Field of Medicine

Medicine And Surgery Program

Pharmacology: (Revision)

Dr : ( M. Habib)
 Choice of Antiemetics
1- Vomiting due to motion sickness (prophylactic better than curative)
• H1 antagonists: e.g. diphenhydramine
• Antimuscarinics: e.g. hyoscine (transdermal patch)

2- Vomiting due to drugs, toxins, and uremia

• D2 receptor antagonists (metoclopramide and domperidone)

3- Postoperative & post radiation nausea & vomiting:

• 5HT3 receptor antagonists (Ondansetron)
• D2 receptor antagonists (Metoclopramide)
4- Anticipatory and psychogenic vomiting:
• Sedatives
 Choice of Antiemetics (Cont.)
5- Vomiting due to chemotherapy (use combinations of antiemetics)
• 5-HT3 antagonists: ondansetron (1st choice, prophylaxis & treatment)
• Corticosteroids potentiate ondansetron
• D2 receptor antagonists: domperidone & metoclopramide
• Neurokinin-1 antagonists: aprepitant
• Sedatives (prior to cytotoxics to avoid anticipatory vomiting)
• Dronabinol (a cannabinoid)
6- Nausea & vomiting of pregnancy:
• Antihistamines or Vitamin B6 eg:
Meclizine, doxylamine or cortigen B6
 Serotonin 5HT3 Antagonist
Ondansetron(zofran)
Mechanism of action ?????
Indications
• Postoperative N/V
• Post-radiation N/V
• Chemotherapy induced N/V
 Adverse Effects
• Constipation
• Flushing sensation in head and epigastrium
• Headache
 Dopamine D2 Antagonist

Domperidone Metoclopramide

Metoclopramide crosses BBB but domperidone cannot

 Pharmacological actions
1. Antiemetic (central)
D2 antagonist in CTZ
Uses
1. Most causes of vomiting except motion sickness:
2. Drug- induced
3. Uremia or toxin- induced
4. Radiation - induced
5. Postoperative vomiting
6. Vomiting in GIT disorders
2. Prokinetic (peripheral)
Promotes gastric emptying
Uses
1. GERD
2. Gastric atony (diabetic gastroparesis)
3. Endoscopy: facilitates GIT intubation
4. GIT radiology (barium meal)
5. Acute migraine attacks
 Adverse Effects
1. Central D2 antagonist effects (less with domperidone)
▪ Drowsiness & nervousness (common).
▪ Extrapyramidal adverse reactions (dystonia, parkinsonism).
▪ ↑Prolactin, menstrual disturbances, galactorrhea,
gynecomastia, impotence.

2. Peripheral prokinetic effect

▪ Diarrhea
 Drugs that antagonize the action of histamine
• H1 receptor blockers (anti-histamines): for allergic reactions
• H2 receptor blockers: for acid-related GIT disorders
• Mast cell stabilizers & β2 agonists: Inhibit HI release used
in allergic reactions (asthma)
• Epinephrine: physiological antidote for histamine
 1st generation Antihistamines
Chlorpheniramine – diphenhydramine - Meclizine

Uses Actions Adverse Effects

Allergic reactions H1 receptor blockade Drowsiness

✓ Rhinitis Agitation (in children)
• Anti-allergic
✓ Urticaria
✓ Anaphylactic shock • CNS Depression
As OTC hypnotic Sedation
Dry cough Antitussive
Motion sickness Anti-emetic
 1st generation Antihistamines (Cont.)

Uses Actions Adverse Effects

• Motion sickness M receptor blockade Atropine-like side effects:

• Pregnancy Vomiting Dry mouth - Confusion - Urine
Anti-emetic
retention

α receptor blockade Postural hypotension

 New generation Antihistamines
Fexofenadine – Cetirizine - Loratadine

▪ Used in allergic conditions

▪ Delayed elimination →prolonged action
Once/day
▪ Less lipophilic → less crossing of BBB
Less sedation
▪ High doses can cross BBB → sedation
 Drug therapy of peptic ulcer
Pathogenesis of Peptic Ulcer & Lines of Treatment

1. ↑ HCl secretion: treated by → antisecretory drugs (PPIs- P-CAB - H2

antagonists – Misoprostol) – neutralization of secreted acid (antacids)

2. Infection with H. pylori: treated by → anti H. pylori therapy )antibiotics

plus antisecretory drugs with or without bismuth)

3. Inadequate mucosal defense against HCl: treated by → mucosal or

cytoprotectives
Treatment of gastric ulcer
1. Treatment with anti-secretory drugs is the main line

2. Mucosal protective drugs & antacids are rarely needed

Treatment of duodenal ulcer

1. Treatment with anti-secretory drugs

2. H. pylori eradication therapy

3. Mucosal protective drugs & antacids are rarely needed

1- Antisecretory drugs
2- Antacids
3- Cytoprotective drugs
4- Anti H. pylori
Anti-secretory Drugs
• Omeprazole
• Lansoprazole
• Pantoprazole
• Rabeprazole
• Esomeprazole
 Mechanism of action
❑Prodrug: Activated in the acid environment of the
secretory canaliculi of the parietal cells of the
stomach

❑Irreversible inhibitor of H+/K+ ATPase enzyme

(disulfide bond)

❑↓Basal & Meal-stimulated acid secretion

❑They possess anti- H. pylori effect

 Pharmacokinetics of PPIs
1. Inactivated by gastric acidity →given in enteric-coated form
2. Enteric-coated form is readily absorbed in alkaline medium of small intestine
(repeated administration ↓ gastric acidity → ↑ bioavailability)
3. Food ↓bioavailability (so, taken on empty stomach)
4. Acidic pH in the parietal cell acid canaliculi is required for drug activation, and
since food stimulates acid production, should be given about 30 minutes
before meals
5. Long duration of effect (24 h)
6. Metabolized in the liver (CYP2C19, CYP3A4) (affected by CYP2C19 polymorphism)
 Adverse effects of PPIs

• GIT : Nausea, Diarrhea & Abdominal colic

• CNS: Headache, Dizziness & Drowsiness
• Hypochlorhydria → In animals (Gastric tumors)
• Vitamin B12 deficiency (long term use)
• Hypomagnesemia (long term use)
• Enzyme inhibition (omeprazole ↓ hepatic activation of clopidogrel)
 3. H2 Blockers

Cimetidine
Ranitidine
Famotidine
Nizatidine
 Cimetidine
1st member developed

-
Enzyme inhibition CNS adverse effects Antiandrogenic
Sedation – confusion - effect
hallucination
 Ranitidine
More potent than cimetidine

FPM
50% bioavailability
50% metabolized in liver (CI in hepatic dysfunction –
used in renal failure)
Anti-H. pylori effect (most efficient)
 Famotidine
The most potent

50% bioavailability

50% decomposed by gastric acidity 50%

Excreted mainly by kidney (preferred in liver dysfunction)

Cytoprotective effect
 Nizatidine
✓100% bioavailability (no 1st - pass effect)

✓Used in liver dysfunction

✓Completely excreted by kidney → CI in renal

dysfunction
1. Diarrhea or constipation
2. CNS: Sedation - Confusion - Hallucinations
3. Anti-androgenic Cimetidine

4. Enzyme inhibition
5. Tolerance
6. Bradycardia if given rapidly IV
 Mucosal Protectives (Cyto-protectives)
1. Sucralfate
Aluminium salt of sulfated sucrose

Mechanism of action
Bile
Acid pepsin
Acidic
medium
-
+

+ Increases PG synthesis and mucus and bicarbonate secretion

 Uses
Stress ulcer prophylaxis (mainly)
Adverse Effects
1. Nausea, vomiting and dry mouth

2. Flatulence, constipation

3. Al3+ toxicity: - Chelates phosphates → osteomalacia

- Encephalopathy in renal diseases

 Anti-H. pylori Drug Therapy

I. Antimicrobials
1. Clarithromycin
2. Amoxicillin
3. Metronidazole - Tinidazole (in patients allergic to amoxicillin)
II. Acid suppressants (PPIs - ranitidine bismuth citrate)
III. Colloidal bismuth: Bismuth subcitrate or subsalicylate
 Anti-H. pylori Drug Regimens
High efficacy anti-H. pylori Triple therapy (10-14 days):
Lansoprazole + Clarithromycin + Amoxicillin (or metronidazole)
Followed by 4-6 weeks: PPI therapy

Sequential therapy: 10 days

Day 1 to day 5: PPI + Amoxicillin
Day 6 to day 10: PPI + Clarithromycin + Tinidazole.
Antacids
 Types of Antacids
Local antacids Systemic Antacids
Al3+ Hydroxide NaHCO3
Constipation
Rapid onset
Mg2+ Salts
Diarrhea Potent (↑ pH > 7)

Ca2+ carbonate Disadvantages

• Constipation • Systemic alkalosis on long- term use

• Rebound hyperacidity • Rebound hyperacidity

• Systemic alkalosis and • Na+ content is dangerous in HF,

hypercalcemia (Milk-alkali hypertension or renal disease

syndrome) • ↑ CO2 → flatulence, eructation

• ↑ CO2 → flatulance & eructation • Alkaline urine → renal stones

 Choice of antacids
Al3+ hydroxide & Mg2+ salts do not result in CO2 release or
systemic alkalosis thus they are the most commonly used
antacids, alone or combined (to neutralize the effects of each
other on bowel habit)

Antacids should be cautiously used in elderly & renal impairment:

- Al3+ antacids → osteomalacia, encephalopathy
- Mg2+ antacids → CNS depression
 Lines of treatment of GERD
A.Life-Style Modification
1. Remaining upright or in a semi-sitting position for 2 hours after meals
2. Elevation of head of patient during sleep
3. Diet:
• ↓ Meal size (large meal → distention of stomach → increasing reflux)
• Food to be avoided: citrus fruits (mucosal irritants) - fried or fatty
food, caffeinated drinks, chocolate, peppermint, spices (↓ LES
pressure)
• Stop Smoking, alcohol, and caffeine
 Lines of treatment of GERD
B. Drug therapy of GERD
1. Acid-suppressive agents (Antisecretory drugs):
• PPIs – P-CAB (the main & most effective treatment)
• H2 antagonists (backup drugs) A night dose may be combined with
PPIs to cover nocturnal breakthrough in HCl release
 Lines of treatment of GERD
B. Drug therapy of GERD
2. Antacids containing alginic acid (regularly after meals):
Alginate forms a floating gel which blocks the reflux & coats esophagus
→ rapid pain relief
 Lines of treatment of GERD
B. Drug therapy of GERD
3. Prokinetics:
✓Increase gastric motility and emptying
✓Improve LES tone & esophageal motility → ↓ reflux & ↑luminal clearance
4. Eukinetics Baclofen (GABA-B agonist)
• Inhibit TLESRs
Esophageal varices
Pharmacological Control of
Bleeding Varices
1.IV Vasopressin or Terlipressin

• VC of mesenteric blood vessels → ↓ portal blood flow

2.IV vasopressin combined with IV nitroglycerin

• Nitroglycerin → VD →

✓ ↓systemic vasoconstriction induced by vasopressin

✓ ↑ its portal hypotensive actions

3. Octreotide:
- Direct vasoconstrictor of splanchnic arterioles
- ↓ release of peptides contributing to hyperdynamic circulation in portal
hypertension (as glucagon)

4. IV antisecretory immediately after control to prevent re-

bleeding (IV ranitidine, PPI)

5. Prophylaxis measures against hepatic encephalopathy

(enema with laxatives)
Prophylaxis of variceal bleeding
in patients with cirrhosis
Non-selective β blockers (propranolol and nadolol) →
Block adrenergic VD tone in mesenteric arterioles →

• Unopposed α action →VC →↓ portal inflow

• ↓Cardiac output
 Management of hepatic encephalopathy
1.Treatment of precipitating factors: infection - GIT bleeding –
hypokalemia (induced by diuretics) - hypoglycemia
2.H2 Antagonists: ↓ acidity, gastric erosions and bleeding
3.Drugs ↓ portal pressure: ↓ bleeding of esophageal varices:
Octreotide - vasopressin (plus nitrates) - β Blockers
4.Flumazenil: benzodiazepine receptor antagonist (minor role)
5. Decrease ammonia by:
• ↓ dietary protein
• Lactulose (mainstay of therapy)
• Evacuant enema with lactulose (the first and most important step)
• Neomycin - Rifaximin (kills bacterial flora → ↓ ammonia
production)
• Probiotics e.g. Lactobacillus → displacement of urease-containing
bacteria
• Stimulation of ammonia metabolism:
i. Ornithine-aspartate: → ↑ increase NH3 removal by liver
ii. Sodium benzoate
 Lactulose
Mechanism of action
A nonabsorbable synthetic saccharide digested by
colonic bacterial flora into short chain organic acids →
acidifies colon contents leading to:
• Binding of ammonia
• Inhibition of ammonia producing bacterial flora
• Osmotic laxative effect
 Drug therapy of diarrhea
Lines of Management
1. Oral rehydration solution (ORS)

2. Frequent fluid intake & tea (astringent→ precipitates surface proteins)

3. Diet: avoid fat, milk, high fiber food

4. Specific antimicrobial therapy against causative organisms:

- Floroquinolones for most bacteria except clostridium difficile

- Metronidazole for clostridium difficile, amoebiasis & giardiasis

5. Symptomatic treatment: antidiarrheal agents

 Antidiarrheal Agents
I. Antimotility Agents:

Diphenoxylate, Loperamide (opioid- related)

Mechanism of Action

- Act on presynaptic opioid receptors in intestine → ↓ ACh release → ↓

peristalsis allowing water and salt to be absorbed back into the body

- Spasmogenic effect (↑ smooth muscle tone) with diphenoxylate

Atropine is combined with diphenoxylate to
• Relieve its spasmogenic effect

• Discourage abuse (which may occur with prolonged use)

• May contribute to the antidiarrheal action

Advantages of Loperamide
• At therapeutic doses they do not cross BBB (act only peripherally)

• Lower abuse potential

 Drug therapy of constipation

Classification According to Mechanisms of Action

1. Bulk Laxatives
2. Osmotic Laxatives
3. Stool Lubricants
4. Stool softeners
5. Stimulants/Irritants
1.Bulk Laxatives
Fibers that are unabsorbed in GIT → adsorb H2O forming a bulky gel → distend colon &
stimulate peristalsis

• Bran - Psyllium
• Methyl cellulose

+++peristalsis
2. Osmotic Laxatives
Non absorbable salts or sugars that hold water by osmotic force →↑ stool fluidity &
intestinal distension → stimulate peristalsis

• MgSO4
• Lactulose
• Sorbitol
• Polyethylene glycol solution (PEG)
3. Stool Lubricants
Paraffin oil
Lubricates hard stool

4. Stool softeners
Soften hard stools (↑ water content of stools) → easy passage

• Evacuant enema & glycerin suppository

• Docusate (enema)
5. Stimulants/ Irritants
They irritate the colon → stimulate peristalsis chemically

• Castor oil
• Bisacodyl
• Anthraquinones (cascara - senna) (delayed onset: 6-8 h)