipril (Altace)

• Oral: 5, 10, 20, 40, mg tablets • Oral: 1.25, 2.5, 5, 10 mg capsules
• Captopril (generic, Capoten) • Trandolapril(Mavik)
• Oral: 12.5, 25, 50, 100 mg tablets • Oral: 1, 2, 4 mg tablets
• Enalapril(Vasotec) • Angiotensin Receptor Blockers
• Oral: 2.5, 5, 10, 20 mg tablets • Candesartan (Atacand)
• Parenteral (Enalaprilat): 1.25 mg/mL for injection • Oral: 4, 8, 16, 32 mg tablets
• Fosinopril(Monopril) • Eprosartan(Teveten)
• Oral: 10, 20, 40 mg tablets • Oral: 400, 600 mg tablets
• Lisinopril(Prinivil, Zestril) • Irbesartan (Avapro)
• Oral: 2.5, 5, 10, 20, 40 mg tablets • Oral; 75, 150, 300 mg tablets
• Moexipril(Univasc) • Losartan (Cozaar)
• Oral: 7.5, 15 mg tablets • Oral: 25, 50, 100 mg tablets
• Perindopril (Aceon) • Olmisartan (Benicar)
• Oral: 2, 4, 8 mg tablets • Oral: 5, 20, 40 mg tablets
• Quinapril(Accupril) • Telmisartan(Micardis)
• Oral: 5, 10, 20, 40 mg tablets • Oral: 20, 40, 80 mg tablets
• Valsartan (Diovan)
• Oral: 40, 80, 160, 320 mg tablet
Preparations available

• Diazoxide (Hyperstat IV) • Reserpine (generic)

• Parenteral: 15 mg/mL ampule • Oral: 0.1, 0.25 mg tablets
• Oral (Proglycem): 50 mg capsule; 50 • Doxazosin(generic, Cardura)
mg/mL oral suspension • Oral: 1, 2, 4, 8 mg tablets
• Fenoldopam(Corlopam) • Prazosin (generic, Minipress)
• Parenteral: 10 mg/mL for IV infusion • Oral: 1, 2, 5 mg capsules
• Hydralazine(generic, Apresoline) • Terazosin (generic, Hytrin)
• Oral: 10, 25, 50, 100 mg tablets • Oral: 1, 2, 5, 10 mg capsules and
• Parenteral: 20 mg/mL for injection tablets
• Minoxidil(generic, Loniten) • Mecamylamine (Inversine)
• Oral: 2.5, 10 mg tablets • Oral: 2.5 mg tablets
• Topical (Rogaine, etc): 2% lotion
• Nitroprusside(generic, Nitropress)
• Parenteral: 50 mg/vial
Preparations available

• Acebutolol(generic, Sectral) • Labetalol (generic, Normodyne, Trandate)

• Oral: 200, 400 mg capsules • Oral: 100, 200, 300 mg tablets
• Atenolol(generic, Tenormin) • Parenteral: 5 mg/mL for injection
• Oral: 25, 50, 100 mg tablets • Metoprolol (generic, Lopressor)
• Parenteral: 0.5 mg/mL for injection • Oral: 50, 100 mg tablets
• Betaxolol(Kerlone) • Oral extended-release (Toprol-XL): 25, 50,
100, 200 mg tablets
• Oral: 10, 20 mg tablets
• Parenteral: 1 mg/mL for injection
• Bisoprolol(Zebeta)
• Oral: 5, 10 mg tablets • Nadolol (generic, Corgard)
• Oral: 20, 40, 80, 120, 160 mg tablets
• Carteolol(Cartrol)
• Penbutolol(Levatol)
• Oral: 2.5, 5 mg tablets
• Carvedilol(Coreg) • Oral: 20 mg tablets
• Pindolol(generic, Visken)
• Oral: 3.125, 6.25, 12.5, 25 mg tablets
• Oral: 5, 10 mg tablets
• Esmolol (BreviBloc)
• Parenteral: 10, 250 mg/mL for injection
Preparations available
• Amlodipine (Norvasc) • Nisoldipine (Sular)
• Oral 2.5, 5, 10 mg tablets • Oral: 10, 20, 30, 40 mg extended-release tablets
• Diltiazem(generic, Cardizem) • Nifedipine(generic, Adalat, Procardia)
• Oral: 30, 60, 90, 120 mg tablets (unlabeled in • Oral: 10, 20 mg capsules (unlabeled in
hypertension) hypertension)
• Oral sustained-release (Cardizem CD, Cardizem SR, • Oral extended-release (Adalat CC, Procardia-XL): 30,
Dilacor XL): 60, 90, 120, 180, 240, 300, 360, 420 mg 60, 90 mg tablets
capsules
• Verapamil(generic, Calan, Isoptin)
• Parenteral: 5 mg/mL for injection
• Oral: 40, 80, 120 mg tablets
• Felodipine (Plendil)
• Oral sustained-release (generic, Calan SR, Verelan):
• Oral extended-release: 2.5, 5, 10 mg tablets 120, 180, 240 mg tablets; 100, 120, 180, 200, 240,
300 mg capsules
• Isradipine(DynaCirc)
• Parenteral: 2.5 mg/mL for injection
• Oral: 2.5, 5 mg capsules; 5, 10 mg controlled-release
tablets • Angiotensin-Converting Enzyme Inhibitors
• Nicardipine (generic, Cardene)
• Oral: 20, 30 mg capsules
• Oral sustained-release (Cardene SR): 30, 45, 60 mg
capsules
• Parenteral (Cardene I.V.): 2.5 mg/mL for injection
Preparations available

• Propranolol(generic, Inderal) • Guanabenz (generic, Wytensin)

• Oral: 10, 20, 40, 60, 80, 90 mg • Oral: 4, 8 mg tablets
tablets; 4, 8 mg/mL oral solution; • Guanfacine(Tenex)
Intensol, 80 mg/mL solution
• Oral sustained-release (generic, • Oral: 1, 2 mg tablets
Inderal LA): 60, 80, 120, 160 mg • Methyldopa(generic)
capsules • Oral: 250, 500 mg tablets
• Parenteral: 1 mg/mL for injection • Parenteral: 50 mg/mL for injection
• Timolol(generic, Blocadren) • Guanadrel (Hylorel)
• Oral: 5, 10, 20 mg tablets • Oral: 10, 25 mg tablets
• Clonidine(generic, Catapres) • Guanethidine(Ismelin
• Oral: 0.1, 0.2, 0.3 mg tablets • Oral: 10, 25 mg tablets
• Transdermal (Catapres-TTS):
patches that release 0.1, 0.2, 0.3
mg/24 h
COMBINATION DIURETIC+OTHER
Name DIURETIC ADJUNCT PRODUCT
Renese-R tab Polythiazide 2mg Reserpine 0.25mg
Aprasazide 50/50 capsules Hydrochlorothiazide 50mg Hydralazine 50mg
Tenoretic 100 tab Chlorthalidone 25mg Atenolol 100mg
Corzide 80/5 tab Bendroflumethiazide 5 mg Nadolol 80mg
Ziac tab Hydrochlorothiazide 6.25mg Bisoprolol 2.5mg
Inderide 40/25 tab Hydrochlorothiazide 25mg Propranolol 40mg
Lopressor HCT 50/25 tab Hydrochlorothiazide 25mg Metoprolol 50mg
Capozide 50/25 tab Hydrochlorothiazide 25mg Captopril 50mg
Accuretic Hydrochlorothiazide 12.5mg Quinapril 10mg
Zestoretic tab Hydrochlorothiazide 12.5mg Lisinopril 10mg
Minizide 5 capsules Polythiazide 0.5mg Prazosin 5mg
TREATMENT OF HYPOTENSION

Acute Hypotension Chronic Hypotension

 Metaraminol Aramine®  Etilephrine Effortil®
 Dobutamine Dobutrex®  Heptaminol Heptamyl®
 Dopamine Dynatra®  Phenylephrine Neosynephrine®
 Norepinephrine Levophed®  Mephentermine Wyamine®
C. HEART FAILURE

Cardiac performance is a function of four primary factors:

1) Preload
2) Afterload
3) Contractility
4) Heart rate

Heart failure is simply defined as a chronic, progressive

disorder in which the heart muscle is unable to pump enough
blood to meet the body's needs. Depending on the primary
cause, heart failure can manifest itself as either systolic or
diastolic dysfunction
Cardiac performance factors

• Preload: The amount of blood in the heart ventricles before

they contract. In heart failure, preload is often increased,
due to fluid retention. This can make it harder for the heart
to pump blood effectively.

• Afterload: The pressure that the heart has to work against to

pump blood out into the body. In heart failure, afterload is
often increased, due to stiffening of the arteries or
narrowing of the heart valves. This can also make it harder
for the heart to pump blood effectively.
Cardiac performance factors

• Contractility: The force with which the heart ventricles

contract. In heart failure, contractility is often reduced, due
to damage to the heart muscle. This can lead to a decrease
in cardiac output, or the amount of blood that the heart
pumps out per minute.

• Heart rate: The number of times the heart beats per minute.
In heart failure, heart rate is often increased, due to the
body's attempt to compensate for the reduced cardiac
output. This can lead to inefficient pumping and further
damage to the heart muscle.
CONGESTIVE HEART FAILURE

Frank-Starling curve Heart failure Compensatory responses

THERAPEUTIC STRATEGIES
THERAPEUTIC STRATEGIES
D. Drugs Used in the Treatment of Angina Pectoris
1. ATHEROSCLEROTIC ANGINA—ATHEROSCLEROTIC
ANGINA IS ALSO KNOWN AS ANGINA OF EFFORT OR CLASSIC
ANGINA. IT IS ASSOCIATED WITH ATHEROMATOUS
PLAQUES THAT PARTIALLY OCCLUDE ONE OR MORE
CORONARY ARTERIES. WHEN CARDIAC WORK INCREASES
(EG, IN EXERCISE), THE OBSTRUCTION OF FLOW AND
INADEQUATE OXYGEN DELIVERY RESULTS IN THE
ACCUMULATION OF METABOLITES, EG, LACTIC ACID, AND
ISCHEMIC CHANGES THAT STIMULATE MYOCARDIAL PAIN
ENDINGS. REST, BY REDUCING CARDIAC WORK, USUALLY
LEADS TO COMPLETE RELIEF OF THE PAIN WITHIN 15 MIN.
ATHEROSCLEROTIC ANGINA CONSTITUTES ABOUT 90% OF
ANGINA CASES.
D. Drugs Used in the Treatment of Angina Pectoris
2. VASOSPASTIC ANGINA—VASOSPASTIC ANGINA, ALSO
KNOWN AS REST ANGINA, VARIANT ANGINA, OR
PRINZMETAL’S ANGINA, IS RESPONSIBLE FOR LESS THAN 10%
OF ANGINA CASES. IT INVOLVES REVERSIBLE SPASM OF
CORONARIES, USUALLY AT THE SITE OF AN
ATHEROSCLEROTIC PLAQUE. SPASM MAY OCCUR AT ANY
TIME, EVEN DURING SLEEP. VASOSPASTIC ANGINA MAY
DETERIORATE INTO UNSTABLE ANGINA.
3. UNSTABLE ANGINA—A THIRD TYPE OF ANGINA—
UNSTABLE OR CRESCENDO ANGINA, ONE MANIFESTATION
OF ACUTE CORONARY SYNDROME—IS CHARACTERIZED BY
INCREASED FREQUENCY AND SEVERITY OF ATTACKS
THAT RESULT FROM A COMBINATION OF
ATHEROSCLEROTIC PLAQUES, PLATELET AGGREGATION
AT FRACTURED PLAQUES, AND VASOSPASM. UNSTABLE
ANGINA IS THOUGHT TO BE THE IMMEDIATE PRECURSOR OF
A MYOCARDIAL INFARCTION AND IS TREATED AS A MEDICAL
EMERGENCY.
Determinants of the volume of oxygen required by the heart and Strategies
for the treatment of effort angina
Pharmacology strategy
 Pharmacology strategy

Action onset Preparation Routes of administration

Fast and Short
3-5 min Amyle Nitrate Spray 0.4mg/dose
10-30 min Nitroglycerin Trinitrine® 0.3mg sublingual
1-2 hrs Dinitrate isosorbide Cedocard® 5mg sublingual
Middle length
4- 8 hrs Nitroglycerin Nitro-dur® 2.5; 6.5mg peroral controlled
Dinitrate isosorbide delivery form
Slow - prolonged
8-10 hrs Nitroglycerin Cordipath®)0.4mg/ Patch transdermal
 Toxicity & Tolerance of Nitrates & Nitrites
• Acute Adverse Effects
• The major acute toxicities of organic nitrates are direct extensions
of therapeutic vasodilation: orthostatic hypotension, tachycardia,
and throbbing headache. Glaucoma, once thought to be a
contraindication, does not worsen, and nitrates can be used safely
in the presence of increased intraocular pressure.
• Nitrates are contraindicated, however, if intracranial pressure is
elevated.
• Tolerance
• With continuous exposure to nitrates, isolated smooth muscle may
develop complete tolerance (tachyphylaxis), and the intact human
becomes progressively more tolerant when long-acting
preparations (oral, transdermal) or continuous intravenous
infusions are used for more than a few hours without interruption.
Preparations Available

• Amyl nitrite (generic, Aspirols, • Nitroglycerin

Vaporole) • Sublingual: 0.3, 0.4, 0.6 mg tablets;
• Inhalant: 0.3 mL capsules 0.4 mg/metered dose aerosol
• Isosorbide dinitrate(generic, Isordil, • Oral sustained-release (generic,
Sorbitrate) Nitrong): 2.6, 6.5, 9 mg tablets; 2.5,
• Oral: 5, 10, 20, 30, 40 mg tablets; 5, 6.5, 9, 13 mg capsules
10 mg chewable tablets • Buccal (Nitrogard): 2, 3 mg buccal
• Oral sustained-release (generic, tablets
Sorbitrate SA, Iso-Bid): 40 mg tablets • Parenteral (Nitro-Bid IV, Tridil,
and capsules generic): 0.5, 5 mg/mL for IV
• Sublingual: 2.5, 5, 10 mg sublingual administration
tablets • Transdermal patches (Minitran, Nitro-
• Isosorbide mononitrate(Ismo, others) Dur, Transderm-Nitro): to release at
rates of 0.1, 0.2, 0.3, 0.4, 0.6, or 0.8
• Oral: 10, 20 mg tablets; extended- mg/h.Topical ointment (generic,
release 30, 60, 120 mg tablets Nitrol): 20 mg/mL ointment (1 inch,
or 25 mm, of ointment contains
about 15 mg nitroglycerin)
• Calcium Channel Blockers
Preparations Available
• Amlodipine (Norvasc) • Nifedipine (Adalat, Procardia, others)
• Oral: 2.5, 5, 10 mg tablets • Oral: 10, 20 mg capsules
• Bepridil (Vascor) • Oral extended-release (Procardia XL, Adalat CC): 30, 60,
90 mg tablets
• Oral: 200, 300 mg tablets
• Nimodipine(Nimotop)
• Diltiazem(Cardizem, generic)
• Oral: 30 mg capsules (Labeled for use in subarachnoid
• Oral: 30, 60, 90, 120 mg tablets hemorrhage, not angina.)
• Oral sustained-release (Cardizem SR, Dilacor XL, others): • Nisoldipine(Sular)
60, 90, 120, 180, 240, 300, 360, 420 mg capsules
• Oral extended-release: 10, 20, 30, 40 mg tablets
• Parenteral: 5 mg/mL for injection
• Verapamil(generic, Calan, Isoptin)
• Felodipine (Plendil)
• Oral: 40, 80, 120 mg tablets
• Oral extended-release: 2.5, 5, 10 mg tablets
• Oral sustained-release: 100, 120, 180, 240 mg tablets or
• Isradipine(DynaCirc) capsules
• Oral: 2.5, 5 mg capsules • Parenteral: 2.5 mg/mL for injection
• Oral controlled release: 5, 10 mg tablets
• Nicardipine (Cardene, others)
• Oral: 20, 30 mg capsules
• Oral sustained-release (Cardene SR): 30, 45, 60 mg
capsules)
• Parenteral (Cardene I.V.): 2.5 mg/mL
E. ANTIARRHYTHMIC AGENTS
Pathophysiology of arrhythmias
 Classes of Antiarrhythmic Agents
Vaugham Williams’s classification

Class 1 Class 2 Class 3 Class 4

Miscellaneous
Action Action Action Action

1a 1b 1c
The most widely used scheme for the classification of antiarrhythmic drug actions
recognizes four classes. Class 1 action is sodium channel blockade Class 2 action is
sympatholytic Class 3 action is manifest by prolongation of the APD (potassium current)
Class 4 action is blockade of the cardiac calcium current. Certain antiarrhythmic agents,
eg, adenosine and magnesium, do not fit readily into this scheme and are described as
miscellaneous. A given drug may have multiple classes of action(e.g.,amiodarone shares
all four classes of action).
 TYPICAL COMMON ARRYTHMIAS

ATRIAL FLUTTER(Pu Sd): the atria beat regularly, but faster than
usual and more often than the ventricles
ATRIAL FIBRILLATION (Tu Sd): Arrhythmias involving rapid reentry
and chaotic OR DISORGANIZED movement of impulses through
the tissue of the atria
VENTRICULAR TACHYCARDIA: ventricular tachycardia may
involve abnormal automaticity or abnormal conduction, usually
impairs cardiac output
VENTRICULAR FIBRILLATION : Arrhythmias involving rapid
reentry and chaotic movement of impulses through the tissue of
the ventricles
 Classes of Antiarrhythmic Agents
• Class 1 action is sodium channel blockade. Subclasses of this
action reflect effects on the action potential duration (APD) and
the kinetics of sodium channel blockade.
• Drugs with class 1A action prolong the APD and prolonged
refractory period, they dissociate from the channel with
intermediate kinetics;
• drugs with class 1B shorten APD and refractory time and
dissociate from the channel with rapid kinetics;
• and drugs with class 1C action have minimal effects on the APD
and dissociate from the channel with slow kinetics.
 Classes of Antiarrhythmic Agents
• Class 2 action is sympatholytic. Drugs with this action reduce β-adrenergic
activity in the heart.
• Class 3 action is manifest by prolongation of the APD. Most drugs with this
action block the rapid component of the delayed rectifier potassium
current.
• Class 4 action is blockade of the cardiac calcium current. This action slows
conduction in regions where the action potential upstroke is calcium
dependent, eg, the sinoatrial and atrioventricular nodes.
Typical antiarrhythmic drugs

Classe Ia Classe II Classe III Classe IV Miscellanous

Quinidine Propranolol Amiodarone Verapamil Digoxin
Disopyramide Esmolol Sotalol Adenosine
Procainamide Acebutolol Bretylium Atropine
Moricizine
Ibutilide
Classe Ib
Lidocaine
Phenytoin
Tocainide
Mexiletine
Classe Ic
Flecainide
Propafenone
Digoxin: normally Na in K out but due to AP additional process happen,
which is balances by Na/K ATPase, we also have Ca/Na exchanger,
digoxin inhibit Na/K ATPase by binding to K binding site, lead to high Na
which is pumped out and Ca comes in increasing myocontractility
Adenosine: natural nucleotide act on receptors in atria, SA and AV node
causing decrease automaticity and conduction velocity and prolonged
refractory period, through IV due to short duration of action, acute
supraventricular tachycardia
Magnesium sulfate: action is not very well known, but is involved in Na,
Ca and K transport across the cell, helpful in torsade de pointe
 Uses of antiarrhythmics
Atrial flutter Quinidine Propranolol Verapamil Digoxin
Atrial fibrillation Quinidine Propranolol Amiodarone Anti-
coagulant
AV node reentry Propranolol Verapamil Digoxin
Acute Verapamil Adenosine
supraventricular
tachycardia

Acute Lidocaine Sotalol

ventricular Amiodarone
tachycardia
Ventricular Lidocaine Sotalol Epinephrine
fibrillation Amiodarone
Commonly used Alternative drugs
Preparations available
• Quinidine sulfate [83% quinidine base] (generic) • Mexiletine (Mexitil)
• Oral: 200, 300 mg tablets • Oral: 150, 200, 250 mg capsules
• Oral sustained-release (Quinidex Extentabs): 300 mg tablets • Moricizine (Ethmozine)
• Quinidine gluconate [62% quinidine base] (generic) • Oral: 200, 250, 300 mg tablets
• Oral sustained-release: 324 mg tablets • Procainamide (generic, Pronestyl, others)
• Parenteral: 80 mg/mL for injection • Oral: 250, 375, 500 mg tablets and capsules
• Quinidine polygalacturonate [60% quinidine base] (Cardioquin) • Oral sustained-release (generic, Procan-SR): 250, 500, 750, 1000 mg tablets
• Oral: 275 mg tablets • Parenteral: 100, 500 mg/mL for injection
• -Blockers Labeled for Use as Antiarrhythmics • Propafenone (Rythmol)
• Acebutolol (generic, Sectral) • Oral: 150, 225, 300 mg tablets
• Oral: 200, 400 mg capsules • Sodium Channel Blockers
• Esmolol (Brevibloc) • Disopyramide (generic, Norpace)
• Parenteral: 10 mg/mL, 250 mg/mL for IV injection • Oral: 100, 150 mg capsules
• Propranolol (generic, Inderal) • Oral controlled-release (generic, Norpace CR): 100, 150 capsules
• Oral: 10, 20, 40, 60, 80, 90 mg tablets • Flecainide (Tambocor)
• Oral sustained-release: 60, 80, 120, 160 mg capsules • Oral: 50, 100, 150 mg tablets
• Parenteral: 1 mg/mL for injection • Lidocaine (generic, Xylocaine)
• Action Potential-Prolonging Agents • Parenteral: 100 mg/mL for IM injection; 10, 20 mg/mL for IV injection; 40, 100, 200
mg/mL for IV admixtures; 2, 4, 8 mg/mL premixed IV (5% D/W) solution
• Amiodarone (Cordarone)
• Oral: 200, 400 mg tablets
• Parenteral: 150 mg/3 mL for intravenous infusion
Preparations available

• Bretylium (generic) • Diltiazem (generic, Cardizem, Dilacor)

• Parenteral: 2, 4, 50 mg/mL for injection • Oral: 30, 60, 90, 120 mg tablets; 60, 90,
• Dofetilide (Tikosyn) 120, 180, 240, 300, 340, 420 mg extended-
or sustainedrelease capsules (not labeled
• Oral: 125, 250, 500 g capsules for use in arrhythmias)
• Ibutilide (Corvert) • Parenteral: 5 mg/mL for intravenous
injection
• Parenteral: 0.1 g/mL solution for IV
infusion • Verapamil (generic, Calan, Isoptin)
• Sotalol (generic, Betapace) • Oral: 40, 80, 120 mg tablets;
• Oral: 80, 120, 160, 240 mg capsules • Oral sustained-release (Calan SR, Isoptin
SR): 100, 120, 180, 240 mg capsules
• Calcium Channel Blockers
• Parenteral: 5 mg/2 mL for injection
• Bepridil (Vascor; not labeled for use in
arrhythmias) • Miscellaneous
• Oral: 200, 300 mg tablets • Adenosine (Adenocard)
• Parenteral: 3 mg/mL for injection
• Magnesium sulfate
• Parenteral: 125, 500 mg/mL for
intravenous infusion
F. MANAGEMENT OF HYPERLIPIDEMIA

• Acronyms
• ACAT: Acyl-CoA:cholesterol acyltransferase
• Apo: Apolipoprotein
• CETP: Cholesteryl ester transfer protein
• HDL: High-density lipoproteins
• HMG-CoA: 3-Hydroxy-3-methylglutaryl-coenzyme A
• IDL: Intermediate-density lipoproteins
• LCAT: Lecithin:cholesterol acyltransferase
• LDL: Low-density lipoproteins
• Lp(a): Lipoprotein(a)
• LPL: Lipoprotein lipase
• PPAR- : Peroxisome proliferator-activated receptor-alpha
• VLDL: Very low density lipoproteins
3 LIPIDS: CHOLESTEROL(SYNTHESIS OF BIOACIDS, STEROID HORMONES
ANDCELL MNE INTEGRITY), TRIGLYCERIDES(SOURCE OF ENERGY) AND
PHOSPHOLIPIDS(CELL MNE AND EMULSIFIERS) ARE TRASPORTED IN
LIPOPROTEINS
LIPOPROTEINS: HYDROPOBIC CORE( CHOLESTEROL AND
TRIGLYCERIDES), HYDROPHILIC SHELL(PHOSPHOLIPIDS AND
APOLIPOPROTEIN), CHOLIMICRON(GUT), VLDL(LIVER),HDL,LDL
APOLIPOPROTEINS: SPECIALISED PROTEINS THAT CONTROL ENZYMES IN
LIPOPROTEINS METABOLISM AND SERVE AS LIGANDS FOR
LIPOPROTEINS RECEPTORS
HDL GOOD CHOLESTEROL, LDL BAD CHOLESTEROL
PATHOPHYSIOLOGY
• The lipids of human plasma are transported in
macromolecular complexes termed lipoproteins (VLDL,
IDL,LDL,HDL).
• A number of metabolic disorders that involve elevations in
levels of any of the lipoprotein species are thus termed
hyperlipidemias.
• The term hyperlipemia denotes increased levels of
triglycerides in plasma.
• The two major clinical sequelae of the
hyperlipoproteinemias are acute pancreatitis and
atherosclerosis. The former occurs in patients with marked
hyperlipemia. Control of triglycerides can prevent recurrent
attacks of this life-threatening disease.
 PATHOPHYSIOLOGY
There are five main types of hyperlipoproteinemia:
• Type I: This type is caused by a genetic defect that prevents the body
from removing LDL (bad) cholesterol from the blood. People with type
I hyperlipoproteinemia typically have very high levels of LDL
cholesterol and may develop xanthomas, which are fatty deposits
around the eyes, tendons, and other parts of the body.
• Type II: This type is also caused by a genetic defect, but it is more
common than type I. People with type II hyperlipoproteinemia have
high levels of LDL cholesterol and may also have high levels of
triglycerides.
• Type III: This type is caused by a combination of genetic and
environmental factors. People with type III hyperlipoproteinemia have
high levels of LDL cholesterol, triglycerides, and intermediate-density
lipoprotein (IDL) cholesterol.
• Type IV: This type is caused by a genetic defect that affects triglyceride
metabolism. People with type IV hyperlipoproteinemia have high levels
of triglycerides and may also have low levels of HDL (good) cholesterol.
 CLINICAL CLASSES OF HYPERLIPIDEMIAS

CLASS INDICES CAUSES

Type-I [Familial hyperchylomicronemia] - Generally at 10 years old
Chylomicrons; VLDL - Very rare
-Deficiency in lipoprotein-lipase
-Deficiency in normal apo CII
- Heredity
Type-II IIa [Familial hypercholesterolemia] -Deficit of tissue LDL receptors
Cholesterol; LDL
IIb [Familial combined hyperlipidemia] -Overproduction of VLDL by the
Cholesterol; LDL; VLDL; Triglycerides liver
Type-III [Familial Dysbetalipoproteinemia] -Atherogenic Type
-VLDL; IDL -Mutant apolipoprotein E
Type-IV [Familial hypertriglyceridemia] -Most in developed countries
VLDL; Triglycerides -Overproduction of VLDL
-Decreased removal of VLDL
triacyglycerides in serum
Type-V [Familial mixed hypertriglyceridemia] - obesity
Serum VLDL, Chylomicrons; Triglycerides - diabetes
- hyperurecemia
 Pharmacology strategies

Resins Statins Niacins Fibrates Probucol

Ezetimibe

(-)Bile salts (-)HMG CoA (-)VLDL (+)Lipoprotein (+)Tissue

cycle reductase Synthesis lipase Metabolism; (-)
Absorption

& Release Cholesterol

oxidation

Ezetimibe: inhibits intestinal absorption of phytosterols

Resins: Colestipol, cholestyramine, and colesevelam
Statins: Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin
Niacins: Niacin (but not niacinamide)
Fibrates: Gemfibrozil and fenofibrate
Probucol:
Pharmacology strategies
Pharmacology strategies
Pharmacology strategies
Pharmacology strategies
Pharmacology strategies
Action of Probucol

• Probucol inhibits the oxidation of cholesterol, resulting in the

ingestion on the oxidized cholesterol-laden LDLs by macrophages.
Loaded with cholesterol, these macrophages become foam cells that
adhere to the vascular endothelium and are the basis for plaque
formation. Thus prevention of the cholesterol oxidation reaction
might slow the development of atherosclerosis.
• Probucol reduces HDL levels to a greater extent than those of LDLs.
Pharmacology strategies
Treatment with Drug Combinations

• Combined drug therapy is useful

• (1) when VLDL levels are significantly increased during treatment of hyper-
cholesterolemia with a resin;
• (2) when LDL and VLDL levels are both elevated initially;
• (3) when LDL or VLDL levels are not normalized with a single agent, or
• (4) when elevated levels of Lp(a) or HDL deficiency coexist with other
hyperlipidemias.
Treatment with Drug Combinations

• Fibric Acid Derivatives & Bile Acid-Binding Resins: This combination

is sometimes useful in treating patients with familial combined
hyperlipidemia who are intolerant of niacin. However, it may increase
the risk of cholelithiasis.

• HMG-CoA Reductase Inhibitors & Bile Acid-Binding Resins:This

highly synergistic combination is useful for treatment of familial
hypercholesterolemia but may not control levels of VLDL in some
patients with familial combined hyperlipoproteinemia. Pravastatin,
atorvastatin, and fluvastatin should be given at least 1 hour before or
4 hours after the resin to ensure their absorption.
ADVERSE EFFECTS OF HYPOLIPIDEMIANTS

Resins Fibrates
• constipation, nausea • diarrhea, nausea
• acidosis hyperchloremic (mostly • Myositis and CPK increase
in children) • Transaminases increase and bile
lithogenicity
• avitaminosis K et D at long term
• Itching, pigmentation
Nicotinic acid derivatives Statins
• Cutaneous flush • Nausea
• Itching and dermatitis • Transaminases increase
• diarrhea, nausea, vomiting • Myalgies and CPK increase
• Gastric ulcer Probucol
• transaminases increase and • diarrhea, nausea, vomiting
hyperuricemia • Seldom cardiac arrhythmias.
• Glucose tolerance reduction
• palpitations and tachycardia
Preparations Available
• Atorvastatin (Lipitor)
• Oral: 10, 20, 40, 80 mg tablets • Gemfibrozil (generic, Lopid)
• Cholestyramine (generic, Questran, Questran Light) • Oral: 600 mg tablets
• Oral: 4 g packets anhydrous granules • Lovastatin (generic, Mevacor)
cholestyramine resin; 210 g (Questran Light), 378 g
• Oral: 10, 20, 40, 80 mg tablets; extended release
• (Questran) cans tablets (Altocar) 10, 20, 40, 60 mg
• Colesevelam (Welchol) • Niacin, nicotinic acid, vitamin B3 (generic, others)
• Oral: 625 mg tablets • Oral: 100, 250, 500, 1000 mg tablets
• Colestipol (Colestid) • Pravastatin (Pravachol)
• Oral: 5 g packets granules; 300, 500 g bottles; 1 g • Oral: 10, 20, 40, 80 mg tablets
tablets
• Rosuvastatin (Crestor)
• Ezetimibe (Zetia)
• Oral: 5, 10, 20, 40 mg tablets
• Oral: 10 mg tablets
• Simvastatin (Zocor)
• Fenofibrate (Tricor)
• Oral: 5, 10, 20, 40, 80 mg tablets
• Oral: 54, 160 mg tablets
• Fluvastatin (Lescol)
• Oral: 20, 40 mg capsules; extended release (Lescol
XL): 80 mg capsules