block 3 - medico...
TRANSCRIPT
BLOCK 3 GASTROINTESTINAL, CARDIOVASCULAR &
RESPIRATORY SYSTEMS
COPYRIGHT MBBS NOTES © DATO FARID FADZILAH
First Edition
GASTROINTESTINAL SYSTEM
A. Drugs for Peptic Ulcer 1. Classify drugs used in acid peptic disease based on their mechanism of action. *** 2. Explain the role of following drugs in acid peptic disease: H2 blockers, proton pump
inhibitors (PPIs) and antacids. *** 3. List the uses of H2 blockers and proton pump inhibitors (PPIs).*** 4. Describe the role of the following drugs in acid peptic disease: sucralfate, colloidal
bismuth subcitrate (CBS), prostaglandin analogues and anticholinergics. ** 5. Describe the pharmacokinetic features of PPIs. *** 6. Explain the drug interaction between antacid/ H2 blocker/PPI and sucralfate. ***
(Tripathi) 7. List the adverse effects of the following: H2 blockers, PPIs and antacids. *** 8. List the adverse effects of the following: sucralfate and prostaglandin analogues. ** 9. Explain the rationale for using antacid combinations in acid peptic disease. *** 10. List the drugs used to eradicate H. pylori. *** 11. Explain the rationale for using US-FDA approved triple drug regimen for H. pylori
eradication. *** 12. Explain the role of each drug used in quadruple therapy for H. pylori eradication. **
B. Anti-emetics (Tripathi)
1. Classify antiemetics based on their mechanism of action. *** 2. Describe the mechanism of antiemetic action of the following: anticholinergics,
(Tripathi) 5HT3 antagonists,(tripathi) prokinetics and antihistaminics. *** 3. Describe the differences between metoclopramide and domperidone. *** 4. Explain how prokinetics are useful in gastroesophageal reflux disease. *** 5. List the adverse effects of the following: hyoscine, promethazine, metoclopramide and
ondansetron. *** 6. Explain the drug interaction between the following: metoclopramide and levodopa,
cisapride and CYP3A4 inhibitors.*** 7. Mention antiemetics of choice in the following: motion sickness, morning sickness,
cancer chemotherapy induced vomiting, drug induced vomiting, vertigo and gastric stasis in diabetes. ***
C. Anti-amoebic Drugs
1. Classify antiamoebic drugs based on their site of action. *** 2. Describe the mechanism of action of metronidazole. *** 3. Describe the therapeutic uses of metronidazole. *** 4. Describe the adverse effects of metronidazole. *** 5. Explain the drug interaction of metronidazole with alcohol. *** 6. Describe the advantages of tinidazole and secnidazole over metronidazole. *** 7. Explain the mechanism of action of diloxanide furoate. *** 8. Describe the therapeutic uses of diloxanide furoate. *** 9. Outline the treatment for the following: asymptomatic intestinal amoebiasis, invasive
intestinal amoebiasis and amoebic liver abscess. *** (Katzung)
D. Anti-helminthic Drugs 1. Describe the mechanism of action of the following: mebendazole/albendazole,
diethylcarbamazine citrate (DEC) and praziquantel. *** 2. List the therapeutic uses of the following: mebendazole, albendazole and DEC. *** 3. Describe the adverse effects of the following: mebendazole,albendazole and DEC. *** 4. Describe the advantages of albendazole over mebendazole. *** 5. Describe the advantages of using albendazole over praziquantel in the treatment of
neurocysticercosis. ** (Tripathi)
E. Drugs for Constipation 1. Classify laxatives and purgatives based on their mechanism of action. *** 2. Describe the mechanism of action of the following: bulk laxatives, lubricant laxatives,
surfactant laxatives,stimulant/irritant purgatives and osmotic purgatives. *** 3. List adverse effects of various classes of laxatives and purgatives. *** 4. Explain the therapeutic uses of lactulose. ** 5. List various indications for each class of laxatives and purgatives. *** 6. Describe purgative habit. **
F. Drugs for Diarrhoea
1. Describe the composition of WHO-ORS. *** 2. Describe the importance of each ingredient in ORS. *** (Tripathi) 3. List non-diarrheal uses of oral rehydration therapy. *** (Tripathi) 4. Describe cereal based ORS. ** 5. Classify non-specific antidiarrheal agents based on their actions.*** 6. List the drugs used in inflammatory bowel disease (IBD). ** 7. Discuss the role of sulfasalazine in IBD. ** 8. Describe the advantages of meselamine (mesalazine) over sulfasalazine. * 9. Explain the rationale for combining diphenoxylate with atropine in the treatment of
diarrhoea. *** 10. Explain the mechanism of action of antimotility and antisecretorydrugs. *** 11. Describe the advantages of loperamide over codeine as an antidiarrhoeal agent. ** 12. Describe adverse effects and contraindications of antimotility and antisecretorydrugs.
***
G. Drugs for Irritable Bowel Syndrome (IBS) 1. List various classes of drugs used in IBS with examples. * 2. Describe the role of alosetron in IBS. *
RENAL AND CARDIOVASCULAR SYSTEMS
A. Diuretics 1. Define diuretics. *** 2. Classify diuretics based on their site of action. *** 3. Explain the mechanism of action of following: loop diuretics, thiazides, potassium
sparing diuretics (amiloride/triamterene and spironolactone) and carbonic anhydrase inhibitors. ***
4. Describe the therapeutic uses of frusemide. *** 5. Describe the adverse effects of loop diuretics. *** 6. Explain the drug interactions of frusemide with digoxin, NSAIDs, aminoglycosides and
lithium. *** 7. Describe the therapeutic uses of thiazides. *** 8. Describe the adverse effects of thiazides. *** 9. Explain the drug interactions of thiazides with digoxin and lithium.*** 10. Describe the therapeutic uses of potassium sparing diuretics.*** 11. Describe the adverse effects of potassium sparing diuretics. ** 12. Explain the drug interaction of potassium sparing diuretics with angiotensin converting
enzyme inhibitors and thiazides/loop diuretics. *** 13. Describe the characteristic features of osmotic diuretics. *** 14. Explain the role of mannitol in cerebral edema and glaucoma.*** 15. List the other therapeutic uses of osmotic diuretics. *** 16. List the adverse effects and contraindications of osmotic diuretics. *** 17. Describe the therapeutic uses of carbonic anhydrase inhibitors.** 18. Describe the adverse effects of carbonic anhydrase inhibitors.**
B. Vasopressin analogues
1. List ADH receptor agonists (vasopressin analogues).** 2. Describe the therapeutic uses of vasopressin and its analogues based on V1 & V2
receptor-mediated actions.** 3. Describe the adverse effects of vasopressin and its analogs. *
C. Drugs Affecting Renin Angiotensin Aldosterone System (RAAS)
1. Draw RAAS cascade and indicate sites of action of groups of drugs with examples that inhibit the cascade. ***
2. Describe the advantages of enalapril over captopril. ** 3. Explain the therapeutic uses of ACE inhibitors. *** 4. Describe the adverse effects of ACE inhibitors. *** 5. Explain the drug interactions of ACE inhibitors with NSAIDs and potassium sparing
diuretics. *** 6. Describe the differences between ARBs and ACE inhibitors. ***
D. Drug therapy of hypertension 1. Depict physiological mechanisms that control blood pressure and indicate the sites of
action of various classes of antihypertensive drugs. *** 2. Explain the antihypertensive action of the following: thiazides, beta blockers, ACE
inhibitors, ARBs, calcium channel blockers (CCBs), clonidine, methyldopa, hydralazine, minoxidil, diazoxide and fenoldopam. ***
3. List the indications of frusemide in hypertension. *** 4. Explain why frusemide is a weaker antihypertensive than thiazides. *** 5. Describe advantages of CCBs over other vasodilators as antihypertensive drugs.*** 6. Describe the differences between verapamil/diltiazem and dihydropyridines. *** 7. Describe the pharmacokinetic features of amlodipine. *** 8. Describe the adverse effects of the following: verapamil, diltiazem and nifedipine. *** 9. List other uses of CCBs 10. List the adverse effects of clonidine and methyldopa. *** 11. Explain the rationale for using the following drug combinations in the treatment of
hypertension:***
Vasodilator and beta blocker
ACE inhibitor/ARB and diuretic
ACE inhibitor/ARB and beta blocker 12. Describe the antihypertensive action of prazosin. *** 13. Describe the therapeutic uses of minoxidil. ** 14. List the adverse effects of hydralazine and minoxidil. ** 15. Discuss the role of sodium nitroprusside in the treatment of hypertension. *** 16. Describe the treatment of hypertensive emergencies. *** 17. Choose the appropriate drug(s) to treat hypertension in the following: diabetes,
pregnancy, elderly patients, peripheral vascular disease, migraine, benign prostatic hypertrophy, coronary artery disease, CCF, supraventricular tachycardia, thyrotoxicosis, hyperlipidemia and bronchial asthma/COPD. ***
18. List the antihypertensive drugs to be avoided in the following: diabetes, pregnancy, peripheral vascular disease, benign prostatic hypertrophy, coronary artery disease, CCF, thyrotoxicosis, hyperlipidemia and bronchial asthma/COPD***
E. Anti-arrhythmic Drugs
1. Describe various types of arrhythmias. ** 2. Classify antiarrhythmic drugs as proposed by Vaughan Williams and Singh. *** 3. Describe the mechanism of action of class I, class II, class III and class IV antiarrhythmic
drugs. *** 4. Explain the role of lignocaine in arrhythmias. *** 5. List the adverse effects of lignocaine. *** 6. List the adverse effects of amiodarone. *** 7. Discuss the role of adenosine in arrhythmias. *** 8. List the other drugs used in paroxysmal supraventricular tachycardia. ***
F. Drugs used in angina pectoris and myocardial infarction 1. Classify antianginal drugs based on their mechanism of action.*** 2. List the drugs used for chronic prophylaxis of angina. *** 3. List the drugs used to terminate an attack of angina. *** 4. Describe the mechanism of action of nitrates. *** 5. Explain the mechanism of relief of chest pain with nitrates in classical angina. *** 6. Describe the mechanism of relief of chest pain with nitrates in variant angina. *** 7. Describe the important pharmacokinetic features of the following: nitroglycerine,
isosorbide dinitrate and isosorbide mononitrate.*** 8. Describe the therapeutic uses of nitrates with route of administration. *** 9. Explain the management of acute attack of angina. *** 10. Explain the role of nitrites in cyanide poisoning. *** 11. Describe the adverse effects of nitrates. *** 12. Describe the drug interaction of nitrates with sildenafil and other vasodilators. *** 13. Explain how CCBs are effective in classical, variant and unstable angina. *** 14. Explain the rationale for using beta blockers in angina. *** 15. Explain why beta blockers are contraindicated in variant angina.*** 16. Explain the rationale for using various drug combinations in angina. *** 17. Explain the role of following drugs in angina: K+ channel openers, trimetazidine,
ranolazine, ivabradine, antiplatelet drugs and statins. ** 18. Outline the drug therapy of myocardial infarction. ***
G. Drug therapy of Heart Failure
1. Classify drugs used in the treatment of heart failure based on their mechanism of action. ***
2. Explain the mechanism of action of digitalis. *** 3. Explain the pharmacological actions of digitalis on the following: heart, blood vessels
and kidney. *** 4. Describe the role of digitalis in the treatment of acute heart failure. *** 5. List the other therapeutic uses of digitalis. *** 6. Describe the adverse effects of digitalis. *** 7. Explain the management of digitalis toxicity. *** 8. Describe the contraindications of digitalis. *** 9. Explain the important drug interactions of digitalis. *** 10. Explain the role of phosphodiesterase III inhibitors in the treatment of heart failure. ** 11. Explain the role of the following drugs in the treatment of heart failure: diuretics, ACE
inhibitors/ARBs, beta blockers, vasodilators, dopamine and dobutamine. ***\Describe the role of furosemide in the treatment of acute pulmonary edema. ***
12. Describe the role of vasopeptidase inhibitors, natriuretic peptides and vasopressin receptor antagonist in the treatment of heart failure. **
13. List the drugs used for the relief of congestive symptoms of heart failure. *** 14. List the drugs that arrest/ reverse disease progression in heart failure. ***
RESPIRATORY SYSTEM
A. Drugs for Bronchial Asthma 1. Classify drugs used in the treatment of bronchial asthma based on their mechanism of
action. *** 2. Explain the role of following drugs in bronchial asthma: beta-2 agonists,
anticholinergics and mast cell stabilisers. *** 3. Describe the adverse effects of beta-2 agonists. *** 4. Describe the mechanism of action of methylxanthines. ** 5. Describe the important pharmacokinetic features of theophylline. ** (Tripathi) 6. Describe the therapeutic uses of methylxanthines. ** 7. Describe the adverse effects of methylxanthines. ** 8. Discuss the role of glucocorticoids in bronchial asthma. *** 9. Describe the role of following drugs in asthma: leukotriene receptor antagonists and
omalizumab. ** 10. Describe the other therapeutic uses of mast cell stabilisers. *** 11. List the adverse effects of the following: mast cell stabilisers and leukotriene receptor
antagonists. ** 12. Describe the advantages of using MDI with spacer.[Tripathi] 13. Describe the other devices used to administer inhalational drugs in asthma.
***[Tripathi] 14. Describe the management of different types of asthma. ***[Tripathi]
B. Drugs for Cough
1. Describe the mechanism of action of the following: expectorants and antitussives. *** 2. List the adverse effects of the following: expectorants and antitussives. *** 3. Describe the advantages of dextromethorphan and noscapine over codeine in the
treatment of cough. *** 4. Describe the role of following drugs in the treatment of cough: antihistamines and
bronchodilators. ** [Tripathi] 5. List the drugs used in the treatment of productive cough and non-productive cough.
***
C. Anti-tubercular Drugs 1. Enumerate first line essential, first line supplemental and second line antitubercular
drugs. *** 2. Describe the mechanism of action of the following: isoniazid (INH), rifampicin,
pyrazinamide and ethambutol. *** 3. Describe the pharmacokinetic features of INH. *** 4. Describe the adverse effects of the following: INH, rifampicin, pyrazinamide and
ethambutol. *** 5. Explain the rationale for using pyridoxine with INH. *** 6. Describe the important drug interactions of rifampicin. *** 7. List the other therapeutic uses of rifampicin. ** 8. Describe the goals of antitubercular chemotherapy. *** [Tripathi] 9. Discuss short course chemotherapy of new sputum positive pulmonary tuberculosis
(category I TB). ***
D. Anti-leprotic Drugs 1. Enumerate drugs used in leprosy. ** 2. Describe the mechanism of action of dapsone and clofazimine.** 3. Describe the adverse effects of dapsone. ** 4. Explain WHO regimens for multibacillary and paucibacillary leprosy. ** 5. List the drugs used in treatment of lepra reaction. **
GASTROINTESTINAL SYSTEM
DRUGS FOR PEPTIC ULCER
PEPTIC ULCER
NORMAL MECHANISM OF ACID SECRETION
The basolateral membrane of parietal cell contains receptors for Gastrin (CCK2 receptor) released from G cells in pyloric glands Histamine (H2 receptor) released from enterochromaffin-like cells (ECL cells) Acetylcholine (M3 receptor) released from vagal efferents
H2 receptors result in an increase in cAMP levels but M3 and CCK2 receptors act by stimulating phospholipase C mobilizes intracellular Ca2+
Gastrin is secreted in response to: Increase in antral pH Food constituents Vagally mediated reflexes involving ENS ganglion cells release gastrin releasing
peptide (GRP) and Acetylcholine
Surface epithelial cells secrete HCO3- which gets trapped in the mucous layer over the mucosal
surface, offering protection against harsh acid condition (stabilized by trefoil peptide) Prostaglandins augment mucous and HCO3
- secretion gives cytoprotective effect PGE2 also inhibits acid secretion by opposing cAMP generation via EP3 receptors (in
parietal cells) and gastrin release (from antral G cells)
The chief cells/peptic cells release pepsinogen which in on acidic medium (pH<2) is cleaved to form pepsin, a proteolytic enzyme
PEPTIC ULCER DISEASE
A localized defect extending at least into the submucosa as a result of acid and pepsin attacks
Usually develops on a background of chronic gastritis, as a result of the imbalance between mucosal defences and damaging forces
Major sites: 1st part of duodenum Junction of antral and body mucosa Distal oesophagus (as a result of GERD or ectopic gastric mucosa) Gastro-enterostomy sites
Defensive forces: Surface mucous secretion Bicarbonate secretion Mucosal blood flow Apical surface membrane transport Epithelial regenerative capacity Elaboration of prostaglandins
AETIOPATHOGENESIS
Helicobacter pylori infection Flagella for motility in viscous mucous Urease generates NH3 from urea elevates pH Adhesins increased bacterial adherence to surface epithelial cells Toxins eg. CagA in ulcer and cancer development
NSAIDs Interfere with cytoprotection provided by prostaglandins Reduces HCO3
- secretion
Alcohol direct cellular injury
Gastric hyperacidity eg. in parietal cell hyperplasia, excessive secretory responses, Helicobacter pylori infection, Zollinger-Ellison syndrome (excess gastin release)
Chronic renal failure and hyperparathyroidism results in hypercalcaemia stimulates gastrin production increases acid secretion
Self-imposed/exogenous psychological stress directly increases gastrin acid secretion
Smoking increases nervous stimulation of stomach secretory glands CLINICAL FEATURES & COMPLICATIONS
Epigastric burning and aching pain
Perforation into adjacent cavity peritonitis
Penetration into adjacent organ eg. liver, pancreas
Haemorrhage from eroded vessels in the ulcer base
Anaemia
Obstruction due to fibrous strictures
Malignant transformation (rare)
CLASSIFICATION OF DRUGS USED IN PEPTIC ULCER
Mechanism of action Drugs
Neutralize gastic acid (antacids)
Systemic antacids: Sodium bicarbonate
Non-systemic antacids: Buffer type: Aluminium hydroxide, Magnesium trisilicate,
Magaldrate Non-buffer type: Magnesium hydroxide, Calcium carbonate Miscellaneous: Alginates, Simethicone
Reduce gastric acid secretion
H2 receptor antagonists: Cimetidine, Ranitidine, Famotidine, Nizatidine, Roxatidine, Loxatidine
Proton pump inhibitors: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole
Anti-cholinergics: Propantheline, Oxyphenonium, Pirenzepine, Telenzepine
Prostaglandin analogues: Misoprostol, Enprostil, Rioprostil
Mucosal protective drugs
Sucralfate, Colloidal bismuth subcitrate, Ranitidine bismuth citrate
Ulcer healing drugs Carbenoxolone
Anti-Helicobacter pylori drugs
Amoxicillin, Clarithromycin, Tetracycline, Metronidazole, Ranitidine bismuth citrate, Bismuth subsalicylate and proton pump inhibitors (in combination)
ANTACIDS
THERAPEUTIC USES
Antacids are weak bases that neutralize gastric HCl, thereby raising the pH of stomach contents, decreasing the acid load delivered to duodenum and reducing activity of pepsin
Minor contributions: Stimulation of PGE2 and PGI2 production by gastric mucosa Also enhances mucosal blood flow, stimulate secretion of mucous and HCO3
- Partly from a protective layer over gastric mucosa
ADVERSE EFFECTS
Distension and belching (bloating) Due to production of CO2 Belching occurs only on using CaCO2 and NaHCO3 No belching occurs on using Mg(OH)2 or no CO2 produces
Hypercalcaemia, renal insufficiency and metabolic alkalosis Excessive dose of CaCO3, given along with milk These are called “milk-alkali syndrome”
Metabolic alkalosis Increased pH of blood and urine Unreacted alkali such as NaHCO3 get readily adsorbed from gastrointestinal lumen
Exacerbation of fluid retention in patients with hypertension, congestive heart failure and renal insufficiency Due to ↑ Na+ load, as it is highly water soluble and rapidly absorbed from the gut
Acid rebound or “rebound acidity” Due to ↑pH (>4.0) Cause reflux secretion of gastrin which stimulates acid production
RATIONALE FOR USING ANTACID COMBINATION IN PEPTIC ULCER DISEASE Advantages of combination of Magnesium salts and Aluminium salts
1. A prompt and sustained effects produced, because
Mg hydroxide fast acting
Al hydroxide slow acting 2. Bowel movement is least affected, because
Mg salts cause diarrhoea
Al salts cause constipation
Hence, both are used together to minimize the impact of bowel movement 3. Gastric emptying is least affected, because
Mg salts enhances the gastric emptying
Al salts delays the gastric emptying 4. Drug combination reduces the dose of the drug, thus reduces their toxicity
H2 RECEPTOR ANTAGONISTS
DRUGS Cimetidine, Ranitidine, Famotidine, Nizatidine, Roxatidine, Loxatidine MECHANISM OF ACTION
Competitively inhibits H2 receptors on parietal cells and suppress basal and food stimulated acid secretion
Block actions of histamine released from ECL cells
Also inhibits direct stimulation on parietal cells by gastrin or Acetylcholine
Results in marked decrease in gastric secretion (long duration) and pepsin production (short duration)
Rank order of potency of the drugs: Nizatidine > Famotidine > Ranitidine > Cimetidine
Nizatidine, Famotidine and Ranitidine are newer drugs, while Cimetidine is the earliest drug THERAPEUTIC USES
Gastroesophageal reflux disease (GERD)
Duodenal and gastric ulcers
NSAIDs induced ulcers
Prevention of stress related gastric bleeding
Prevention of ulcer recurrence
Zollinger-Ellison syndrome (widespread severe peptic ulceration)
Chronic urticarial ADVERSE EFFECTS
Extremely safe drugs
Headache, fatigue, myalgia and constipation may occur, but rarely
Mental status changes may occur with I.V. Cimetidine only
Endocrinal effects are seen in Cimetidine only It inhibits the binding of dihydrotestosterone to androgen receptors causing
impotence in males) It inhibits metabolism of estradiol and increases serum prolactin level causing
gynaecomastia in males and galactorrhoea in females (on long term use)
H2 blockers reduce the secretion of intrinsic factor but no vitamin B12 deficiency occurs even after prolonged use
They cross placental barrier but have no harmful effects on foetus
They are secreted into breast milk, hence should be provided during pregnancy and lactation
PROTON PUMP INHIBITORS
DRUGS Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole PHARMACOKINETICS
Absorption occur in intestine
Drug is given orally as enteric coated formulation
Pantoprazole can be both oral and I.V.
Bioavailability of respective drugs:
Food decreases their bioavailability: Drugs should be administered on an empty stomach However, in fasting state, only 10% proton pumps are active, rest are in dormant state Therefore, drugs must be administered in the morning before taking breakfast This is because peak serum concentration coincides with the maximum activity of
proton pumps Optimal binding of proton pumps to PPIs occurs when pumps are in active state
They require acid for activation therefore, other acid suppressing agents are not co-administered
The drugs are highly protein bound
Short serum half-life: 1-2 hours However, duration of acid inhibition lasts upto 24 hours It is because PPIs are irreversible inactivator, so at least 18 hours is needed for the
synthesis of new H+/K+–ATPase pump
Rapid first pass metabolism
Metabolized by liver
In case of liver impairment, dose reduction is needed
Excretion is through urine and faeces ROLES OF PPIs
Mainly decrease acid secretion
Also inhibit gastric mucosal carbonic anhydrase
Hence decrease HCO3- secretion in mucous
Features of PPIs Prodrug Active form is sulfonamide cation Weak base Irreversible binding
MECHANISM OF ACTION
PPIs enter parietal cell from blood by passive diffusion across lipid membrane ↓
In canaliculi of parietal cells, PPIs (weak base) which are exposed to acidic environment get concentrated by ion trapping mechanism, where they are activated
↓ Formation of sulfonamide cation (activated form)
↓ They bind covalently with sulfhydryl group of cysteines from extracellular domain H+/K+–ATPase
pump ↓
Inactivating it irreversibly and shutting off acid secretion
Acid secretion will only resume after newly synthesized pumps are inserted into luminal membrane of parietal cells
THERAPEUTIC USES
Duodenal and gastric ulcer disease
Gastroesophageal reflux disease (GERD)
NSAIDs induced ulceration
Prevention of ulcer recurrence
Zollinger-Ellison syndrome
Helicobacter pylori associated ulcers PPIs promote eradication of Helicobacter pylori by raising the intragastric PH which
helps in lowering the minimal inhibitory concentration (MIC) of antibiotics used against Helicobacter pylori
Most effective regimen of Helicobacter pylori eradication is a combination of two antibiotics and one PPI given twice daily
ADVERSE EFFECTS
PPIs are quite safe, yet diarrhoea, headache and abdominal pain may occur
They cross BBB, but not teratogenic
However, their safety during pregnancy and lactation has not been established
PPIs inhibit absorption of vitamin B12 on prolonged use
PPIs cause hypochlorhydria, theoretically, should increase the risk of enteric infections due to Shigella and Salmonella and by bacterial strains that have the potential to convert ingested nitrates into carcinogenic nitrites and nitrosamines
Increased risk of gastric neoplasia on prolonged use Suppressed gastric HCl secretion Feedback inhibitory role of stomastatin over gastrin release is endangered Gastrin level rise 2-4 fold in patients taking PPIs Gastrin causes hyperplasia of ECL cells which may transform into carcinoid tumour
Increased risk of chronic inflammation of gastric body with prolonged use of PPIs, in patients with Helicobacter pylori associated peptic ulcers which culminate into atrophic gastritis and intestinal metaplasia
SUCRALFATE
It is an aluminium salt of sulfated sucrose
Unabsorbed, hence devoid of side effects
However, as it also binds phosphate ions in intestine, hypophosphataemia may occur
Antacids lower its efficacy as polymerization only occurs in acidic media
Sucralfate adsorbs Tetracyclines, Fluoroquinolones, H2 blockers, Phenytoin and Digoxin hence decrease their absorption
MECHANISM OF ACTION
1. In acidic environment (pH<4), it polymerizes by cross-linking of molecules forms a sticky-like gel over ulcer crater which acts as acid-resistant barrier
2. Dietary as well as mucosal proteins also get adsorbed over this coat, forming another layer to provide further resistance
3. There is evidence that suggest it also stimulates mucosal PGE2 synthesis and HCO3- secretion
4. It is also believed to bind epithelial as well as fibroblast growth factors which promotes mucosal repair
5. Promotes ulcer healing (but it has no acid neutralizing action and delays gastric emptying), but not effective against NSAIDs-induced ulcers
ADVERSE EFFECTS
Hypophosphataemia
Constipation
Dry mouth
Nausea DRUG INTERACTION WITH ANTACIDS
Antacids should not be taken with Sucralfate because its polymerization is dependent on the pH of the acid Sucralfate polymerizes at pH <4 by cross-linking of molecules Antacids neutralize gastric acid and raise pH of gastric contents Hence, this combination is not synergistic
Antacids given concurrently reduce the efficacy of Sucralfate
COLLOIDAL BISMUTH SUBCITRATE
In gastric acidic media, it forms an acid-protective coating over ulcer base
Reported to stimulate PGE2, mucous and HCO3- secretion
It dislodges Helicobacter pylori from the surface of gastric mucosa and has direct antimicrobial activity against this organism
Many duodenal ulcer cases which did not heal after H2 blocker treatment, get healed after 4 subsequent weeks treatment with Colloidal bismuth
Heals peptic ulcer within 4-8 weeks of treatment
Given orally, excellent safety profile (but can cause blackening of stool & darkening of tongue)
On prolonged use, Bismuth toxicity can occur (osteodystrophy, encephalopathy and albeit)
Antacids reduce its efficacy
Another bismuth salt used in clinical practice is Ranitidine bismuth citrate, which upon hydrolysis by gastric acid releases Bismuth as well as Ranitidine
Currently used as one of the agents in an anti-Helicobacter pylori treatment regimen
PROSTAGLANDIN ANALOGUES
DRUGS Misoprostol, Enprostil, Rioprostil MECHANISM OF ACTION They mimic the protective role of PGE2 and PGI2 on gastric mucosa by:
Inhibiting acid secretion by inhibiting CAMP in parietal cells
Inhibiting gastrin release from antral cells (G cells) ↓ intracellular Ca2+ and histamine release ↓ acid secretion
Stimulating the secretion of mucous and HCO3-
Acts as a buffer to neutralize the acid secreted Reinforce the protective effects of mucous layer covering gastric and duodenal mucosa
Enhances mucosal blood flow MISOPROSTOL
Used to heal peptic ulcer in patients using NSAIDs and in chronic heavy smokers
But not widely accepted due to its adverse effects and a need for multiple daily dosing due to short plasma half-life of 25-30 minutes
PPIs are equally effective and better tolerated for this indication ADVERSE EFFECTS
Diarrhoea and colicky pain (because it increases water and electrolyte secretion in intestine)
Other GIT side effects include nausea, vomiting and flatulence
Headache and dizziness can occur
It causes uterine contraction and uterine bleeding (hence should not be given to pregnant or women that may become pregnant)
ANTI-CHOLINERGICS
SELECTIVE M1 RECEPTOR BLOCKERS
Examples: Pirenzepine, Telenzepine
They block M1 receptor of paracrine cells in gastric mucosa ↓ histamine release ↓ acid secretion
Effectively heals and prevent recurrence of duodenal ulcers
Side effects: Dry mouth Blurred vision Constipation Urinary retention
No CNS side effects as they do not cross BBB NON-SELECTIVE ANTI-MUSCARINICS
Examples: Propantheline, Oxyphenonium
They are not used to treat peptic ulcer anymore because of: Peripheral side effects: dry mouth, blurred vision, constipation, urinary retention Increase gastric emptying time prolong exposure of ulcer bed to gastric acid Increase gastric emptying time and relax lower oesophageal sphincter exacerbate
GERD by allowing food reflux into oesophagus
DRUG REGIMEN
DRUG COMBINATIONS
a) Triple therapy (14 days)
Omeprazole (or Lansoprazole) + Clarithromycin + Amoxicillin (or Metronidazole)
Ranitidine bismuth citrate + Tetracycline + Metronidazole (or Clarithromycin) b) Quadruple therapy (14 days)
Omeprazole (or Lansoprazole) + Bismuth subsalicylates + Metronidazole + Tetracycline c) Sequential therapy (10 days)
For first 1-5 days, Omeprazole (or Lansoprazole) + Amoxicillin
For next 6-10 days, Omeprazole (or Lansoprazole) + Clarithromycin + Tinidazole TRIPLE THERAPY REGIMEN
Has comparable success rates that are desired
Combination therapy for 14 days provides greatest efficacy compared to 7-10 days short term regimen
Efficacious combination should provide eradication rate of >90% ROLE OF EACH DRUG IN QUADRUPLE THERAPY REGIMEN
Omeprazole Inactivate proton pump irreversibly and shutting off acid secretion
Inhibits gastric mucosal carbonic anhydrase and reduces HCO3- secretion
to mucous
Bismuth subsalicylate
Dislodges Helicobacter pylori from surface of gastric mucosa
Direct antimicrobial activity against this organism
Gets converted to Bismuth oxychloride and Bismuth citrate with chelate glycoproteins and amino acids at ulcer base to form acid resistant protective coating
Metronidazole
Metronidazole enters the microorganism
Nitro group in Metronidazole acts as electron acceptor
Nitro group is reduced by ferredoxins
Binds to microorganism protein
Disrupts replication, transcription and repair process of DNA
Causes cell death (bactericidal activity)
Tetracycline
Broad spectrum antibiotics
The drug passes through outer membrane of Gram negative bacteria by diffusing through porin channel
Binds reversibly to 30S ribosomal subunit
Prevents binding of aminoacyl tRNA to mRNA ribosomal complex
Prevents the addition of amino acid to the growing peptide chain
Inhibits bacterial protein synthesis (bacteriostatic activity)
ANTI-EMETICS
ANTI-EMETICS BASED ON THEIR MECHANISM OF ACTION
Anti-cholinergics (M1 blocker) Hyoscine (Scopolamine)
Dicyclomine
H1 anti-histaminics (Anti-cholinergic + anti-serotonin +
Ca2+ channel blocker)
Promethazine
Diphenhydramine
Dimenhydrinate
Doxylamine
Cyclizine
Meclizine
Cinnarizine
Neuroleptics (D2 blocker)
Chlorpromazine
Triflupromazine
Prochlorperazine
Haloperidol
Prokinetic drugs
Metoclopramide
Domperidone
Cisapride
Mesapride
Itopride
5-HT3 antagonist
Ondansetron
Granisetron
Palonosetron
Ramosetron
NK1 receptor antagonist Aprepitant
Foxaprepitant
Adjuvant emetics
Dexamethasone
Benzodiazepines
Dronabinol
Nabilone
DRUGS MECHANISM OF ACTION
Anticholinergics Hyoscine Dicyclomine
Blocking conduction of nerve impulse across a cholinergic pathway from vestibular apparatus to the vomiting centre
Has poor efficacy of vomiting of other aetiology
H1 anti-histaminics
Promethazine Diphenhydramine Dimenhydrinate
Effects are based on anti-cholinergic, anti-histaminic, weak anti-dopaminergic, and sedative properties
Central anti-cholinergic action block the extrapyrimidal side effect of metoclopramide while supplementing its anti-emetic effect
Promethazine has weak anti-dopaminergic action
Cinnarizine Inhibits influx of Ca2+ from endolymph into the vestibular sensory cell which mediates labyrinthine reflexes
Neuroleptics Prochlorperazine
Act by blocking D2 receptor in the CTZ
Antagonize apomorphine induced vomiting
Additional anti-muscarinic, M1 as well as H1 anti-histaminic properties
Prochlorperazine is a labyrinthine suppressant
Prokinetics drug Metoclopramide D2 antagonist: It inhibits the dopamine receptor thus causing increase in acetylcholine release at primary cholinergic neuron
5-HT4 agonist: Activation of 5-HT4 receptor at excitatory interneuron, thus enhance acetylcholine release by myenteric motor neuron
5-HT3 antagonist: At high concentration, it block 5-HT3 receptor at inhibitory interneuron, thus suppress NO release, thus enhance acetylcholine release by myenteric motor neuron
All of this then lead to increase in LES tone, facilitate gastric peristalsis and speed up gastric emptying
Domperidone Similar to metoclopramide
Peripheral D2 receptor blocker
Cisapride 5-HT4 agonist action which promote acetylcholine release form myenteric plexus aided by 5-HT3 antagonism
5-HT3 antagonist Ondansetron Granisetron Palonosetron
Block the depolarizing action of 5-HT exerted through 5-HT3 receptor on vagal afferent in the GIT as well as NTS and CTZ
Blocks emertogenic impulses arised in GIT
METOCLOPRAMIDE
MECHANISM OF ACTION
It is a D2 receptor antagonist, 5-HT3 receptor antagonist and 5-HT4 receptor agonist
Central actions (anti-emetic effect): Mainly due to blockade of D2 receptor in CTZ At high concentration, it also blocks 5-HT3 receptor in CTZ It also blocks D2 receptor in basal ganglia causes extrapyramidal symptoms
Peripheral action (prokinetic effect): Activation of 5-HT4 receptor present in excitatory interneurons enhance Acetylcholine
release from primary cholinergic neuron in myenteric plexus (major mechanism) Due to blockade of D2 receptor, Dopamine loss its inhibitory control over Acetylcholine
release from primary cholinergic neuron in myenteric plexus Blockade of 5-HT3 receptor on inhibitory interneurons (in high doses only) suppress the
release of NO, which indirectly facilitates Acetylcholine release in myenteric plexus
Metoclopramide
D2 receptor antagonist ↓
Acts on myenteric neuron ↓
↓ inhibitory action on myenteric motor neuron
5-HT3 receptor antagonist ↓
Acts on inhibitory ENS interneuron (IEI)
↓ ↓ release of NO from IEI
5-HT4 receptor agonist ↓
Acts on excitatory ENS interneuron (EEI)
↓ ↑ release of Acetylcholine from
EEI
↑ Acetylcholine release from myenteric motor neuron ↓
↑ smooth muscle contraction ↓
Effects
Increases LES tone
Facilitates gastric peristalsis
Speeds up gastric emptying
PROKINETIC AGENTS Drugs that enhance the co-ordinated activity among various segments of the gut to propel luminal content
1. Stimulate GIT motility 2. Increase lower oesophageal sphincter pressure (hence useful for GERD) 3. Speed up gastric emptying (hence useful in gastroparesis) 4. Stimulate small intestine (hence beneficial for post-operative paralytic ileus and
colonic pseudo-obstruction) 5. Enhance colonic transit time (hence useful for treating constipation)
ADVERSE EFFECTS As Metoclopramide being a central and peripheral D2 blocker, it produces:
Drowsiness
Dizziness
Diarrhoea
Sedation
Muscle dystonias can be treated with centrally acting anti-cholinergics (Benzhexol) or anti-histaminics with anti-cholinergic action (Promethazine)
Extrapyramidal side effects (in high doses) like tremor and rigidity – due to blockade of D2 receptor in basal ganglia
Galactorrhoea in female
Gynaecomastia in male
Menstrual irregularities METOCLOPRAMIDE & LEVODOPA
Metoclopramide acts centrally and peripherally D2 receptor antagonist 5-HT3 receptor antagonist (only at high doses) 5-HT4 receptor agonist
By blocking Dopamine receptor in basal ganglia, it abolishes therapeutic effect of Levodopa
Hence, peripheral acting anti-emetic drug is more preferable to treat Levodopa-induced vomiting
Due to blockade of inhibitory effect of Dopamine on Prolactin release (on long term use)
DOMPERIDONE
MECHANISM OF ACTION
It is a prokinetic drug
Mechanism of action is similar to Metoclopramide
However, its anti-emetic efficacy is lower than Metoclopramide
Domperidone
D2 receptor antagonist ↓
Acts on myenteric neuron ↓
↓ inhibitory action on myenteric motor neuron
5-HT3 receptor antagonist ↓
Acts on inhibitory ENS interneuron (IEI)
↓ ↓ release of NO from IEI
5-HT4 receptor agonist ↓
Acts on excitatory ENS interneuron (EEI)
↓ ↑ release of Acetylcholine from
EEI
↑ Acetylcholine release from myenteric motor neuron ↓
↑ smooth muscle contraction ↓
Effects
Increases LES tone
Facilitates gastric peristalsis
Speeds up gastric emptying DIFFERENCES BETWEEN METOCLOPRAMIDE & DOMPERIDONE
Metoclopramide Domperidone
Rapidly absorbed after oral administration
Usually oral but oral bio-availability is low (extensive first pass metabolism)
More potent and efficacious Less potent and less efficacious
Extrapyramidal side effect main Lack of extrapyramidal side effect
Penetrate/cross BBB Poorly cross BBB
CISAPRIDE
MECHANISM OF ACTION
No D2 receptor blocking properties
Hence, does not act on CTZ
Thus, facilitates GIT motility with no anti-emetic action
Cisapride
5-HT3 receptor antagonist ↓
Acts on inhibitory ENS interneuron (IEI)
↓ ↓ release of NO from IEI
5-HT4 receptor agonist ↓
Acts on excitatory ENS interneuron (EEI)
↓ ↑ release of Acetylcholine from
EEI
↑ Acetylcholine release from myenteric motor neuron ↓
↑ smooth muscle contraction ↓
Effects
Increases LES tone
Facilitates gastric peristalsis
Speeds up gastric emptying CISAPRIDE & CYP3A4 INHIBITOR
Cisapride is primarily inactivated by CYP3A4
Administration of CYP3A4 inhibitor causes significant rise in Cisapride plasma level
At high concentration, Cisapride blocks delayed rectifying K+ channels in the heart
Thus, prolongs QT interval and predisposes to ventricular fibrillation
New congeners like Mosapride, Renzapride and Zacopride are preferred as they do not cause QT prolongation or arrhythmias
PROKINETICS IN GASTROESOPHAGEAL REFLUX DISEASE (GERD)
Metoclopramide, Cisapride and other prokinetics drug may relieve regurgitation and heartburn by: Increasing LES tone Improving esophageal clearance Facilitate gastric emptying Do not affect gastric acidity or promote healing of oesophagitis
Symptoms control afforded by prokinetics is much inferior compared to PPIs/H2 blockers. Their use in GERD has declined. It is now co-prescribed with PPIs/H2 blockers
ADVERSE EFFECTS
DRUGS ADVERSE EFFECTS
Hyoscine
(Scopolamine)
Sedation, dryness of mouth, blurred vision, cyclopegia, sedation, sleepiness and other anti-cholinergic side effects
Promethazine Sedation, dryness of mouth, nausea, vomiting
Metoclopramide
Usually-well tolerated Sedation, dizziness, loose stool, muscle dystonias (especially in
children) Long term effects: parkinsonism, galactorrhoea, gynaecomastia, no
teratogenic effect, but suckling infant may develop loose motion, dystonias, myoclonus
Ondansetron
Usually well-tolerated Most common: headache and dizziness Mild constipation, abdominal discomfort Hypotension, bradycardia, angina, and allergic reaction (especially
after I.V.)
ANTI-EMETICS OF CHOICE
CAUSE OF VOMITING PREFERRED DRUG
Motion sickness
Anti-cholinergics
Anti-histaminics
Anti-dopaminergic
Anti-HT3 drug
Morning sickness
Promethazine
Neuroleptics (Prochloperazine)
Metoclopramide (in low dose)
Dicyclamide
* Most cases of morning sickness can be managed by reassurance and dietary adjustment
Cancer chemotherapy induced vomiting
Ondansetron (prototype drug)
Aprepitant
Promethazine + Metoclopramide or Domperidone
Neuroleptics (Prochloperazine)
Drug-induced vomiting Neuroleptics (Prochloperazine)
Metoclopramide
Ondasetron
Vertigo Prochloperazine
Gastric stasis in diabetes Metoclopramide
first drug of choice
less effective
ANTI-AMOEBIC DRUGS
CLINICAL PRESENTATIONS OF AMOEBIASIS
Asymptomatic intestinal infection: carriers, passing cysts
Mild to moderate intestinal disease: non-dysenteric colitis
Severe intestinal infection
Hepatic abscess, amoeboma and other extra-intestinal disease CLASSIFICATION OF ANTI-AMOEBIC DRUGS
Luminal amoebicides Amides: Diloxanide furoate 8-Hydroxyquinolines: Iodoquinol Antibiotics: Paromomycin, Tetracyclines
Tissue amoebicides a) For intestinal and extra-intestinal amoebiasis
Nitroimidazoles: Metronidazole, Tinidazole, Ornidazole, Secnidazole, Satranidazole
Alkaloids: Emetine, Dehydroemetine b) For extra-intestinal amoebiasis only
Chloroquine
METRONIDAZOLE (PRODRUG)
MECHANISM OF ACTION
Drug of choice for intestinal and extra-intestinal amoebiasis
Acts on trophozoites
Has no effect on cysts
Nitro group of metronidazole is reduced by protozoan (ferredoxin) leading to cytotoxic reduced product that binds to DNA and proteins resulting into parasite death
THERAPEUTIC USES
Extra-luminal amoebiasis (combined with luminal amoebicide)
Trichomoniasis
Giardiasis
Broad spectrum of anaerobic bacteria eg. Helicobacter pylori infection, pseudomembranous colitis (Clostridium difficile), pelvic inflammatory disease and lung abscess
Amoebic brain abscess
Vincent’s angina
Prophylaxis after colorectal surgery
Helps in removal of guinea worm
ADVERSE EFFECTS
GIT: nausea, vomiting, dry mouth, metallic taste, diarrhoea
CNS: neurotoxicological effect Insomnia, dizziness Peripheral neuropathy, paresthesia Encephalopathy, convulsion (I.V. infusion, rare)
Dysuria, dark urine
Neutropenia
Disulfiram-like effect if taken with alcohol DRUG INTERACTIONS Metronidazole x Alcohol
When metronidazole is given with alcohol abdominal distress, nausea, vomiting, flushing or headache, tachycardia, hyperventilation
Metronidazole blocks aldehyde dehydrogenase enzyme
Ethanol Acetyldehyde Acetate OTHER DRUGS Tinidazole, ornidazole, secnidazole and satranidazole have longer duration, simpler dosing regimen, less toxicity compared to metronidazole, but are equally active
DILOXANIDE FUROATE
Split in the intestine (diloxanide + furoic acid), most of diloxanide is absorbed, conjugated to form a glucuronide which is excreted in urine (90%)
The unabsorbed diloxanide is the amoebicidal agent (10%) THERAPEUTIC USES
Drug of choice for asymptomatic intestinal infection
For eradication of infection and all forms of amoebiasis
Dose: 500 mg three times/day for 10 days
Alcohol dehydrogenase
Aldehyde dehydrogenase
Clinical setting Drug of choice
Asymptomatic intestinal infection
Luminal agent: Diloxanide furoate 500 mg TID for 10 days OR
Iodoquinol 650 mg TID for 21 days OR
Paromomycin 10 mg/kg TID for 7 days
Mild to moderate intestinal infection
Metronidazole 750 mg TID for 10 days OR
Tinidazole 2 g daily for 3 days + Luminal agent
Severe intestinal infection
Metronidazole 750 mg TID for 10 days OR
Tinidazole 2 g daily for 3 days + Luminal agent
Hepatic abscess, amoeboma, other extra-intestinal diseases
Metronidazole 750 mg TID for 10 days OR
Tinidazole 2 g daily for 3 days + Luminal agent
* Luminal agent and iodoquinol is contraindicated in pregnancy
ANTI-HELMINTHIC DRUGS
INTRODUCTION
The helminths are macroscopic, multicellular organisms having their own digestive, excretory, reproductive & nervous system
Anthelminthics are drugs that act either locally to expel worms from the GIT (vermifugal) or systemically to eradicate adult helminthes (vermicidal) or act on developmental forms that invade organs and tissues
Helminths harm the host by depriving him of food, causing blood loss, injury to organs, intestinal or lymphatic obstruction & by secreting toxins
Helminthiasis is rarely fatal, but is a major cause of ill health CLASSIFICATION
Nematodes Round worm (Ascaris lumbricoides) Hook worm (Necator americanus & Ancylostoma duodenale) Whip worm (Trichuris trichuria) Thread worm (Strongyloides stercoralis) Pin worm (Enterobius vermicularis) Filariasis (Wuchereria bancrofti or Brugia malayi) Elephantiasis (lymphatic filariasis of the lower extremity associated with Wuchereria bancrofti
infection) Onchocerciasis (Onchocerca volvulus) Guinea worm (Dracunculus medinensis)
Helminths
Platyhelminths (flat bodied
worms)
Trematodes (flukes)
Cestodes (tape worms)
Nemathelminths (round bodied
worms)
Trematodes Blood fluke (Schistosomiasis) Liver fluke (Fascioliasis) Intestinal fluke Lung fluke (Paragonimiasis)
Cestodes Beef tape worm (Taenia saginata) Pork tape worm (Taenia solium) Cysticercosis (pork tape worm larval stage) Fish tape worm Dwarf tape worm Dog tape worm (hydatid disease)
ANTHELMINTHICS
Kill helminths (vermicide)
Expel helminthes (vermifuge)
Drugs exert their anti-parasitic effects by interfering with: a) Neuromuscular functions b) Microtubular functions c) Calcium permeability d) Energy metabolism
BROAD SPECTRUM ANTHELMINTHICS
Benzimidazole group: Mebendazole, Albendazole, Thiabendazole, Triclabendazole
Mechanism of action of benzimidazoles:
Bind to β-tubulins & prevent their polymerization ↓
Breakdown of cytoplasmic microtubules ↓
Selective and irreversible inhibition of glucose uptake ↓
Depletion of glycogen stores, formation of ATP, disruption of metabolic pathways ↓
Parasitic death
ALBENDAZOLE
Pharmacokinetics
Administered orally
Fatty food increases its absorption
It is metabolized in the liver
It produces an active metabolite, albendazole sulfoxide which is widely distributed, including hydatid cyst. Hence preferred in the treatment of hydatid disease
Half-life is 8-12 hours
Clinical uses
Administered on an empty stomach when used against intraluminal parasites, but with a fatty meal when used against tissue parasites
Drug of choice for: Round worm (Ascaris lumbricoides) Hook worm (Necator americanus & Ancylostoma duodenale) Whip worm (Trichuris trichuria)
Recommended dose: Adults & children above 2 years 400 mg orally as a single dose at night For children of 1-2 years of age 200 mg OD
As an alternative for: Thread worm (Strongyloides stercoralis) Pin worm (Enterobius vermicularis) Liver fluke (Clonorchis sinensis) To treat or control lymphatic filariasis (Albendazole + Diethylcarbamazine/Ivermectin =
synergistic combination)
Preferred drug to treat: Cysticercosis (pork tape worm larval stage)
Albendazole + Corticosteroids to prevent inflammation caused by dying organism (toxins are released)
Cutaneous larval migrans Skin disease in human, caused by the larvae of various nematode parasites of
the hook worm family Visceral larval migrans
Caused by worms that are found in the intestines of dogs and cats. The dog parasite is called Toxocara canis & the cat parasite is called Toxocara cati
Hydatid disease (a cyst in the lung or liver containing larva of Taenia echinococcus) Treatment of choice for medical therapy & is useful adjunct to surgical removal
or aspiration of cysts Better results when albendazole is used along with praziquantel
Advantages of albendazole over mebendazole
Single dose administration in Ascaris, hook worm, Enterobius and Trichuris (3 day treatment with mebendazole)
Broader spectrum
Better tolerated
In strongyloidosis, albendazole is more effective than mebendazole
Also has weak microfilarial action, kills cysticerci, hydatid larvae, ova of Ascaris or hook worm & is effective in cutaneous larva migrans
Adverse effects
Short term therapy (up to 1 month): free of side effects
Long term use (for 3 months): epigastric distress, headache, alopecia, fatigue & lassitude, insomnia, transcient increase in aminotransferase enzyme (hepatotoxicity)
Teratogenic in animals, hence avoided during pregnancy
MEBENDAZOLE
Highly effective against gastrointestinal nematode infections
Particularly valuable for the treatment of mixed infections Pharmacokinetics
Administered orally (chewable tablets available)
Fatty food increases its absorption
Half-life is 2-6 hours Clinical uses
Drug of choice for Round worm (Ascaris lumbricoides) Hook worm (Necator americanus & Ancylostoma duodenale) Whip worm (Trichuris trichuria) Pin worm (Enterobius vermicularis) provides cure rate of 95-100%
As an alternative drug for Trichinella spiralis (trichinosis) Visceral larval migrans Capillaria philippinensis (intestinal capillariasis) Taenia saginata (beef tape worm)
Adverse effects
Short term therapy: free of side effects
Nausea, vomiting, diarrhoea and abdominal discomfort
Higher doses: rash, urticarial and elevation of liver enzymes such as aminotransferase (hepatotoxicity)
Contraindications
Pregnancy
Patients with liver cirrhosis
DIETHYL CARBAMAZINE (DEC)
Is a piperazine derivative available as citrate salt Mechanism of action The exact mode of action is unknown
i. DEC alters microfilarial surface structure, displace them from tissues phagocytosed by tissue fixed monocytes
ii. DEC hyperpolarizes worm’s musculature expelled iii. DEC blocks synthesis of prostaglandins capillary vasoconstriction blocks passage of
microfilariae through capillaries Clinical uses
Drug of choice for lymphatic filariasis due to Wuchereria bancrofti (bancroftian filariasis), Brugia malayi (brugian filariasis) & Loa loa (loiasis) Active against both microfilarial & adult worm Synergistic with albendazole Anti-histaminics & glucocorticoids may be required to control allergic reaction Also used for chemoprophylaxis of loiasis & filariasis
Visceral larva migrans (toxocariasis)
To treat tropical eosinophilia Tropical pulmonary eosinophilia (TPE) is a syndrome of wheezing, fever & eosinophilia Has been replaced by ivermectin for the treatment of onchocerciasis
Adverse effect
Pharmacological dose dependant effects: headache, weakness, malaise, anorexia, nausea, vomiting, dizziness and lethargy
Allergic side effects due to dying filariae: fever, lymphadenopathy, cutaneous swelling, leucocytosis, eosinophilia, oedema rashes, proteinuria, at times renal haemorrhage and encephalopathy
PRAZIQUANTEL
Effective against trematodes & cestodes, not nematodes Mechanism of action
a) In cestodes, Praziquantel causes influx of Ca2+ from endogenous stores intense contractions
expulsion of the worm from GIT b) In schistosomes (flukes),
Ca2+ influx damages tegument (outer body covering) vacuoles (holes) formed hidden parasite antigen is exposed
Host antibodies bind to these antigens & destroy them by phagocytosis Clinical uses
Schistosomiasis: drug of choice for all forms
Also effective against other flukes except F. hepatica
Tape worm infestations
Neurocysticercosis: albendazole is preferred Why albendazole is preferred over praziquantel in the treatment of neurocysticercosis? The course of treatment is shorter than praziquantel Cure rates in terms of resolutions of symptoms and disappearance of cysts are higher than
praziquantel Corticisteroids anhance absorption of albendazole, but lower the blood levels of praziquantel Albendazole is cheaper
DRUGS FOR CONSTIPATION
LAXATIVES
Laxatives are used to: 1. Treat constipation 2. To avoid undue straining at defaecation in cases having hernia, haemorrhoids or
cardiovascular disease 3. Before or after any anorectal surgery 4. In bed ridden patients
Result in elimination of soft semi-solid stool
Laxatives have mild activity and are usually faecal softeners
Type of laxatives Example
Bulk forming laxatives Wheat bran, Psyllium husk, Ispaghula husk, semisynthetic cellulose such as carboxyl-methyl cellulose and polycarbophils (synthetic fibers)
Osmotic laxatives Lactulose, Sorbitol
Lubricant laxatives Liquid paraffin
Surfactant laxatives Dioctyl sodium sulfosuccinate (Docusate sodium)
PURGATIVES
Purgatives are used to: 1. Complete colonic cleansing prior to gastrointestinal endoscopic procedures 2. For post-operative or post MI bed-ridden patients 3. To flush out worms after the use of an anti-helminthic drug 4. To prepare the bowel before surgery or abdominal X-ray 5. May be needed for neurologically impaired patients
Purgatives either provide semi-fluid stool or lead to watery evacuation. In low doses, these can be used as laxatives
Types of purgatives Examples
Osmotic purgatives (lead to watery evacuation)
a) Saline purgatives: Magnesium sulfate, Magnesium hydroxide (milk or magnesia), Sodium sulfate and Sodium phosphate
b) Polyethylene glycol (PEG): Electrolyte osmotic purgative
Irritant purgatives (provide soft semifluid stools)
a) Anthraquinone group: Senna, Cascara and Aloe b) Organic irritants: Phenolphthalein, Bisacodyl (and
its suppository), Sodium picosulfate c) Oils: Castor oil
MECHANISM OF ACTION
These are luminally active, hydrophilic, indigestible vegetable fibres
They stimulate peristalsis and defaecation reflexes by increasing faecal bulk due to their water absorbing and retaining capacity
Bulk Laxatives
It is also luminally active agent
It is pharmacologically inert mineral oil
It is a faecal lubricant and stool softener as it retards water absorption from the stool
Lubricant laxatives
It is again a luminally active agent and is anionic surfactant which softens the stool by decreasing the surface tension of fluids in the bowel
It also acts as a wetting agent for the bowel, because by emulsifying the colonic contents it facilitates the mixing of water into fatty substances of the faeces
Surfactant laxatives
They stimulate peristalsis by irritant action on intestinal mucosa
They also stimulate colonic electrolyte and fluid secretion by altering the absorptive and secretory activity of the mucosal cells
Aloe, senna and cascara occur naturally in plants. Senna is most commonly used. These plant purgatives contain anthraquinone glycosides
On reaching the colon, the bacteria degrade them to the active principle "anthrol" which either acts locally or it is absorbed into the circulation
After being excreted through bile, it then stimulates small intestine
Stimulant/irritant purgatives
They act on small as well as large intestine
Saline purgatives are soluble inorganic salts which increase the faecal bulk by retaining water by osmotic effect, thus increasing peristalsis indirectly
Magnesium salts also release cholecystokinin which further helps in increasing intestinal secretions and peristalsis. Polyethylene glycol (PEG) which is electrolyte osmotic purgative contains a non-absorbable (PEG) which is a sugar that retains water by virtue of its high osmotic nature
It is also used in a form of a balanced isotonic solution prepared by adding sodium chloride, sodium sulfate, sodium bicarbonate and potassium chloride
The isotonic solution of (PEG) is so designed that no electrolyte shift occurs across the intestinal wall. Therefore, the preparation is safe for all patients
Osmotic purgatives
ADVERSE EFFECTS OF LAXATIVES a) Bulk forming laxatives:
Not absorbed (quite safe)
May cause abdominal discomfort (bacterial digestion of vegetable fibers within the colon lead to bloating and flatus)
b) Osmotic laxatives:
Non-toxic (suitable for long term use)
Flatulence (common)
Cramps (may occur in few)
May feel nauseated due to its peculiar sweet taste
c) Lubricant laxatives:
Frequent use leads to deficiency of fat soluble vitamins as they are carried away with stool
Forcible administration can lead to aspiration lipid pneumonia
Delays the healing of enteric fistula
* Though used only occasionally, it is useful when straining at defecation is to be avoided
d) Surfactant laxatives
Not absorbed (non-toxic)
Being bitter in taste, it can cause nausea
Cramps and abdominal pain
Hepatotoxicity (prolonged use)
Increase the absorption of liquid paraffin, hence should not be given together ADVERSE EFFECTS OF PURGATIVES
a) Osmotic purgatives
May induce vomiting due to irritant effect
Hyperosmolar agents may lead to intravascular fluid depletion and electrolyte disturbance
Should not be given for long term use and to hypertensive and CHF patient
Magnesium salts should not be used for long period with renal insufficiency patient due to risk of hypermagnesaemia, as about 20% of ingested magnesium is normally absorbed
b) Irritant purgative
Senna glycosides are secreted through milk, so should be avoided in lactating mothers
These glycosides turn urine colour to yellowish brown (acidic urine) or to red (alkaline urine). Chronic use leads to brown pigmentation of the colon known as (melanosis coli)
Contraindicated in pregnancy to avoid pelvic congestion
All anthraquinone produce abdominal cramps and nausea
About 15-20% of phenolphthalein undergoes enterohepatic circulation and hence exhibits prolonged action. It may turn urine reddish pink
Skin rash (rare)
Uses are drastically decline because of the reports about its cardiac toxicity and carcinogenicity
THERAPEUTIC USES OF LACTULOSE
As osmotic laxatives
Used for the treatment of hepatic encephalopathy
For this purpose, a dose of 20g TDS orally is needed
In hepatoencephalopathy there is a severe hepatocellular damage because of which the portal blood is directly shunted to systemic circulation
Hence several toxic metabolites from the colon (eg. NH3) get accumulated in the blood leading to CNS toxicity
Lactulose is degraded to lactic acid and converts NH3 to ionized NH4+ salt which is then
excreted INDICATIONS OF LAXATIVES
Constipation
To avoid undue straining of defaecation in patient with hernia, haemorrhoids or CVS disease
Before and after any anorectal surgery
Bed ridden patients CONTRAINDICATIONS OF LAXATIVES
a) Bulk-forming laxatives
Not absorbed, and quite safe
May cause abdominal discomfort due to bloating and flatus (cause by bacterial digestion of vegetable fibre)
b) Osmotic laxatives
Non-toxic, suitable for long term use
Flatulence, abdominal cramps
Nausea (have peculiar sweet taste) c) Lubricant laxatives
Not palatable (can be given in emulsified form or juice)
Fat soluble vitamins (A,D,E,K) deficiency (carried away with stool in emulsified form)
Aspiration lipid pneumonia (forced administration)
Delay healing of enteric fistula d) Surfactant laxatives
Not absorbed, non-toxic
Nausea (bitter taste)
Abdominal cramps and pain
Prolonged use, cause hepatotoxicity
Increase absorption of liquid paraffin
PURGATIVE HABIT
Purgatives empty the entire colon
Hence, after successfully using one purgative, few days are needed at least before normal defaecation process restart
However, during this phase, patient may feel constipated and takes purgative again, leading to development of a vicious cycle
This is known as ‘purgative habit’
DRUGS FOR DIARRHOEA
COMPOSITION OF NEW FORMULA WHO-ORS
High sodium content ORS is use for adult diarrhoea
For children and infants, low sodium glucose-based formulation is preferred because losses of sodium are less
Can be used in cholera
May cause hyponatremia in adults with cholera
The composition of new 245 mmol/L formula:
Contents Concentrations
Sodium chloride – 2.6 g Potassium chloride – 1.5 g Sodium citrate – 2.9 g Glucose – 13.5 g Water – 1.0 L Total osmolarity = 245 mmol/L
Na+ – 75 mM K+ – 20 mM Cl- – 65 mM Citrate – 10 mM Glucose – 75 mM
IMPORTANCE OF EACH INGREDIENT IN ORS
1) Potassium: Important constituent; to replace substantial loss of K+ during acute diarrhoea 2) Base (citrate, lactate, bicarbonate): To correct acidosis which developed due to loss of alkali in
stools. May independently promote sodium and water absorption 3) Glucose: To capitalize on the intactness of glucose coupled Na+ absorption 4) Na+: Increase Na+ level will facilitate water retention to counter dehydration
NON-DIARRHOEAL USES OF ORAL REHYDRATION THERAPY
Post-surgical, post-burn and post-trauma maintenance of dehydration and nutrition (in place of I.V. infusion)
Heat stroke
During changeover from intravenous to enteral alimentation
SUPER ORS
ORS replaces the fluid or electrolytes what the body has lost due to diarrhoea
Glucose-based ORS can easily be made at home as per WHO standard formula: High sodium preparation
Sodium chloride 3.5 g
Potassium chloride 1.5 g
Sodium citrate 2.9 g
Glucose 20.0 g
Water 1.0 L
Total osmolarity : 311 mmol/L Preparation available:
1. RELYTE: one sachet dissolve in 200 ml water
2. PEDITRAL & GENLYTE: one sachet dissolve in 100 ml water
Cereal-based ORS (Super ORS) Has advantage of controlling diarrhoea much more effectively than the glucose-based
ORS Undigested starch is fermented in the colon to short chain fatty acid stimulate
sodium and water absorption back from the colon Rice powder also has protein which on hydrolysis, yields amino acid stimulate
colonic salt and water absorption Commonly used cereal-based ORS formula:
Super ORS
Pre-cooked rice flour 10.15 g
Sodium chloride 0.94 g
Sodium citrate 0.20 g
Potassium citrate 0.44 g
Water 200 ml
Total osmolarity : 311 mmol/L Preparation available:
1. CERELYTE, RICETRAL: one sachet dissolve in 200 ml water
Sodium chloride 2.6 g
Potassium chloride 1.5 g
Sodium citrate 2.9 g
Glucose 13.5 g
Water 1.0 L
Total osmolarity : 245 mmol/L Preparation available:
1. ELECTRAL MULTIDOSE, PUNARJAL, ELECTROKIND: one sachet dissolve in 1.0 L water
Low sodium preparation
NON-SPECIFIC ANTI-DIARRHOEAL AGENTS Anti-motility & anti-secretory agents:
1) Opiod agonists: Acts by stimulating peripheral µ and δ receptors on small intestine and large intestine. µ receptors decrease motility, while δ receptors decrease intestinal secretions Loperamide Diphenoxylate Difenoxin Racecadotril
2) Anti-cholinergic:
Decrease bowel motility Hyosyamine Dicyclomine
3) α₂-adrenergic receptor agonists:
Facilitates absorption, inhibits secretions of fluids and electrolytes & increase intestinal transit time Clonidine
4) Octreotide:
Action is similar to somatostatins. Inhibit the release of 5-HT3, gastrin, secretin, CCK, motilin, pancreatic polypeptide. Reduce GIT motility, intestinal fluids & electrolytes secretions, pancreatic secretion, gall bladder contraction
DRUGS USED IN INFLAMMATORY BOWEL DISEASE
Ulcerative Colitis Crohn’s Disease
1. Aminosalicylates: Sulfasalazine Olsalazine Balsalazine
2. Immunosupressant: Glucocorticoids: Prednisone
& Prednisolone Cyclosporine Azathioprine & 6-
Mercaptopurine
1. Anti-TNFα Drugs : Infliximab Adalimumab Certolizumab
2. Methotrexate 3. Antibiotics:
Metronidazole Ciprofloxacin
4. Anti-Integrin Monoclonal antibody : Natalizumab
Role Of Sulfalazine In Inflammatory Bowel Disease
Is a prodrug
An aminosalicylate
Commonly used in ulcerative colitis
Composed of sulfapyridine & 5-aminosalicylic acid (5-ASA)
On oral administration, sulfasalazine reach colon
Broken down by colonic bacteria (azoreductase enzyme) to sulfapyridine & 5-ASA
5-ASA acts locally by inhibiting the production of inflammatory mediators: Inhibits the synthesis of prostaglandins (by inhibiting
cyclo-oxygenase Inhibit the production of cytokinins Inhibit the activity of nuclear factor-kB Suppress the generation of superoxide free radicals
While sulfapyridine get absorbed and causes side effects: nausea, vomiting, headache Advantages Of Mesalazine Over Sulfalazine
Also 5-ASA
Well absorbed in the upper GIT, therefore has to be given as special formulations (delayed release capsule or pH-dependent tablets)
Have a lower incidence of side effects and more efficacious compared to sulfasalazine Rational For Combining Diphenoxylate With Atropine In The Treatment Of Diarrhoea
Most popular formulation – LOMOTIL contains diphenoxylate (2.5 mg) with small doses of atropine (0.025 mg) to discourage abuse potential
Atropine, besides providing anti-spasmodic effects, prevents the possible abuse of diphenoxylate
Undesirable effects of atropine would appear prior to the pleasurable effects of the opioid, if the dose is increased for abuse
MECHANISM OF ACTION OF ANTI-MOTILITY & ANTI-SECRETORY DRUGS 1) Opiod agonists
Drugs: Loperamide, Diphenoxylate, Difenoxine (an active metabolite of diphenoxylate), Racecadotril
Mechanism of action: Stimulate peripheral µ as well as δ receptors present on small and large intestine
Effects: Activation of µ receptor decreases motility, while activation of δ receptor decreases intestinal secretion
Racecadotril (enkephalinase inhibitor) increases local concentration of enkephalins in intestinal mucosa which then stimulate µ and δ receptors
2) Anti-cholinergics
Drugs: Hyoscyamine, Dicyclomine
Effects: decrease bowel motility which results in an increase of fluid absorption, back from the intestinal tract, and a decrease in abdominal cramps
3) α2 adrenergic receptor agonists
Drug: Clonidine
Effects: facilitates absorption, inhibits secretion of fluids and electrolytes as well as increases the intestinal transit time
4) Octreotide
Actions are similar to Somatostatin
Mechanism of action: Inhibition of the release of 5-HT, gastrin, secretin, CCK, motilin and pancreatic polypeptide
Effects: It reduces GIT motility, intestinal fluid and electrolyte secretion, pancreatic secretion and gall bladder contractions
Lactase digests lactose and prevents drawing of water into the GIT Advantage Of Loperamide Over Codeine As An Anti-Diarrhoeal Agent
CNS effects and dependence liability of codeine limit its usefulness
Loperamide does not cross BBB and has neither analgesic effects nor any addiction liability ADVERSE EFFECTS AND CONTRAINDICATIONS
1) Opiod agonists
Adverse effects: abdominal discomfort and dry mouth
Contraindications: patients with colitis, acute bacterial diarrhoea associated with high fever or blood in stool, and also for children below 2 years of age
2) Anti-cholinergics
Adverse effects: usual anti-cholinergic effects 3) α2 adrenergic receptor agonists
Adverse effects: blood pressure lowering effect 4) Octreotide
Short term adverse effects: nausea, abdominal discomfort, pain at the site of injection
Long term adverse effects: gall stone formation, hypothyroidism
DRUGS FOR IRRITABLE BOWEL SYNDROME (IBS)
INTRODUCTION
IBS includes Crohn’s disease and ulcerative colitis
Characterized by variety of GI symptoms such as disordered bowel habits (constipation, diarrhoea or both) in association of abdominal pain and bloating
Generally fall into two categories: Constipation-dominant-IBS or Diarrhoea-dominant-IBS DRUGS USED IN IBS
DRUGS EXAMPLES
Anti-diarhoeal-Anti-spasmodic drug Loperamide, Diphenoxylate, Fedotozine, Dicyclomine, Hyoscyamine, Mebeverine
Anti-depressant Amytriptyline, Desipramine
5-HT3 receptor antagonist Alosetron
5-HT4 receptor agonist Tegaserod
Chloride channel activator Lubiprostone
Miscellaneous agent Clonidine, Buspirone
Given to relieve abdominal pains and discomfort & also improving bowel disorder
Usually, for diarrhoea-dominant-IBS, anti-diarrhoeal agents are used
For constipation-dominant-IBS, fibre supplements are administered with enough water intake ROLE OF ALOSETRON IN IBS
A potent and selective 5-HT3 antagonist 5-HT3 is an inotropic receptor belonging to nicotinic-acetylcholine super family of
receptors which in GIT activate visceral afferent pain from the gut to CNS Blockade will also inhibit colonic motility by decreasing ion permeability besides
inhibiting unpleasant pain sensation
Previously used in women with diarrhoea-dominant abdominal pain associated with IBS who failed to respond to conventional therapy
Efficacy in man has not been established
In dosage 1 mg OD or BD, it reduces all IBS symptoms including pain and diarrhoea
Prolongs total colonic transit time by inhibiting colonic hypermotility but not used as anti-emetic (just like Ondansetron, yet Ondansetron is not used for treating IBS)
Side effects: constipation, sleep disorders and abdominal discomfort Constipation induced by it may results to Fatal Ischemic Colitis (FIC) Hence the drug has to be discontinued immediately if constipation or symptoms of FIC
occur Re-initiation of drug after treating FIC is also not advisable
From the year 2000, FDA has restricted its use in women with diarrhoea-dominant IBS not responding to other therapies
RENAL & CARDIOVASCULAR
SYSTEMS
DIURETICS
FUNCTIONS OF KIDNEY
Regulatory: fluid & electrolyte balance, acid-base balance
Excretory: excretion of nitrogenous waste products
Hormonal: production of renin, production of erythropoietin
Activation of vitamin D The mechanism of urine formation is by:
1) Glomerular filtration - Filtrate contains low molecular weight plasma components such as glucose, Na+, K+, Ca2+,
Cl- and HCO3- plus amino acids & organic solutes
- Most of the filtrate is reabsorbed from different segments of the renal tubule - Everyday, only 1.5 L of urine is produced
2) Tubular reabsorption DIURETICS
Diuretics are the drugs that promote the excretion of Na+ and water from the body by an action of the kidney
Most diuretics act from the luminal side of the membrane & must be present in the urine
Some directly act on different segments of the nephron
Some indirectly modify the contents of the urinary filtrate CLASSIFICATION
1) Diuretics acting directly on different segments of the nephron a) Drugs acting on the thick ascending limb of loop of Henle
Loop diuretics or high ceiling diuretics: Furosemide, Bumetanide, Torsemide, Piretanide, Ethacrynic acid, Indacrinone
b) Drugs acting on the proximal (early) part of the distal tubule Thiazide group: Chlorothiazide, Hydrochlorothiazide, Benzthiazide,
Polythiazide, Bendroflumithiazide, Clopamide Chlorthalidone, Xipamide, Indapamide, Metolazone, Quinethazone
c) Drugs acting on the collecting ducts and tubules K+ sparing diuretics: Amiloride, Triamterene
d) Aldosterone receptor antagonists at distal (later) part of the distal tubule & collecting tubule K+ sparing diuretics: Spironolactone, Eplerenone
2) Diuretics acting indirectly by modifying the contents of urinary filtrate Osmotic diuretics: Mannitol, Glycerol
3) Weak diuretics which mainly have non-diuretic use Carbonic anhydrase inhibitors: Acetazolamide, Dorzolamide, Ethoxzolamide,
Dichlorphenamide, Methazolamide
LOOP DIURETICS (HIGH-CEILING DIURETICS)
Site of action: thick ascending limb of loop of Henle
Most powerful of all diuretics
Capable of excreting 20-30% of Na+
Steep dose response curve, hence called high-ceiling diuretics
Administered by oral, I.M. and I.V. routes
Duration of effect for furosemide is usually 2-3 hours Mechanism of action
Enter proximal tubule via organic transporter
Blocks Na+, K+,2Cl- symporter in the thick ascending limb of loop of Henle
Increase Na+ concentration reaching the distal tubule promotes H+ and K+ secretion results in metabolic alkalosis (in high doses)
Inhibit Ca2+ and Mg2+ reabsorption
Inhibit uric acid secretion at proximal tubule hyperuricemia can lead to gout Therapeutic uses of furosemide
Oedematous states: congenital heart failure, cirrhosis of liver, renal disease
Hypertension associated with renal impairment
Acute pulmonary oedema: Furosemide induces renal prostaglandin synthesis ↑ renal blood flow & ↑ venous capacitance right ventricular filling pressure ↓ produces quick relief of left ventricular pressure & pulmonary oedema
Acute renal failure: enhance K+ excretion
Mild hyperkalemia
Anion overdose: bromide, fluoride & iodide, which are reabsorbed in the thick ascending limb
Non-diuretic uses: mild to moderate hypercalcemia Adverse effect
Hyperuricemia: may precipitate attacks of gout
Hypercalciuria and hypomagnesemia
Hypokalemia with hypokalemic alkalosis
Ototoxicity: due to extrusion of Na+ from endolymph to perilymph
Hyperglycemia: due to ↓ insulin release
Hypersensitivity reactions: in patients allergic to sulfonamides Drug interactions of furosemide
With digoxin: loop diuretics may enhance digitalis toxicity and can cause cardiac irregularities due to hypokalemia
With NSAIDS: NSAIDS inhibits PGE2 and PGI2 synthesis (they contribute to Na+ and K+ excretion to some extent), thus diminish the action of furosemide
With aminoglycosides: they exhibit additive ototoxicity and should not be used together
With lithium: serum lithium levels may rise with loop diuretic therapy as they increase the reabsorption of Li+ from the proximal tubule
THIAZIDES
Site of action: proximal (early) part of the distal tubule
Most widely used diuretics
Sulfonamide derivatives
All have equal maximal diuretic effect; differ in duration of action and potency
Inhibit the Na+,Cl- symporter
Moderately efficacious drug Mechanism of action
↑ Na+ concentration reaching the distal tubule promotes H+ and K+ excretion results in metabolic alkalosis
Enhance Ca2+ reabsorption
Also induce synthesis of prostaglandins
Also inhibit carbonic anhydrase in the proximal tubule Therapeutic uses Diuretic use (oedematous condition)
Pulmonary oedema due to congestive heart failure
Renal (nephrotic syndrome, chronic renal failure, acute glomerulonephritis)
Hypertension – 1st drug to be used Non-diuretic use (non-oedematous condition)
Idiopathic hypercalciurea calcium nephrolithiasis (renal calcium oxalate stone) Nephrogenic diabetes insipidus
Thiazide has paradoxical effect
Thiazides ↓ ECF volume hyponatremia enhance Na+ and water reabsorption from proximal tubule ↓ delivery of filtrate to distal tubule ↓ urinary output
Adverse effect
Hypokalemia – exchange of Na+ and K+ (more Na+ reabsorbed, more K+ excreted)
Metabolic alkalosis
Hyperuricemia
Hypercalcemia – rare, but they can unmask hypercalcemia due to other causes eg. hyperparathyroidism
Hyperglycaemia
Hyperlipidaemia on chronic use
Erectile dysfunction – idiosyncratic reaction
Hypersensitivity reactions – skin rashes, blood dyscrasias & rarely pancreatitis Drug interactions
With digoxin: thiazides may enhance digitalis toxicity and can cause cardiac irregularities due to hypokalemia
With lithium: serum lithium levels may rise with thiazide therapy as they increase the reabsorption of Li+ from the proximal tubule
Thiazides should be avoided or used with caution in patients having oedema due to liver cirrhosis because hypokalemia and hypochloraemic alkalosis may precipitate hepatic encephalopathy and generates more NH3 which a cirrhotic liver cannot convert to urea!!!
① INHIBITORS OF NA+ CHANNELS AT COLLECTING DUCTS
Example: Triamterene, Amiloride
Site of action: distal part of distal tubule and collecting tubules Mechanism of action
Block renal epithelial Na+ channel inhibit Na+ reabsorption and K+ excretion
↓ secretion of H+ results in metabolic acidosis
Mode of action of both are independent of aldosterone Therapeutic uses Major utility is in combination with other diuretics to prevent hypokalemia & to augment the
diuretic and hypertensive response Diuretic use
Liver cirrhosis: used with thiazides
Hypertension: used with thiazides/loop diuretics Non-diuretic use
Li+ induced polyuria: Amiloride blocks Li+ reabsorption through Na+ channels in the collecting duct
Cystic fibrosis: Amiloride aerosol ↑ fluidity of respiratory secretion
In conditions of hypokalemia Adverse effect
Hyperkalemia
Triamterene: ↑ blood urea, nausea, dizziness, muscle cramps, precipitate renal stones
Amiloride: diarrhoea and rarely skin rashes; IV or IM route ↓ blood pressure due to histamine release
K+ SPARING DIURETICS
② ALDOSTERONE RECEPTOR ANTAGONIST
Spironolactone: a synthetic steroid
Has limited diuretic action
Has long duration of action
Canrenone is the active metabolite of Spironolactone
Undergoes enterohepatic circulation Mechanism of action
Aldosterone binds to aldosterone receptor ↓
Attach to DNA ↓
Transcription, translation & production of aldosterone’s mediator proteins
↓ Na+ reabsorption & K+ excretion
Spironolactone blocks aldosterone receptor, therefore following steps cannot progress anymore. Hence, no Na+ reabsorption & K+ excretion
Therapeutic uses Diuretic use (oedematous conditions)
Primary hyperaldosteronism (Conn’s syndrome)
Secondary hyperaldosteronism caused by liver cirrhosis
In hypertension: with thiazides or loop diuretics Non-diuretic use
In congestive heart failure: retards disease progression and reduces mortality
In conditions of hypokalemia Adverse effects
Hyperkalemia
Delays healing of peptic ulcer
Gastrointestinal disturbances
Skin rashes
Gynaecomastia & menstrual irregularities (with use of higher doses on chronic basis) Drug interactions
With angiotensin converting enzyme inhibitors: this combination should be avoided to avoid exacerbation of hyperkalemia
With thiazides/loop diuretics: this combination is used to treat hypertension, because it checks hypokalemia, a side effect of these diuretics
Examples: Mannitol, Glycerol (hypertonic drugs)
Pharmacologically inert
Freely filtered at the glomerulus
Incompletely reabsorbed or not at all reabsorbed in the nephron
Non-metabolizable
Act indirectly by modifying the contents of urinary filtrate by increasing the osmolarity
Site of action: proximal tubule, descending limb of loop of Henle, collecting tubule Mechanism of action
Mannitol I.V. ↓
↑ osmolarity of ECF ↓
H2O shifts from ICF to ECF ↓
↑ filtration load at glomerulus; mannitol gets filtered ↓
Hypertonicity of fluid in the lumen ↑ ↓
↓ H2O reabsorption (from parts of the nephron that are freely permeable to H2O)
↓ Urine volume ↑ due to ↑ H2O excretion
Small ↑ in Na+ excretion Other electrolytes are also excreted
Therapeutic uses
To treat oliguria state (no urine formation) in shock or crush injury. In such conditions, GFR is decreased compensatory reabsorption of NaCl & H2O from proximal tubule distal part of nephron dries up urine flow ceases (osmotic diuretics retain fluid in the tubule & prevents onset of renal failure
To treat acutely raised intracranial pressure (cerebral oedema)
To treat acutely raised intraocular pressure (acute glaucoma): Mannitol I.V. increased plasma osmolarity ICF shifts from brain and eye into circulation decrease pressure
Adverse effect
Transcient expansion of ECF volume – may worsen congestive heart failure, pulmonary oedema or both (hyponatremia adds to this effect)
Orally osmotic diarrhoea. Hence used orally with activated charcoal to eliminate toxic substances/poisons from GIT
Contraindication
Anuria due to severe renal disease or acute tubular necrosis
Heart failure / acute left ventricular failure / pulmonary oedema
Active intracranial bleeding
OSMOTIC DIURETICS
Examples: Acetazolamide, Dorzolamide, Ethoxzolamide, Dichlorphenamide, Methazolamide
Rarely used as diuretics now; clinical applications involve sites other than kidney
They inhibit both the membrane-bound and cytoplasmic forms of carbonic anhydrase ↓
Complete abolition of NaHCO3 reabsorption in the proximal convoluted tubule ↓
↑ urinary excretion of HCO3- (alkaline urine containing NaHCO3, KHCO3 & H2O)
Mechanism of action
NaHCO3
- depletion, metabolic acidosis ↓
Compensatory reabsorption of Na+, Cl- from remaining segments of nephron ↓
The diuretic efficacy of Acetazolamide decreases significantly within 2-3 days (self-limiting action) Therapeutic uses
Glaucoma: Acetazolamide (oral), Brimzolamide & Borzolamide (eye drops)
To alkalinize the urine (to treat urate calculi and cystinuria)
Metabolic alkalosis
Petit mal epilepsy (absence seizure) Metabolic acidosis increase plasma CO2 decrease pH prevent convulsions ↑ Cl- in plasma stabilize neuronal membrane by causing hyperpolarisation
Acute mountain sickness: Acetazolamide ↓ CSF formation & ↓ its pH ↑ ventilation & ↓ symptoms of mountain sickness
Adverse effect
Refractoriness after repeated use
Hyperchloremic metabolic acidosis
Drowsiness and paraesthesia
Hypokalemia
CARBONIC ANHYDRASE INHIBITORS
VASOPRESSIN ANALOGUES
ADH RECEPTOR AGONIST
Drug Acts on
Vasopressin V1 & V2 receptor
Desmopressin V2 receptor action
Terlipressin Selective V1 with minimal V2 receptor
Felypressin Mainly vasoconstriction action of V1 receptor
Lypressin Vasopressor action of V1 receptor
THERAPEUTIC USES
Based on V1 receptor action
1. Bleeding oesophageal varices Preferred drug is Terlipressin V1 receptor mediated constriction of mesenteric blood vessels Results in reduction of blood flow through the liver to the varices Hence stops the bleeding of the oesophageal varices Simultaneous addition of Nitroglycerine with vasopressin (or Terlipressin) reduces the
cardiotoxic effects of vasopressin, while enhances the beneficial splanchnic effects of the drug
Terlipressin has lesser side effects than vasopressin
2. Post-operative paralytic ileus and to drive out intestinal gas before abdominal radiography Action of contraction of intestinal smooth muscle
3. Used during abdominal surgery in patients with portal hypertension
To reduce risk of haemorrhage
4. Prevent bleeding in acute haemorrhagic gastritis Vasoconstriction of gastric vascular bed
Based on V2 receptor action (preferred drug is Desmopressin)
1. Diabetes insipidus (DI) Only central DI (neurogenic or neurohypophyseal DI) response to the administration of
Desmopressin Nephrogenic DI does not response due to non-functional ADH receptors on collecting
duct Vasopressin is not used due to its short duration of action as treatment of DI needs long-
term therapy Desmopressin is also used to differentiate between neurogenic & nephrogenic DI
2. Primary nocturnal enuresis
Desmopressin is used intranasally with restricted fluid intake and behavioural conditioning
3. Relieve post-lumbar puncture headache
Due to its water retention property, it facilitates equilibration of fluid osmolarity in the CNS
4. Bleeding disorders in patients of haemophilia A and von Willebrand’s disease
Desmopressin elevates factor VIII and von Willebrand factor Shortens time of bleeding
5. Renal concentration test
ADVERSE EFFECT
1. V1 receptor mediated Adverse effects are more with vasopressin, Terlipressin and Lypressin than with Desmopressin Facial pallor – due to cutaneous vasoconstriction Nausea Abdominal cramps Urge to defecate – due to increased intestinal motility Precipitation of angina – due to constriction of coronary arteries Contraindicated in patients of hypertension & ischaemic heart disease
2. V2 receptor mediated
Fluid retention Hyponatremia
3. Common to vasopressin and Desmopressin
Irritation, ulceration and rhinitis (intranasal administration) Urticarial and pruritus Other form of allergy (rare)
DRUGS AFFECTING RAAS
RAAS CASCADE
Drugs Example
Renin release inhibitors Clonidine
Renin inhibitors Enalkiren, Remikiren, Aliskiren
Angiotensin-converting enzyme inhibitors
Captopril, Enalapril, Lisinopril, Ramipril, Benazepril, Perindopril, Quinapril, Trandolapril, Fosinopril, Moexipril, Imidapril
Angiotensin receptor antagonists Saralasin, Losartan, Valsartan, Telmisartan, Irbesartan, Eprosartan, Olmesartan, Candesartan
Advantages of Enalapril over Captopril
More potent effective dose 5-20 mg OD or BD
Its absorption is not affected by food
Onset of action is slower, less liable to cause abrupt first dose hypotension
Longer duration of action (treated hypertension with single dose)
Rashes and alteration of taste is less frequent THERAPEUTIC USES OF ACEIS ACEIs decrease systemic vascular resistance without increase the heart rate and promote natriuresis, thus it is used to:
Treat hypertension
Decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction
Treat patients with diabetic nephropathy as they decrease proteinuria and stabilize renal functions
Prevent the incidence of diabetic retinopathy in patient of type I diabetes
Produce dramatic improvement in otherwise prognostically grim condition of scleroderma renal crisis
ADVERSE EFFECTS
Adverse effect Reason
Hypotension
Hypotension after the first dose, particularly in sodium- depleted patients (those using loop diuretics, or on salt restriction or suffering with GIT fluid loss)
The treatment should be initiated with small doses of ACEIs
Dry cough Accumulation of bradykinin in the bronchial mucosa
Not dose related & occurs more frequently in women
Once ACEIs are stopped, the cough disappears within a week
Renal failure
In patient with bilateral renal artery stenosis or with stenosis of the artery to a single remaining kidney
Angiotensin II constricts the efferent arteriole, maintaining adequate GFR even when renal perfusion is low
Inhibition of ACE can induce acute renal insufficiency in such cases
Hyperkalemia In patients with renal failure or in patients taking K+ sparring
diuretics, owing to reduced, angiotensin II stimulated, aldosterone secretion
Teratogenic effect
ACEIs are not teratogenic during 1st trimester
Continued administration can cause foetal hypotension, anuria, renal failure, fetal malformations and even neonatal death
Angioneurotic oedema
Accumulation of bradykinin
Induction of tissue specific auto-antibodies
Minor adverse effect
Neutropenia, cholestatic type hepatotoxicity, glycosuria, proteinuria, altered sense of taste, allergic skin rashes
DRUG INTERACTION
With NSAIDS: Impair the hypotensive effect of ACEIs by blocking bradykinin-mediated vasodilation
With K+ sparring diuretics: Exacerbate ACEIs-induced hyperkalemia
Differences between ARBs and ACE inhibitors
ARBs have no effect on bradykinin metabolism, therefore it is more selective blockers of angiotensin-II effects than ACEIs
ARBs capable of blocking the effects of angiotensin II regardless any biochemical pathway for angiotensin II formation. ACEIs may not suffice for total elimination of angiotensin II
Both group stimulate renin release but ARBs cause circulating angiotensin II to raise but not with ACEIs. ACEIs stimulate AT2 receptors, causes vasodilation
ARBs do not cause cough or angioneurotic edema because they do not build up bradykinin levels
ARBs do not produce dysgeusia (distortion of taste perception) Similarities between ARBs and ACE inhibitors
Both can cause fetal toxicity and should be discontinued before second trimester of pregnancy
Both may precipitate renal failure in patients with bilateral renal artery stenosis
Both drugs can cause hyperkalemia in patients with renal failure or in patients taking K+ supplements or K+ sparring diuretics
First-dose hypotension, in rare cases, may occur
ANTI-HYPERTENSIVE DRUGS
HYPERTENSION
Arterial blood pressure >140/90 mmHg
Types of hypertension Primary or essential: no known cause, occurs in 95% of cases Secondary: hypertension results from the underlying disease present or drug
Stages of hypertension:
Stage Systolic range (mmHg) Diastolic range (mmHg)
Pre-hypertension <120-139 80-89
Stage I – Mild hypertension 140-159 90-99
Stage II – Moderate hypertension 160-179 100-109
Stage III – Severe hypertension >180 >110
Major risk of hypertension: Smoking Dyslipidaemia Diabetes mellitus Age >60 years Gender: men, post-menopausal women Family history
Usually no symptoms
The silent killer
May have headache, blurry of vision, fatigue and palpitation FACTORS THAT AFFECT BLOOD PRESSURE
Blood pressure
Cardiac output
Heart rate
Stroke volume
Contractility
Filling pressure
Blood volume
Venous tone
Peripheral resistance
Arterial diameter
Blood volume (viscosity)
TARGETS FOR ANTI-HYPERTENSIVE DRUGS
Heart rate
Contractility of heart
Blood volume
Venous tone
Arterial diameter ANTI-HYPERTENSIVE DRUGS
A: Aldosterone inhibitor, ACE inhibitor, α-blocker, ARBs
B: β-blocker
C: Calcium channel blocker
D: Diuretic, Directly acting vasodilator
Renin inhibitors
ACEI
ARB
Diuretic
Aldosterone antagonist
β-BLOCKERS
Mechanism of action:
β-blocker should be withdrawn gradually to prevent rebound hypertension
Indications: Mild to moderate hypertension along with diuretics give additive effect Used along with vasodilators
Reflexly mediated cardiac stimulation is a common feature of vasodilator treatment and may severely limit its anti-hypertensive effectiveness
A β-blocker prevents cardiac stimulation & thus preserves the effectiveness of the vasodilator
Further, vasodilator treatment initiates a reflex increase in plasma renin activity which is blunted by the use of a β-blocker
Contrarily, the vasodilator will prevent an increase in peripheral vascular resistance that results with the use of β-blockers
Used along with ACEI ACEI ↑ renin while β-blockers block renin release super additive effect
Contraindications: Concomitant insulin dependent diabetes Bronchial asthma or chronic obstructive pulmonary disease Raynaud’s phenomenon Variant angina Chronic congestive cardiac failure Peripheral vascular disease
β + α BLOCKERS
LABETALOL
Mixed (α + β) antagonist
It exhibits Selective blockade of α1 adrenoceptor Inhibition of neuronal uptake of norepinephrine Blockade of β1 receptors Partial agonist activity (ISA) at β2 receptors Some direct vasodilator properties
It is given orally to treat hypertension in elderly people where increased peripheral resistance is not desired
It is particularly useful in pheochromocytoma and for controlling rebound hypertension after clonidine withdrawal
It is also employed for the treatment of hypertensive patients because usually these patients are not adequately controlled by β-blockers
Side effects: postural hypotension, hepatotoxicity CARVEDILOL
It is a β1, β2 and α1 adrenoceptor blocker but its β1 and β2 blocking effects are greater than its α1 blocking effects
It inhibits free radical induced lipid peroxidation
It also prevents vascular smooth muscle mitogenesis (independent of α or β adrenoceptor blockade)
These effects may prove to be cardioprotective in patients of congestive heart failure
α-BLOCKER
Non-selective: Phenoxybenzamine
α1 selective: Prasozin, Terazosin, Doxazosin
Dilate arteries ↓ peripheral vascular resistance
Dilate veins ↓ venous return
Indications: Non-selective α-blocker is used in pheochromocytoma α1 selective blocker is used in hypertension with benign prostatic hyperplasia
CENTRAL SYMPATHOLYTICS
Also known as centrally acting anti-hypertensive drugs
Site of action: vasomotor centre in the brain METHYLDOPA
Mechanism of action: At adrenergic nerve ending
Methyldopa ↓
α-methyldopamine ↓
α-methylnorepinephrine ↓
Stored in vesicles ↓
Central α2 receptors at vasomotor centre ↓
↓ sympathetic outflow, hence ↓ blood pressure
Side effects of methyldopa: Mental related: sedative,
nightmares Tolerance Hepatotoxicity Psychological upset
Lactation in female Dry mouth Oedema Parkinsonism Anaemia (haemolytic)
Methyldopa is used to treat hypertension during pregnancy CLONIDINE
Mechanism of action: Partial agonist at α2A receptors in vasomotor centre in medulla
↓ ↓ sympathetic outflow
↓ ↓ heart rate, ↓ force of contraction
↓ ↓ venous capacitance, ↓ peripheral vascular resistance
↓ ↓ blood pressure
Activation of imidazoline receptor modulation of α2A receptor activity
Adverse effects: Mental related: sedation Dry mouth Nasal stuffiness Oedema
Impotence Rebound hypertension after
sudden withdrawal
DIRECT VASODILATORS
① ARTERIOLAR VASODILATORS Examples: Hydralazine, Minoxidil, Diazoxide, Fenoldopam HYDRALAZINE
Mechanism of action: Opens K+ channels Hyperpolarization of smooth muscle Vasodilation (↓
peripheral vascular resistance) ↓ blood pressure Release of NO (endothelial-derived relaxing factor) Vasodilation (↓ peripheral
vascular resistance) ↓ blood pressure
Arteriolar vasodilators
Adverse effects: activation of compensatory mechanisms Reflex tachycardia Renin release: ↑ aldosterone secretion Na+ and fluid retention
* How to prevent? Using: o β-blocker (Hydralazine + β-blocker) o Diuretics (Hydralazine + Thiazide)
Other adverse effects: Headache Nasal stuffiness
Used to treat hypertension during pregnancy MINOXIDIL
Mechanism of action: Minoxidil Active form Opens K+ channels Hyperpolarization of smooth muscle Vasodilation (↓ peripheral vascular resistance) ↓ blood pressure
Adverse effects: Tachycardia Palpitations Oedema Headache Nasal stuffiness Hirsuitism
Other use: male pattern baldness (when drug is applied topically) FENOLDOPAM
D1 agonist dilates peripheral arteries and cause natriuresis
Used in hypertensive emergencies DIAZOXIDE
Diazoxide Opens K+ channels Hyperpolarization of smooth muscle Vasodilation (↓ peripheral vascular resistance) ↓ blood pressure
Used in hypertensive emergencies
② ARTERIOLAR + VENOUS VASODILATOR Example: Sodium nitroprusside
Mechanism of action:
Sodium nitroprusside causes arteriolar and venous dilatation
Decreases preload and afterload thus improve ventricular function
I.V. infusion: rapid onset of action (30 seconds), brief duration is 10 minutes
Uses: Hypertensive emergencies Acute congestive heart failure
Regular monitoring of blood pressure
Administer only fresh solution
Cover the infusion bottle with black paper
Adverse effects: Accumulation of cyanide hypoxia Accumulation of thiocyanate disorientation, convulsion Vasodilation Reflex tachycardia
Treatment of cyanide toxicity: Administration of sodium thiosulfate and hydroxycobalamine can be used to trap
cyanide ions Sodium thiosulfate acts as a sulfur donor & facilitates metabolism of cyanide to sodium
thiocyanate which is excreted in urine Hydroxycobalamine combines with cyanide ion to form non-toxic cyanocobalamine
ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI)
Examples: Enalapril, Lisinopril
Angiotensin-II: Release of norepinephrine from sympathetic neurons Absorption of Na+ from proximal tubule Cell growth in heart
Action of drugs: Inhibit ACE No angiotensin-II ↓ blood pressure
Adverse effects: Hypotension after first dose Dry cough Angioneurotic oedema Hyperkalemia Hyponatremia Foetal hypotension with a risk of foetal malformations if administered during II and III
trimester of pregnancy Altered sense of taste
Additional mechanism:
ACEI is one of the 1st choice of drugs in all grades of hypertension
Preferred in patients with: Diabetes – prevent diabetic
nephropathy Nephropathy
Left ventricular hypertrophy Congestive heart failure Post myocardial infarction
Adverse effects/limitations of captopril: Dry cough Hypotension Proteinuria Renal failure Hyperkalemia Teratogenic effect
Angioneurotic oedema Neutropenia Allergic skin rashes Altered sense of taste Glycosuria
Contraindication: Hypertension with bilateral renal artery stenosis
Explain the rationale for using ACEI with: β-blocker in hypertension: ACEI ↑ renin release, prevented by using β-blocker Diuretic in hypertension: ACEI ↑ renin release, diuretic ↓ renin release (synergistic
combination) NSAIDS in hypertension: NSAIDS ↓ prostaglandin synthesis
ANGIOTENSIN ANTAGONISTS
Also known as angiotensin receptor blockers
Examples: Losartan, Candesartan
They block AT1 receptors where angiotensin-II acts
Advantages over ACEIs: no cough and angioedema
Indicated in patients who develop cough with ACEI
DIURETICS
"COLT Pee” Carbonic anhydrase inhibitors (at the proximal tubule) Osmotic diuretics (at the Loop of Henle and other parts) Loop diuretics (at the ascending loop) Thiazides (at the distal tubule) Potassium-sparing diuretics (at the collecting tubules)
Diuretics used in hypertension: 1. Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide 2. K+ sparing: Spironolactone, Amiloride 3. High ceiling diuretic: Furosemide
THIAZIDES
Mechanism of action:
Role of thiazides: Cheaper Low dose, hence well tolerated Used with K+ sparing diuretics
Contraindications: Diabetes mellitus Gout Hyperlipidaemia Renal insufficiency Pregnancy
FUROSEMIDE
Strong diuretic
Weaker anti-hypertensive effect
Mechanism of action:
Role of high ceiling diuretics: Severe hypertension with renal disease Hypertension with heart failure Hypertension with fluid retention
Not used for mild to moderate hypertension due to rapid diuresis and electrolyte imbalance
CALCIUM CHANNEL BLOCKERS (CCB)
Dihydropyridines (DHP): Nifedipine, Amlodipine, Nicardipine, Nimodipine
Non-dihydropyridines (Non-DHP): Verapamil, Diltiazem
Mechanism of action:
Block use dependent L-type of calcium channels ↓
Stabilize them in inactivated state ↓
Decreased frequency of opening of channels Blood vessels: Relaxation of smooth muscle Vasodilation ↓ blood pressure Heart: No generation of action potential in automatic fibers
↓ heart rate, ↓ AV conduction, ↓ contractility Use: Supraventricular arrhythmias
Dihydropyridines (DHP) Non-Dihydropyridines (Non-DHP)
Therapeutic uses
Hypertension with neuropathy
Hypertension with diabetic nephropathy
To treat hypertension in patients with asthma, peripheral vascular disease and angina
Hypertension in pregnancy (safe)
Angina pectoris
Hypertension with neuropathy
Hypertension with diabetic nephropathy
To treat hypertension in patients with asthma, peripheral vascular disease and angina
Angina pectoris
Supraventricular arrhythmia
Not safe in pregnancy
Adverse effects & contraindications
Headache
Flushing
Oedema
Tachycardia
Gingival hyperplasia
Less vasodilatory adverse effect
No tachycardia
Constipation
Contraindication: conduction defects in heart and heart failure
Oedema with calcium channel blockers
Dihydropiridine
Nifedipine Amlodipine
Short acting
Frequent dosing or sustained release preparation
Low bioavailability
Fast oral absorption high vasodilatory adverse effect hence given with β blocker
Long acting (t1/2 : >35 hours)
Once daily, orally
Higher bioavailability
Slow oral absorption less vasodilatory adverse effect
Dilatation Increased
hydrostatic pressure
Oedema
HYPERTENSIVE EMERGENCIES
Hypertensive emergency is a situation in which blood pressure must be reduced by 25 mmHg within 1-2 hours to avoid risk of severe morbidity and death
These include patients with asymptomatic hypertension, with progressive target organ damage
It is the latter that determines the seriousness of the emergency and the selection of the drug
Emergencies include: Hypertensive encephalopathy (headache, irritability, confusion and altered mental
status due to cerebrovascular spasm) Hypertensive nephropathy (haematuria, proteinuria and progressive renal dysfunction
due to renal arteriolar necrosis) Intracranial haemorrhage Dissecting aneurysm Pre-eclampsia-eclampsia Pulmonary oedema Unstable angina Myocardial infarction Malignant hypertension
The initial goal in hypertensive emergency is to reduce blood pressure by no more than 25% (within few minutes to 1-2 hours) and then toward a level of 160/100 mmHg within next 2-6 hours
Subsequently, the blood pressure can be reduced to normal levels using oral medication over several weeks
Rapid and complete normalization of blood pressure should be avoided because chronic hypertension is always associated with autoregulatory changes in cerebral blood flow
Thus a rapid normalization of blood pressure would lead to cerebral, coronary or renal ischaemia
TREATMENT
Sodium nitroprusside Effective in treating hypertensive crisis associated with
encephalopathy, intracranial haemorrhage, myocardial infarction, aortic dissection
Glyceryl trinitrate I.V. infusion Action in 2-5 minutes Effective in acute left ventricular failure, myocardial infarction
Labetalol and hydralazine Effective in hypertensive crisis in pregnancy
Esmolol Effective in aortic dissection, myocardial infarction
Fenoldopam <5 minutes, I.V. infusion It also dilates renal blood vessels and promotes natriuresis Useful in hypertensive emergencies with impaired renal function
Enalapril and nicardipine
CONCOMITANT CONDITION DRUGS OF CHOICE DRUGS TO BE AVOIDED
Angina β-blockers; CCBs Vasodilators
Asthma & COPD CCBs; Diuretics; AT1 receptor antagonists
β-blockers; ACEIs
Benign prostatic hyperplasia α-blocker CCBs
Congestive heart failure Diuretics; ACEIs Verapamil and other CCBs
except Amlodipine; α-blokers
Diabetes (insulin-dependent) ACEIs; CCBs β-blockers; Diuretics
Hyperlipidaemia ACEIs; CCBs; α-blockers β-blockers (non-ISA); Diuretics
Isolated systolic hypertension in older patients
CCBs; Diuretics; α-blockers –
Post-myocardial infarction β-blockers (non-ISA); ACEIs β-blockers with ISA
Pregnancy Methyldopa; Dihydropyridine group of CCBs; Cardioselective β-blockers
ACEIs; AT1 receptor antagonists; Diuretics; Propranolol; Labetalol
Peripheral vascular disease CCBs; α-blockers β-blockers
Renal insufficiency CCBs; Diuretics K+ sparing diuretics
Supraventricular tachycardia Verapamil; Diltiazem –
Thyrotoxicosis β-blockers (without ISA) Drugs causing tachycardia
ANTI-ARRHYTHMICS
CARDIAC ELECTROPHYSIOLOGY
NORMAL CONDUCTION PATHWAY
ACTION POTENTIAL OF THE HEART
The slope of phase 0 = conduction velocity
Also the peak of phase 0 = Vmax
PACEMAKER ACTION POTENTIAL
EFFECTIVE REFRACTORY PERIOD (ERP)
It is also called as absolute refractory period (ARP) In this period the cell cannot be excited It takes place between phase 0 and 3
ARRHYTHMIA/DYSRHYTHMIA Abnormality in the site of origin of impulse, rate or conduction
Automaticity: ability of a cell to depolarize spontaneously
Fastest and steepest phase 4 in SA node
Conductance: phase 0 ARRHYTHMOGENIC MECHANISMS
Disorders in impulse formation or disorders in conduction
Disturbances of impulse formation a) Enhanced/ectopic pacemaker activity determined by ↑ slope of phase 4 b) Triggered activity: the next action potential (“after-depolarizations”) occurs before
phase 4 crosses the threshold potential
After potential in Phase 2 or 3 After potential in Phase 4
Disturbances of impulse conduction a) Re-entry: due to circus movement b) Wolff-Parkinson-White syndrome
ACTION OF DRUGS
Re-entry Wolff-Parkinson-White syndrome
IMPORTANT CARDIAC ARRHYTHMIAS
Extrasystoles (ES): AES, VES, nodal ES
Atrial flutter: Atrial rate: 200-350/min with 2:1 to 4:1 block
Atrial fibrillation: Atrial rate: 350-550/min Asynchronous activation of atrial fibers
Ventricular tachycardia: 4 or more consecutive extrasystoles
Ventricular fibrillation: irregular, rapid, uncoordinated contraction of ventricular fibers Loss of pumping function Leads to sudden cardiac death
Torsades de pointes: twisting of the points
Polymorphic ventricular tachycardia
Paroxysmal supraventricular tachycardia (PSVT): atrial tachycardia with 1:1 conduction (150-200) – due to re-entry or after depolarization
AV block: 1st, 2nd or 3rd degree (complete) TYPES OF ARRHYTHMIAS
Bradyarrhythmias
Tachyarrhythmias POSSIBLE MECHANISMS OF DRUG ACTION
Decrease conduction velocity (block Na+ or Ca+ channels)
Change the duration of the effective refractory period (block K+ channels)
Suppress abnormal automaticity (block Ca2+ channels or block β receptors) CLASSIFICATION Proposed by Vaughan Williams and Singh in 1969
Class Basic mechanism Drugs
I IA IB IC
Sodium channel blockers
Moderate
Weak
Strong
Quinidine, Procainamide
Lignocaine, Mexiletine
Propafenone, Flecainide
II Beta blockers Propranolol, Esmolol, Metoprolol
III Potassium channel blockers Amiodarone, Bretylium
IV Calcium channel blockers Verapamil, Diltiazem
* Biggest problem – anti-arrhythmics can cause arrhythmia!!!
CLASS I DRUGS – Na+ CHANNEL BLOCKERS
CLASS IA DRUGS
Effects on depolarization: Blockade Na+ channels: Activated (phase 0) > inactivated Slows the rate of rise of Phase 0 and decrease conduction of impulse
Effects on repolarization: prolonged repolarisation ↑ ERP
Slow the rate of rise of phase 0 of the action potential
Useful in atrial and ventricular arrhythmias CLASS IB DRUGS
Blockade Na+ channels: Inactivated (phase 2) > activated
Rapidly associate and dissociate from Na+ channels shorten the phase 3 repolarisation, hence decrease the ERP as well as APD
Effective in ventricle arrhythmias and in partially depolarised tissue (ischaemia) as in myocardial infarction more inactivated channels are available
Lignocaine is given I.V. as loading and maintenance dose I.V. due to high first pass metabolism LD and MD dose due to high volume of distribution and short duration of action
Indication: Acute ventricular arrhythmias following myocardial infarction and cardiac surgery
Pharmacokinetics of Lignocaine: Inactive orally Distributes rapidly Duration of action: 10-20 minutes Metabolism depends on hepatic blood flow
Adverse effects of Lignocaine: drowsiness, slurred speech, paresthesia, agitation, confusion, convulsion, least cardiotoxic (it has no effect on normal myocardium)
CLASS IC DRUGS Effects on depolarization:
Blockade Na+ channels: Activated (phase 0) > inactivated
Dissociates slowly
Have effect on normal myocardium (cause arrhythmias)
Markedly decrease the rate of phase 0 depolarisation in Purkinje and ventricular myocardial fibres
SUMMARY
Sodium channel blockade: IC > IA > IB
Increasing the ERP: IA > IC > IB (↓) ANS REGULATION OF HEART RATE
SNS: β1 receptors: ↑cAMP
PNS: M2 receptors: ↓ cAMP
↑cAMP: ↑ Ca2+ influx ↑ automaticity and conduction in pacemaker cells ↑ K+ efflux Shorten APD
CLASS II DRUGS – β BLOCKERS
SA node: ↓ automaticity Use: Exercise induced arrhythmias, arrhythmias in hyperthyroidism
AV node: ↑ERP Use: to control supraventricular arrhythmias
Prevent re-infarction and sudden cardiac death in post myocardial infarction patients
Uses of esmolol Short acting β blocker Used I.V. in acute arrhythmias
CLASS III DRUGS – K+ CHANNEL BLOCKERS
Block K+ channels
Prolong repolarization
Prolong duration of AP without altering phase 0
Prolong ERP Amiodarone is used commonly
Additional mechanism of action: Blocks inactivated Na+ channels Blocks Ca2+ channels and beta receptors
Hence has a broader spectrum of action
Used in supraventricular and ventricular arrhythmias Adverse effects of amiodarone:
↓BP, bradycardia
Nausea, GI upset
Photosensitization and skin pigmentation
Corneal deposits
Pulmonary alveolitis, fibrosis
Peripheral neuropathy
Liver damage
Abnormality in thyroid status (Amiodarone is an iodine containing drug hence causes altered thyroid function)
Less arrhythmogenic CLASS IV DRUGS – Ca2+ CHANNEL BLOCKERS
Inhibit L-type Ca2+ channels
Depress depolarization (phase 0) in automatic fibers decrease conduction in AV node
Decrease in phase 4 spontaneous depolarization decrease automaticity in SA node
Uses of Verapamil: Supraventricular arrhythmias PSVT (as first line drug) To control ventricular rate in AF and AFl
ADENOSINE
Naturally occurring nucleoside
Actions: Decreases conduction velocity Prolongs refractory period Mechanism of action: Stimulates adenosine receptors (A1 receptors) opens K+
channels hyperpolarisation in SA and AV nodes and atrium prolongs refractory period, ↓ conduction
Acute supraventricular arrhythmias and PSVT
Pharmacokinetics: t1/2 = 10 seconds taken by RBCs and endothelial cells
Adverse effects: flushing, bronchospasm
Drugs for PSVT Drugs for AV block
Diltiazem
Verapamil
Propranolol
Esmolol
Digoxin
Atropine
Adrenaline
Isoprenaline
Condition Drug Comments
Sinus tachycardia Class II, IV Other underlying causes may
need treatment
Atrial fibrillation/flutter Class IA, IC, II, III, IV, Digitalis Ventricular rate control is
important goal; anti-coagulation is required
Paroxysmal supraventricular tachycardia
Class IA, IC, II, III, IV, Adenosine –
AV block Atropine –
Ventricular tachycardia Class I, II, III –
Premature ventricular complexes
Class II, IV, Magnesium sulphate PVCs are often benign and do
not require treatment
Digitalis toxicity Class IB, Magnesium sulphate –
ANTI-ANGINAL & ANTI-ISCHAEMIC DRUGS
INTRODUCTION
Angina pectoris is caused by ischaemia, characterized by chest pain
There is an imbalance between oxygen supply & oxygen demand
Determinants of myocardial O2 consumption: O2 demand: heart rate, contractility, preload, afterload O2 supply: coronary blood flow, regional myocardial blood flow
Angina pectoris is a clinical manifestation of reversible myocardial ischaemia
Symptom: suffocating substernal pain in the chest
On exertion, angina pain mediates to neck, jaw, upper abdomen, shoulders and arms
It is relieved by rest
Hence, angina pectoris isreferred to chest pain due to an imbalance between the O2 requirement of the heart & O2 supplied to it via the coronary vessels
TYPES OF ANGINA
Classical/Stable angina Also called as angina of effort or exertional angina
There is increased myocardial O2 requirement
Cause: atherosclerosis of larger coronary arteries
Variant/Prinzmetal’s angina
The pain appears even during rest or sleep
There is recurrent localized coronary vasospasm – “vasospastic angina”
There is reduction in coronary blood flow
If it is untreated, it may deteriorate into unstable angina
Unstable angina
There are recurrent attacks of angina
Can occur during minimal exertion or during rest
Progressive occlusion of the coronary artery
Platelet aggregation at the ruptured plaque
CLASSIFICATION OF DRUGS 1) Nitrates
a. Rapid onset, short acting: Nitroglycerine (Glyceryl trinitrite), Isosorbide dinitrite (sublingual route)
b. Slow onset, long acting: Isosorbide dinitrite (oral route), Isosorbide mononitratre, erythrityl tetranitrate
2) β-blockers: Propranolol, Metoprolol, Atenolol, Bisoprolol, Celiprolol 3) Calcium channel blockers (CCBs)
a. Phenylakilamine: Verapamil b. Benzothiazepine: Diltiazem c. Dihydropyridines (DHPs)
Short acting: Nifedipine, Nicardipine Intermediate acting: Nitrendipine Long acting: Felodipine, Amlodipine
4) Miscellaneous a. Potassium channel openers: Nicorandil b. Cytoprotective drugs: Trimetazidine, Ranolazine c. Anti-platelet drugs: Aspirin, Ticlopidine, Clopidogrel, Dypiridamole d. Bradycardic drugs: Ivabradine e. HMG-coA reductase inhibitors: Statins
CLINICAL CLASSIFICATION Used to terminate an attack of angina: Nitroglycerine, Isosorbide dinitrate (sublingually) Used for chronic prophylaxis: All other drugs
NITRATES
Mechanism of action
Pharmacological actions 1) Vascular smooth muscle
Preload reduction (prominent action)
Afterload reduction
Redistribution of coronary blood flow
Dilatation of capacitance vessels ↓
Peripheral pooling of blood ↓
Decrease in venous return to heart ↓
Decrease in ventricular end-diastolic pressure
↓ Decrease in preload
↓ Decrease in cardiac workload &
O2 requirement
* Major beneficial effect in classical angina
Arteriolar dilatation ↓
Decrease in total peripheral resistance
↓ Decrease in afterload
↓ Decrease in cardiac workload &
O2 requirement
* Large doses of the drug ↓ peripheral vascular resistance ↓ blood pressure reflex sympathetic stimulation reflex tachycardia precipitates angina
Relaxation of bigger conducting
coronary arteries ↓
Redistribution of blood flow to ischaemic areas in angina
patients
* Nitrates cause dilatation of collateral vessels (secondary channel) allow blood that flow in primary blood flow to be distributed to ischaemic area, without an increase in blood volume
2) Dilatation of cutaneous, meningeal and retinal vessels 3) Action on other smooth muscles: relaxation of smooth muscles of the bronchi, biliary tract
and oesophagus
Pharmacokinetics
Nitrates are lipid soluble
Low oral bioavailability
Nitrates are inactivated in the liver – nitroglycerine has the highest inactivation in the liver
Thus, high first pass metabolism (except isosorbide mononitrate)
Through sublingual route: short acting
Through oral route: long acting
GTN (transdermal patch) – steady delivery of the drug in the circulation
GTN (volatile liquid) – stored in a tightly closed amber colored glass container Therapeutic uses
1) Angina pectoris
Nitrates in classical angina: reduction in cardiac workload by action on capacitance vessels
Nitrates in variant angina: dilatation of larger coronary vessels – relieves coronary artery spasm
Nitrates in unstable angina: dilatation of epicardial coronary arteries and reducing myocardial O2 demand
Hence, nitrates are only favourable to be used in classical and variant angina
Acute attack – GTN sublingual tablet/spray or isosorbide dinitrate sublingually
Can be repeated after 5 minutes
Not more than 3 tablets to be taken in 15 minutes
Prophylaxis of angina: longer acting nitrates (oral), GTN (transdermal)
Unstable angina: I.V. nitrates along with anti-platelet drugs 2) Myocardial infarction
GTN I.V./transdermal has protective effect against myocardial infarction
Relieves chest pain, pulmonary congestion & limits the area of necrosis
Post-infarction period – relieves angina pain 3) Congestive heart failure & acute left ventricular failure
I.V./Sublingual GTN or isosorbide dinitrate: reduces preload and afterload improvement in left ventricular function and pulmonary congestion
4) Oesophageal spasm
GTN sublingually
Cause relaxation of smooth muscles of the oesophagus 5) Biliary colic
GTN/Isosorbide dinitrate sublingually
Cause relaxation of smooth muscle of the gall bladder
Nitrites in cyanide poisoning Cyanide
↓ Chelates Fe3+ of cytochrome oxidase
↓ Tissue anoxia, seizures, coma
↓ Death
Haemoglobin
↓ Methemoglobin
↓ Cyanomethaemoglobin (unstable)
↓ Methemoglobin + sodium thiocyanate
↓ Excreted in urine
Adverse effects
Throbbing headache – because of dilatation of meningeal vessels
Flushing of face
Palpitation, dizziness, sweating
Postural hypotension
Tolerance
Dependence Tolerance Develops with all nitrates if there is continuous exposure It is dose-dependent It disappears within hours after stopping the drug Tolerance can be avoided:
By using the least effective dose Drug free interval
“Monday disease” is due to nitrate this is the evidence of development of tolerance Dependence Sudden withdrawal after prolonged exposure Precipitates coronary vasospasm and myocardial infarction
Drug interactions
1) Nitrates x Vasodilators Severe hypotension 2) Nitrates x Sildenafil
- Sildenafil is a phosphodiesterase-5 inhibitor results in ↑ cGMP - Hence, potentiates nitrate action - Results in severe hypotension, myocardial infarction, death
Sodium nitrite/Amyl nitrite I.V.
Cyanide
Sodium thiosulphate I.V.
CALCIUM CHANNEL BLOCKERS (CCBs)
Voltage-sensitive Ca2+ channels
Mediates entry of extracellular Ca2+ in response to depolarization
3 major types: L, N & T types
L-type Ca2+ channels: cardiac and smooth muscles, SA node & AV node
Composed of α1, α2, β, γ and δ subunits
Function: Smooth muscle contraction Regulate E-C coupling Regulate pacemaker activity Regulate conduction velocity
Mechanism of action
Normal mechanism CCBs action
In cardiac muscles ↓
Ca2+ enters the cell ↓
Binds to the ryanodine receptors in the sarcoplasmic reticulum
↓ Release of Ca2+ from the sarcoplasmic reticulum
↓ Binds to troponin C on the actin filaments
↓ Muscle contraction
Calcium channel blockers ↓
Bind to α1 subunit of L-type Ca2+ channels ↓
Reduces the frequency of their opening in response to depolarisation
↓ Decrease in transmembrane Ca2+ current
↓ Smooth muscle relaxation, decreased
contractility in cardiac muscle, decrease in pacemaker activity & conduction velocity
Actions
Verapamil Relatively cardio-selective Direct negative chronotrophic, dromotrophic and inotrophic effects
Nifedipine Relatively vascular smooth muscle selective Dilates arterial resistance vessels
Diltiazem Intermediate selectivity
CCBs in angina
Classical angina Coronary dilatation Peripheral vascular disease: ↓ in peripheral vascular resistance, ↓ in afterload ↓ in
myocardial O2 demand Decrease in heart rate, contractility, conduction velocity (verapamil, diltiazem)
reduces myocardial O2 demand
Variant angina Relieves and prevents coronary artery spasm (Dihydropyridine)
Unstable angina CCB is used as an adjuvant, along with nitrates and β-blockers
β-BLOCKERS
Blockade of cardiac β1 receptors
↓ Decrease in heart rate & myocardial
contractility ↓
Decrease in cardiac workload ↓
Decrease in myocardial O2 requirement
Blockade of dilator β2 receptors ↓
Decreases total coronary blood flow
β-blockers also inhibit platelet aggregation
Blockade of dilator β2 receptors is not favourable in angina. Therefore, non-selective β-blockers are not used in angina
However, as β1-blocker ↓ heart rate, it increases diastolic perfusion time increases blood flow to ischaemic area
Cardioselective β-blockers are preferred over non-selective β-blockers
When there is abrupt withdrawal, there will be sudden increase in sympathetic tone of heart precipitate an angina attack and acute myocardial infarction
β-blocker is contraindicated in variant angina Blockade of β2 receptors unopposed α1 receptor mediated coronary constriction
accentuates coronary spasm in variant angina β2 action is dilatation, while α action is constriction
In classical angina It decreases frequency and severity of attacks It increases exercise tolerance
In unstable angina, it is used along with nitrates or CCBs DRUG INTERACTIONS
1) β-blockers + Long acting nitrates in classical angina Nitrates cause reflex tachycardia (blocked by β-blocker) β-blocker cause ↑ in end-diastolic volume, reduction in total coronary blood flow,
coronary spasm (counteracted by nitrates) 2) β-blockers + CCBs
Verapamil/Diltiazem should not be combined with β-blocker, due to addition of depressant effects on SA and AV nodes
No net effect as β-blocker causes bradycardia, while nifedipine causes reflex tachycardia
3) Nitrates + CCBs Nitrates decrease preload, while CCBs decrease afterload Hence, ↓ workload of the heart effectively rather than being used alone Useful in severe vasospastic angina
4) Nitrates + CCBs + β-blockers Nitrates ↓ preload CCBs ↓ afterload, ↑ coronary blood flow β-blocker ↓ cardiac workload Useful in severe and resistant cases of classical angina Verapamil/Diltiazem (Dihydropyridine) should be avoided
K+ CHANNEL BLOCKERS
They activate ATP sensitive K+ channels Hyperpolarization of vascular smooth muscle Vasodilation – decreases preload and afterload
They have nitrate like effect increases cGMP
Effective in classical and variant angina
Increases coronary blood flow
Does not produce tolerance like nitrates
Example of drugs: Nicorandil, Pinacidil, Cromakalim
TRIMETAZIDINE
It is a pFOX (partial fatty acid oxidation) inhibitor – partially inhibits fatty acid oxidation
It inhibits 3-ketoacyl coA thiolase (the key enzyme in fatty acid synthesis)
It prevents degradation of membrane unsaturated fatty acid, hence reduces myocardial O2 demand
Improves metabolic status of ischaemic tissue
Useful in stable angina
RANOLAZINE
Blockade of a late sodium current that facilitates calcium entry via the sodium-calcium exchanger – decreases contractility
Reduces angina frequency & increases exercise capacity
Prophylaxis of angina – adjuvant drug
IVABRADINE
Funny channels regulate pacemaker activity of SA node, which are activated upon hyperpolarization at voltages in the diastolic range
Funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate
Ivabradine blocks hyperpolarization-activated current (If) through Na+ channels in SA node
Hence, it decreases heart rate decreases myocardial O2 demand
ANTI-PLATELET DRUGS
They inhibit platelet aggregation
Cause coronary vasodilatation
Useful in unstable angina
STATINS
HMG-coA reductase inhibitor
Decreases in LDL levels
Improves endothelial function
Reduces platelet aggregation
Stabilization of atherosclerotic plaque
DRUG THERAPY OF MYOCARDIAL INFARCTION
Anti-platelet drugs (Aspirin, Clopidogrel)
Thrombolytic therapy (Streptokinase, Alteplase, Reteplase, Tenecteplase)
Nitroglycerine: relieves pulmonary congestion, limits infarct size
β-blockers (Metoprolol): Reduces infarct size & duration of ischaemia Prevents re-infarction Reduces incidence of ventricular fibrillation
ACE inhibitors (Ramipril, Lisinopril): prevents remodeling, decreases the chances of congestive heart failure
Opioid analgesics (Morphine, Phetidine): relieves pain
Diazepam/Alprazolam: relieves anxiety
Anti-coagulant (Heparin, Enoxaparin): prevention of thrombus extension, embolism, venous thrombosis
CARDIAC GLYCOSIDES & DRUGS FOR HEART FAILURE
It occurs when cardiac output is inadequate to provide the O2 needed by the body
Heart is Unable to pump sufficient amount of blood Unable to receive sufficient amount of blood
Causes: arteriosclerotic heart disease, myocardial infarction, ventricular tachycardia, anaemia
Types of heart failure: 1) Low output failure = Metabolic demands of the body is within normal limits but heart
is unable to meet them 2) High output failure = Due to co-existing conditions. Increased cardiac output is unable
to meet the excessive metabolic demands of the body
Left-sided heart failure is characterized by pulmonary congestion, oedema, shortness of breath, dyspnoea
Right-sided heart failure is characterized by peripheral oedema Compensatory mechanisms of a failing heart:
Increased sympathetic activity
Activation of RAAS
Ventricular remodeling Symptoms of heart failure
Pulmonary and peripheral oedema
Tachycardia
Dyspnoea with cyanosis and decreased exercise tolerance
Cardiomegaly and hepatomegaly Decompensated heart
Pulmonary and peripheral oedema
Dyspnoea with cyanosis
Hepatomegaly
Cardiomegaly
Reflex tachycardia
Decreased urine formation
Decreased exercise tolerance and fatigue Treatment goals
To provide symptomatic relief and restoration of cardiac performance
To slow disease progression
To improve survival
HEART FAILURE
DRUGS USED IN HYPERTENSION A) Positive inotropic drugs
1. Cardiac glycosides: Digoxin, Digitoxin 2. Phosphodiesterase III inhibitors: Amrinone, Milrinone, Levosimendan 3. β-adrenergic agonists: Dopamine, Dobutamine, Dopexamine
B) Drugs without positive inotropic effects 1. Diuretics: Thiazides, Furosemide, Spironolactone 2. Vasodilators: Hydralazine, Nitrates, Sodium nitroprusside 3. β-blockers: Metoprolol, Bisoprolol, Carvedilol 4. Angiotensin converting enzyme inhibitors: Enalapril, Lisinopril, Ramipril 5. Angiotensin receptor blockers: Losartan, Candesartan, Irbesartan 6. Vasopressin receptor antagonists: Conivaptan, Tolvaptan
NORMAL IONIC MOVEMENTS – CONTRACTION
1 – Na+-K+ ATPase 2 – Voltage sensitive L-type Ca2+ channel 3 – Na+-Ca2+ exchanger 6 – Sarcoplasmic reticulum calcium channel 9 – Sarcoplasmic reticulum Ca2+ ATPase
Digitalis is a major source of digoxin and Digitoxin
Mechanism of action: Digitalis
↓ Binds to and inhibits Na+-K+ ATPase on cardiac cell membrane
↓ Progressive accumulation of intracellular Na+ & loss of intracellular K+
↓ Reduction in calcium expulsion from the cell by Na+-Ca2+ exchanger
↓ Increase in cytoplasmic Ca2+ – sequestered by SERCA in the sarcoplasmic reticulum
↓ Increase in release of Ca2+ from sarcoplasmic reticulum
↓ Triggers contractile response of failing heart
↓ Increases cardiac output
PHARMACOLOGICAL ACTIONS
A) Heart – improves ventricular performance without affecting myocardial O2 demand
Heart failure – increases force of contraction and cardiac output
Shortens systole – more time for ventricular rest and filling
Reduces heart rate by vagal action on SA node, extravagal action – a direct depressant action on SA and AV nodes & also opposes compensatory sympathetic overactivity
Decreases conduction velocity – AV node and His-Purkinje fibres – prolongs effective refractory period (ERP)
Increased ERP and decreased A-V conduction – protects ventricle from atrial flutter or fibrillation
At smaller doses, ↑ conduction velocity ↓ ERP of atrial muscle
At higher doses, ↑ automaticity and contractility (shortens ERP of atrial muscles and ventricles – extrasystoles, pulsus bigeminus, ventricular fibrillation)
Cholinergic innervation is upto AV node – vagal effects of digitalis is more pronounced at AV node and atria
ECG shows: Prolongation of PR interval Shortening of QT interval Depression of ST segment Inversion or disappearance of T wave
B) Blood vessels
Opposes compensatory sympathetic overactivity in heart failure – decrease in peripheral vascular resistance, heart rate, venous return
Decreases preload
No prominent effect on blood pressure C) Kidneys
Diuresis in heart failure patients. Shifts oedematous fluid into circulation
CARDIAC GLYCOSIDES
THERAPEUTIC USES – CONGETIVE HEART FAILURE
Digitalis enhances contractility – increases ventricular ejection & shifts the ventricular function curve towards normal
Improves tissue perfusion – withdrawal of sympathetic overactivity – decrease in heart rate and central venous pressure
Diuresis – clearing of oedema
Subsides pulmonary congestion, relieves dyspnoea and cyanosis
Especially useful in patients with dilated heart and low ejection fraction
Cardiac arrhythmias – atrial flutter, atrial fibrillation and paroxysmal supraventricular tachycardia (PSVT) Depressant effect on AV conduction Increases ERP of AV node PSVT – increase vagal tone & depresses the pathway through SA and AV nodes
Dilated heart – restores cardiac compensation ADVERSE EFFECTS
Cardiac side effects Extracardiac side effects
Bigeminy Ectopic beats
Ventricular tachycardia Ventricular arrhythmias
Bradycardia AV block
Anorexia Nausea
Vomiting Fatigue
Headache Gynaecomastia
Neuralgia
TREATMENT OF DIGITALIS TOXICITY
Tachyarrhythmias: Caused by chronic use of digitalis – infuse KCl I.V.
Ventricular arrhythmias: Lidocaine I.V. suppresses the excessive automaticity
Supraventricular arrhythmias: Propanolol I.V. or orally
AV block and bradycardia: Atropine I.M. or cardiac pacing
Severe digitalis intoxication: Administer digoxin antibody eg. digibind Fab fragments PRECAUTIONS & CONTRAINDICATIONS
Hypokalaemia – enhances digitalis toxicity by increasing its binding to Na+-K+ ATPase
Elderly, renal or hepatic disease, children below 10 years
Myocardial infarction
Acute myocarditis
Hypothyroidism
Ventricular tachycardia, partial AV block – can cause complete AV block
Wolff-Parkinson-White syndrome – can cause ventricular fibrillation
DRUG INTERACTIONS
Diuretics – hypokalaemia – increased digitalis toxicity
Calcium salts – synergistic action – increased digitalis toxicity
Quinidine – reduces binding of digitalis to tissue proteins & also reduces its clearance – increased digitalis toxicity
Adrenergic drugs, Succinylcholine – induce arrhythmias in digitalized patients
Metoclopramide, Sucralfate, Antacids, Neomycin – decreases digitalis absorption
Propranolol, Verapamil, Diltiazem – additively depress AV conduction & oppose positive inotropic action of digitalis
Phenobarbitone, Phenytoin – enzyme inducers – increases metabolism of digitalis and decreases its effect
Positive inotropic and direct vasodilation Inhibits phosphodiesterase III that converts cAMP to AMP
↓ cAMP activates protein kinase that phosphorylates Ca2+ channel
↓ Increases Ca2+ flow into the cell – increases myocardial contractility
Short term I.V. use in severe and refractory congestive heart failure
Adverse effects: Inamrinone: thrombocytopenia, nausea, diarrhoea, arrhythmias Milrinone: can cause arrhythmias
DOPAMINE
D1 agonist action – renal vasodilation – improves renal perfusion and GFR
β1 agonist action – increases cardiac output
Low output heart failure with compromised renal function DOBUTAMINE
β1 agonist – inotropic action
Preferred drug (I.V. infusion) – acute heart failure accompanying myocardial infarction, advanced decompensated CHF
Prolonged use cause development of tolerance
PHOSPHODIESTERASE III INHIBITORS
Β-ADRENERGIC AGONISTS
Improve ventricular function & prolongs survival in CHF patients
Non-selective β and α blocking drug is favoured – Carvedilol
Carvedilol has β1, β2 and α blocking properties
Additional property: Inhibits free radical induced lipid peroxidation
Prevents cardiac and vascular smooth muscle mitogenesis
Attenuates adverse effects of high concentration of catecholamines
Mild to moderate cases of dilated cardiomyopathy with systolic dysfunction
Useful in mild cases and advanced CHF
Loop diuretics – reduces pulmonary oedema and cardiac size
They stimulate the release of prostaglandin
Loss of Na+ and water – increases excretion of H+ and K+ – arrhythmias and may enhance digitalis toxicity
Toxicity can be overcome by loop diuretics with K+ sparing diuretics SPIRONOLACTONE
Enhances diuresis by promoting Na+ and water excretion
Retains K+
Prevents cardiac remodeling by preventing myocardial and vascular fibrosis
Requires serum K+ monitoring
Arteriolar dilatation – reduces afterload – enhances ventricular stroke volume and improves ejection fraction
Venodilatation – reduces preload – improvement in left ventricular function
Prolong survival by preventing pathological remodeling of heart and blood vessels
Provides symptomatic as well as disease modifying benefits
Recommended in all grades of CHF
ARBs are used when patient is intolerant to ACE inhibitors with cough and angioedema, or pregnancy
β-BLOCKERS
DIURETICS
ACE INHIBITORS & ARBs
Reduce pulmonary congestion
Reduce preload and afterload – increases cardiac output
Prevent cardiac remodeling
Useful in acute heart failure
Heart failure + dyspnoea – venodilator like nitroglycerine or long action nitrates
Heart failure with low ventricular output – arteriolar dilator like hydralazine (↓ afterload)
Severe chronic heart failure – hydralazine with long acting nitrate (↓ preload and ↓ afterload)
Vasopressin through V1 receptor vasoconstriction
Vasopressin through V2 receptor anti-diuretic action
Conivaptan is V1 and V2 receptor antagonist – used in acute heart failure with hyponatremia
Tolvaptan is oral V2 receptor antagonist
Nesiritide – recombinant form of human B type natriuretic peptide
Secreted by ventricles – increases cGMP – reduces venous and arteriolar tone
Acute decompensated heart failure with dyspnoea at rest
Omapatrilat, Sampatrilat (drugs without positive inotropic effect)
Inhibits neutral endopeptidases and angiotensin converting enzymes
Decreases formation of angiotensin II – vasodilatation with Na+ and water excretion
Heart failure – improves cardiac function
VASODILATORS
VASOPRESSIN RECEPTOR ANTAGONISTS
NATRIURETIC PEPTIDES
VASOPEPTIDASE INHIBITORS
DRUGS USED IN HEART FAILURE
A) To provide symptomatic relief and restoration of cardiac performance
Inotropic drugs: Cardiac glycosides, Phosphodiesterase III inhibitors, β-adrenergic agonists
Diuretics
Vasodilators
β-blockers B) To slow disease progression and prolong survival
ACE inhibitors
ARBs
β blockers
Aldosterone antagonists
Combined hydralazine – nitrate therapy
RESPIRATORY SYSTEM
DRUGS FOR BRONCHIAL ASTHMA
DRUGS AFFECTING BRONCHIAL TONE
SITES OF ACTION OF ANTI-INFLAMMATORY DRUGS IN ASTHMA
CLASSIFICATION OF DRUGS FOR ASTHMA A) Bronchodilators
1. Selective β2 receptor agonists: Salbutamol, Torbutaline, Salmeterol, Formoterol, Bambuterol
2. Non-selective sympathomimetics: Epinephrine, Ephedrine, Isoprenaline
3. Anti-cholinergics: Ipratropium, Tiotropium, Oxitropium
4. Methylxanthines: Teophylline, Aminophylline
B) Anti-Inflammatory Drugs
1. Corticosteroids i. Oral: Prednisone, Prednisolone, Methylprednisolone
ii. Parenteral: Methylprednisolone, Hydrocortisone iii. Inhalational: Beclomethasone, Fluticasone, Budesonide, Triamcinolone, Flunisolide
2. Mast cell stabilisers: Sodium cromoglycate, Nedocromil 3. Leukotriene modulators
i. 5-lipoxygenase inhibitor: Zileuton ii. Cysteinyl leukotriene receptor antagonists: Montelukast
4. Monoclonal anti-IgE antibody: Omalizumab 5. Miscellaneous: Nitric oxide donors
SELECTIVE β2 RECEPTOR AGONISTS
Short acting (short term relievers): Salbutamol, Terbutaline
Long acting (long term prevention): Salmeterol, Formoterol, Bambuterol MOLECULAR MECHANISM OF AIRWAY SMOOTH MUSCLE RELAXATION Adrenergic drugs β2 receptors
Bronchial smooth Mast cells muscle cells ↑ CAMP production Bronchial relaxation ↓ mediators release ↓ inflammation
Adenylyl cyclase
stimulate
BENEFICIAL EFFECTS
Mainstay – reversible airway obstruction (asthma)
Caution – Blood pressure instability, ischaemic heart disease patients
Additional anti-inflammatory property (drawback desensitization due to down-regulation of β2 receptors)
Selectivity to β2 receptors minimal cardiac stimulation and minimal side effects
Inhaled medication targeted, more β2 selective and lessens systemic side effects
Improve mucociliary transport
Effective and fastest bronchodilator property SABA VS. LABA
SABA (Short acting β2 receptor agonists) LABA (Long acting β2 receptor agonists)
They bind to active site of β2 adrenoreceptor
Less lipid soluble
Early onset of action (<5 minutes), persists for 4-6 hours
Orally, inhalational (metered dose/dry powder/nebuliser), I.V. and I.M. route
Drug of choicefor acute attacks of asthma
Terbutaline is safe bronchodilator in pregnancy
They bind to active site and exo-site of β2 adrenoreceptor
Highly lipid soluble
Delayed onset
Inhalational and oral route
Indicated in nocturnal asthma and long-term prevention of asthma
ADVERSE EFFECTS
Minimal if inhaled (preferred)
Oral route Muscle tremors (direct + β2 in skeletal muscle) Tachycardia (chronotropic β2 and in high doses, β1 receptor is activated) Hyperglycaemia (↑ gluconeogenesis and ↑ glycogenolysis) Hypotension (peripheral vasodilatation)
Continued use Desensitization/down-regulation of receptors Diminished responsiveness to the previous dose Prevented by concurrent use of glucocorticoids (there is risk of ↓ K+)
Aerosol preparations – myocardial toxicity (fluorocarbons)
NON-SELECTIVE SYMPATHOMIMETICS
Epinephrine & Ephedrine (α & β)
Isoprenaline (β1 & β2)
Non-selective action cardiac side effects (↑ blood pressure, tachycardia, arrhythmia)
Epinephrine Can cause effective and rapid bronchodilatation Drug of choice for acute asthma till β1 agonists were available Rarely used due to cardiac side effects (tachycardia, hypertension, worsening of
angina, myocardial infarction and arrhythmias)
ANTI-CHOLINERGICS
Act as pharmacological antagonists of acetylcholine released from parasympathetic fibres
Ipratropium, Tiotropium & Oxitropium (aerosol) MOLECULAR MECHANISMS OF AIRWAY SMOOTH MUSCLE CONTRACTION
Acetylcholine acts on M3 receptor of airway smooth muscle cells and mucous glands ↓
Cause ↑in cGMP ↓
CGMP activates phospholipase C, PIP2 is converted into IP3 ↓
Release of Ca2+ from sarcoplasmic reticulum ↓
Bronchodilation ROLE IN ASTHMA
Less effective than selective β2 agonists
Also blocks M2 presynaptic autoreceptors (↑ acetylcholine release) ↓ Rx efficacy
Relieved by inhalational route (MDI, rotacaps, nebulizer)
Delayed onset of action (>30 minutes)
Poor absorption into systemic circulation (quartenary compounds)
Lacks classic anti-cholinergic side effects)
Additional to brochodilatory action, they also decrease mucous secretion (unlike atropine, lesser drying effect on mucous no mucous plugs)
No effect on late asthmatic response (inflammatory stage)
Second line drugs in moderate to severe asthma used as an adjuvant to β2 agonists/glucocorticoids (longer duration)
Action of acetylcholine is blocked by anti-
cholinergics, hence cause
bronchoconstriction
METHYLXANTHINES
Natural alkaloids: Caffeine, Theophylline, Theobromine
Beverages: coffee, tea, chocolate
Drugs: Theophylline, Aminophylline, Diprophylline
Mechanism of action: Inhibition of PDE-IV (eosinophils & mast cells) Inhibition of PDE-III (airway smooth muscle) Adenosine receptor inhibitor (bronchodilation)
Exhibits bronchodilatory + anti-inflammatory + immunomodulatory
Increase mucous clearance
Used in combination with β2 agonists – asthma and chronic obstructive pulmonary disease PHARMACOKINETICS OF THEOPHYLLINE
Absorption Well absorbed orally (sustained release preparation – SR)
Rectal absorption – suppositories (erratic)
Distribution
Distributed to all tissues
Crosses placenta
Secreted in milk
50% PPB (plasma protein binding)
Metabolism
Metabolized extensively in liver by CYP1A2 (>85%)
Metabolizing enzymes are saturable
At higher doses, first order kinetics (t1/2: 4-6 hours) zero order kinetics disproportionate ↑ plasma concentration
Prolongation of t1/2: 60 hours
Excretion Unchanged in urine (10%)
Elimination rate is variable
Varies according to age, comorbidities and concurrent medications
FACTORS AFFECTING ELIMINATION RATE (CLEARANCE) OF THEOPHYLLINE
Faster elimination Slower elimination
Children (t1/2: 3-5 hours)
Smoking
Cystic fibrosis
Hyperthyroidism
Adults (t1/2: 7-12 hours)
Elderly >60 years
Premature infants
Hypothyroidism
Cirrhosis
Congestive heart failure
Febrile viral illness, pneumonia
↓ breakdown of CAM ↑ cAMP
ADVERSE EFFECTS OF METHYLXANTHINES
Has a narrow safety margin (therapeutic window)
Therapeutic plasma range: 10-20 µg/ml
Dose dependent toxicity: >20 µg/ml
Systems affected: GIT, CNS and CVS Relationship between plasma concentration of
theophylline to its effects
Toxic effect
Therapeutic effect
Sub-therapeutic effect
>60 µg/ml: death
>40 µg/ml: seizures, diuresis, fever, arrhythmias
>30 µg/ml: tachypnoea, flush, hypotension
>20 µg/ml: nausea, vomiting
DRUG INTERACTIONS WITH THEOPHYLLINE 1) Agents which ↑ CYP1A2 (enzyme inducers) decrease theophylline concentration
Drugs: Phenytoin, Rifampicin, Phenobarbitone, Carbamazepine
Charcoal broiled meat
Smoking 2) Agents that inhibit theophylline metabolism
Drugs: Erythromycin, Ciprofloxacin, Cimetidine, Oral contraceptives, Allopurinol 3) Theophylline enhances the effects of sympathomimetics, digitalis, furosemide, hypoglycaemic
agents, oral anticoagulants THERAPEUTIC USES OF METHYLXANTHINES
Management of bronchial asthma
Treat chronic obstructive pulmonary disease (COPD)
Dyspnoea associated with pulmonary oedema that develops from congestive heart failure DRUGS FOR MANAGING “LATE ASTHMATIC RESPONSE” WITH ANTI-INFLAMMATORY PROPERTY Mainly a prophylactic role – “controllers of symptoms”
Corticosteroids: Systemic & Inhalational
Mast cell stabilizers : Inhalational
Leukotriene (LT) modulators : Oral
Anti-IgE antibody: S.C. / I.V.
20
10
0
Plasma conc.
(µg/ml)
CORTICOSTEROIDS
Inhaled/Systemic corticosteroids mainstay for Rx of moderate to severe asthma – “preventers” of attack
Anti-inflammatory and immunosuppressant
↓ mucosal oedema & bronchial hyper reactivity to allergens
Symptomatic reliefs, improve airflow, retard disease progression, reduce asthma exacerbations
Long term – adverse effects with oral CS are worse than asthma itself, tapering dose essential
Prophylaxis and treatment of seasonal and perennial allergy DRUGS
Oral: Prednisone, Prednisolone, Methylprednisolone
Parenteral: Methylprednisolone, Hydrocortisone
Inhalational: Beclomethasone, Fluticasone, Budesonide, Triamcinolone, Flunisolide, Ciclesonide
ROUTES OF ADMINISTRATION
Inhalation: ↑ topical action, ↓airway remodeling, ↓inflammation, long term treatment of asthma & COPD (combination with SABA/LABA)
Systemic: Severe chronic asthma when not controlled by other drugs – shift to inhaled steroid Following severe acute asthma (7-10 days) – oral corticosteroids Status asthmaticus – start with I.V., then switch to oral
Intranasal spray: Allergic rhinitis, nasal polyposis ADVERSE EFFECTS
Inhalational: dryness of mouth, voice changes & oral candidiasis
Ciclesonide: higher topical:systemic ratio
Oral: short courses (<2 weeks) – no HPA (hypothalamic-pituitary-adrenal) axis
Parenteral: used during status asthmaticus only for a brief period oral route (Hydrocortisone hemisuccinate)
MAST CELL STABILIZERS
Sodium cromoglycate & Nedocromil sodium (inhalation)
Inhibit degranulation of mast cells (all inflammatory cells)
Inhibit release of histamine, leukotrienes, platelet activating factor, interleukins
Prevent bronchospasm/asthma by allergens
Decrease frequency and severity of attacks
Effect over 4 weeks and lasts 2 weeks after discontinuation MECHANISM OF ACTION
THERAPEUTIC USES
Prophylaxis of chronic & seasonal asthma: long term in mild to moderate cases (not in acute)
Prophylaxis allergic rhinitis (nasal spray)
Allergic conjunctivitis (eye drops)
Preferred in patient having multiple allergic disorders ADVERSE EFFECTS
Inhalational: least systemic side effects
Cromoglycate inhalation: throat irritation, cough, arthralgia, headache
Mast cell degranulation
LEUKOTRIENE ANTAGONIST
Zileuton – blocks leukotriene receptor & leukotriene synthesis
Montelukast, Zafirlukast – leukotriene receptor blocker
Antagonise – leukotriene receptor mediated actions like bronchospasm, eosinophil accumulation in lung, bronchus inflammation, hyper reactivity
THERAPEUTIC USES
Prophylactic treatment of mild to moderate asthma as adjuvants with inhaled corticosteroids or selective β2 agonists
Prophylaxis in severe asthma: permit reduction in steroid dose, rescue β2 inhalation
Effective in aspirin induced asthma ADVERSE EFFECTS
Gastrointestinal distress, headache, rashes, eosinophilia
Churg-Strauss syndrome (vasculitis with eosinophilia)
Zileuton: hepatotoxic
MONOCLONAL ANTI-IGE ANTIBODY
The allergic cascade is interrupted by omalizumab
Omalizumab is a monoclonal antibody
It neutralizes free IgE in circulation
Little IgE available to bind mast cell to release mediators
Reserved for resistant asthma cases
Not useful for acute attacks or status asthmaticus
High cost limits its use as first line drug
DRUGS & DEVICES USED FOR ADMINISTRATION
INHALATIONAL DRUGS
β2 agonists: Salbutamol, Terbutaline, Salmeterol, Formoterol
Anti-cholinergics: Ipratropium, Tiotropium
Mast cell stabilizer: Cromoglycate
Glucocorticoids DRUG PARTICLE SIZE
Large particles – settle on oropharynx
1-5µm diameter – deposits on bronchioles
Very fine particles are exhaled out
Slow and deep inbreathing & hold the breath after inhalation * Inhalation devices: 10% drug reaches lung AEROSOLS
Drug in solution Metered dose inhaler (MDI) Nebulizer
Dry powder inhalers Rotahaler Spinhaler/Twisthaler
METERED DOSE INHALER (MDI)
Actuation – coordination with deep inspiration
Device – carried along, convenient
Improve drug delivery: spacer, face mask
Don’t require synchronized coordination with inspiration
Advantages of using a spacer
Improves drug delivery
Does not require synchronized coordination with inspiration
Increases inhaled to swallowed drug ratio
Decreases deposition of larger particles in the mouth (candidiasis) NEBULIZER
Produces mist of drug solution by pressurized air or O2
Inhaled through mouthpiece or face mask
Used at bed side
Severe episodes of asthma – kids and elderly
More drugs can be mixed simultaneously
ROTAHALER
Rotacap – capsule containing drug
Punctured while rotating the cap
Drug is aerosolized by inspiratory air flow
Requires high velocity of airflow (kids, elderly and sick patients)
Powder – irritate, cough, spasm SPINHALER/TWISTHALER
Keep drug
Use it
Reset to use again
STATUS ASTHMATICUS
Hydrocortisone hemisuccinate 100 mg I.V., followed by 100 mg 4th hourly infusion
Nebulized salbutamol (5 mg) + ipratropium (0.5 mg)
Salbutamol 4 mg I.M. (inhaled drug don’t reach smaller bronchi – severe narrowing/plugging)
High flow humidified oxygen inhalation
Intubation & mechanical ventilation
Sodium bicarbonate + saline – correct dehydration
Antibiotics – treat infection
ASTHMA SEVERITY CLASSIFICATION
Clinical course, severity
Daytime asthma symptoms
Night time awakenings
FEV1, PEF
Intermittent <1/week 2 and <2/month >80% predicted. Daily
variability <20%
Mild persistent ≥1/week but not daily >2/month >80% predicted. Daily variability is 20-30%
Moderate persistent Daily >1/week >60% but <80% predicted.
Variability >30%
Severe persistent Persistent, which limit
normal activity Daily
<60% predicted. Variability >30%
CHOICE OF DRUG FOR MANAGEMENT OF VARIOUS TYPES OF ASTHMA
Step-wise guidelines are recommended
After asthma control for 3-6 months, reduction of medication stepwise
Types Steps Drug therapy
Seasonal asthma – Regular inhaled: cromoglycates or low dose
steroids
Episodes: inhaled SABA
Mild episodic asthma Step 1
Inhaled SABA
Mild chronic asthma with occasional exacerbation
Step 2
Regular inhaled: cromoglycates or low dose steroids
Moderate asthma with frequent
Step 3
↑ dose inhaled corticosteroids + LABA
Additional: theophylline
Severe asthma Step 4 High doses inhalational corticosteroids + LABA
Additional: Leukotriene antagonist/oral theophylline/oral β2 agonist/inhaled ipratropium
Not controlled severe asthma
Step 5
High inhaled steroid + LABA
Add oral steroid
DRUGS FOR COUGH
ANTITUSSIVES
1. Centrally acting antitussive
Opioids (Codeine and Pholcodeine) Selectively block cough centre Suppress cough for 6 hours Administered orally Adverse effects: constipation, respiratory depression, drowsiness, convulsions,
postural hypotension, tachycardia
Non-opioids (Dextromethorphan, Noscapine, Pipazethate)
Drug Mechanism of action Adverse effect
Noscapine Block cough centre Headache, nausea, tremor
bronchoconstriction
Dextromethorphan Increase threshold of cough
centre Dizziness, nausea, drowsiness, ataxia
2. Central as well as peripheral action (Benzonatate)
Inhibits the afferent cough impulses to suppress the central cough centre
Inhibits the pulmonary stretch receptors
Possesses mild local anaesthetic action as well
Admistered orally
Adverse effects: drowsiness, nausea, headache, vertigo
3. Peripheral action (Prenoxdiazine)
Inhibits the pulmonary stretch receptors to relieve bronchospasm
Administered orally
Adverse effects: mild and infrequent EXPECTORANTS
1. Mucokinetics
Example: Essential oil, Ammonium chloride, Sodium citrate, Guaiacol, Guaifenesin
Stimulate the flow of respiratory tract secretions by stimulating the bronchial secretory cells (to increase the volume) and the ciliary movement (to facilitate their removal)
They also have reflex irritant effect on gastric mucosa that initiate the reflex secretions of respiratory tract fluid
Adverse effects: ammonium salt metabolic acidosis, nausea
DEMULCENTS: Honey, Liquorice, Syrup tolu, Syrup vasaka LOCAL ANAESTHETICS: Xylocaine, Bupivacaine
2. Mucolytics
Examples: Acetylcysteine, Carbocysteine, Bromhexine, Ambroxol, Dornase-alfa
Alter the chemical characteristics of mucus to decrease its viscosity and to facilitate its removal by ciliary action or coughing
Drug Mechanism of action Adverse effect
Acetylcysteine Decrease the mucosity of mucus by splitting the disulfide bond of mucoproteins
Gastrointestinal irritation, nausea, vomiting, rashes, bronchospasm, stomatitis
Carbocysteine Not clear -
Bromhexine Depolymerizes mucopolysaccharides of mucus directly and increase lysomal enzyme activity
Rhinorrhoea, lacrimation, gastric irritation, hypersensitivity
Dornase-alfa Cleaves the DNA -
Advantages of Dextromethorphan and Noscapine over codeine
Least addiction liability
No analgesic action
Least constipating effects
Minimal drowsiness Role of anti-histamines & bronchodilators
Anti-histamines Afford relief in cough due to sedative and anticholinergic actions Lack selectivity for cough centre No expectorant property Reduce secretion Example: Chlorpheniramine, Diphenhydramine, Promethazine
Bronchodilators Clearing secretion by increasing surface velocity of airflow during cough Used only when an element of bronchoconstriction is present and not routinely
Drugs used in the treatment of productive cough & non-productive cough
Productive cough (expectorants) Non-productive cough (antitussive)
Essential oil
Ammonium chloride
Sodium citrate
Guaiacol
Guaifenesin
Acetylcysteine
Carbocysteine
Bromhexine
Ambroxol
Dornase-alfa
Codeine
Pholcodeine
Dextromethorphan
Noscapine
Pipazethan
Benzonatate
Prenoxdiazine
ANTI-TUBERCULAR DRUGS
CLASSIFICATION
First line essential
Isoniazid (INH)
Rifampicin (Rifampin, RMP)
Pyrazinamide (PZA)
Ethambutol (ETB)
First line supplemental
Streptomycin (SM)
Rifabutin
Rifapentine
Second line anti-tuberculosis
Fluoroquinolones
Amikacin
Capreomycin
Ethionamide
Para-aminosalicylic acid (PAS)
Cycloserine
Thiacetazone
ISONIAZID
MECHANISM OF ACTION
Mycobacterial catalase peroxidase convert Isoniazid (prodrug) to biologically active form which inhibit mycolic acid synthesis
Bactericidal to actively growing tuberculous bacilli but not for dormant which only get inhibited
Active against Mycobacterium tuberculosis and Mycobacterium kansasi
It acts on both intracellular and extacellular tubercle bacilli
Equally active in acidic and alkali medium PHARMACOKINETIC FEATURES
Acetylator status influences the nature of INH toxicity but not anti-tubercular response because its plasma concentration normally above its inhibitory concentration
Rapid acetylator: Plasma half-life is 1 hour Seen in Eskimos, Japanese, 30% of Indian
Slow acetylator: Plasma half-life is 3 hours Seen in Egyptian, Mediterrinean jews, Swedes and 70% of Indian
It is absorbed well orally get distributed to pleural, peritoneal and synovial fluid
CSF concentration can reach upto 100% if there is meningitis
Metabolized by N-acetyltransferase to Acetylisoniazid in the liver
ADVERSE EFFECTS
Peripheral neuritis (paresthesias, numbness) More common with slow acetylators because of
↑ excretion of pyridoxine in urine Accumulated INH inhibits pyridoxine kinase which converts pyridoxine to
pyridoxine phosphate (active form) Prevented by prophylactic use of vitamin B6 (pyridoxine)
Hepatotoxicity Hepatitis ↑ risk in people aged 50-65 years, patients with liver disease, alcoholic or
in fast acetylators Fast metabolism of Isoniazid provides high concentrations of hepatotoxic metabolites
Acetylisoniazid and Acetylhydralazine
Nausea
Appetite loss
Abdominal pain
Rises in aminotransferases
Allergic reactions
Xerostomia
Haematological changes
Convulsion in seizure prone patients
Drug-induced systemic lupus erythematosus RATIONALE FOR USING ISONIAZID WITH PYRIDOXINE
INH is structurally similar to pyridoxine
In peripheral neuritis, accumulated Isoniazid inhibits pyridoxine kinase which converts pyridoxine to pyridoxine phosphate (active form) and ↑ excretion of pyridoxine in urine
Pyridoxine (vitamin B6) is given prophylactically to prevent the neurotoxicity even with the higher doses
Pyridoxine with Isoniazid will reduce the risk of peripheral neuritis
Prophylactic pyridoxine must be given to the diabetic, chronic alcoholics, malnourished, pregnant, lactating and HIV infected patients
Isoniazid neurotoxicity is treated by pyridoxine
Drug should be discontinued at the onset of these symptoms
RIFAMPICIN
MECHANISM OF ACTION
It binds to bacterial DNA-dependant RNA polymerase but does not bind to mammalian RNA polymerase, hence host cells are safe
Bactericidal for both intracellular and extracellular tubercle bacilli
Active against Mycobacterium tuberculosis, Staphylococcus aureus, Neisseria meningitidis, Haemophilus influenzae, Brucella sp. and Legionella sp.
OTHER THERAPEUTIC USES
Leprosy in combination of Dapsone
Prophylaxis of meningococcal and Haemophilus influenzae meningitis and carrier state
Second/third choice of drug for MRSA, diphtheria and Legionella infection
Combination of Doxycycline and Rifampicin is the first line therapy of brucellosis
For prosthetic valve endocarditis ADVERSE EFFECTS
Hepatitis Increased risk if used with Isoniazid or patients with liver disease Dose-dependent and reversible
Gastrointestinal disturbances
Rashes
Dizziness
Flu-like syndrome
Fever
Chills
Myalgias
Thrombocytopenia
Harmless red orange colour urine DRUG INTERACTIONS
Accelerates the metabolism of several other drugs such as oral contraceptives, anticoagulants and protease inhibitors used in HIV patients due to its enzyme inducing properties (induction of cytochrome P-450 isoforms) hence cause therapeutic failure of those drugs
It also enhances its own metabolism as well as corticosteroids, sulfonylureas, steroids, non-nucleoside reverse transcriptase inhibitors (NNRTIs), theophylline, metoprolol, fluconazole, ketoconazole, clarithromycin, phenytoin, etc.
PYRAZINAMIDE
MECHANISM OF ACTION
It enters Mycobacterium tuberculosis via passive diffusion
Bacterial pyrazinamidase convert Pyrazinamide to pyrazinoic acid (active metabolite) which inhibits mycobacterial fatty acid synthase-1
Hence mycolic acid synthesis as well as cell wall formation disrupted
Since it is active in low pH it is effective against intracellular bacilli ADVERSE EFFECTS
Hepatotoxicity
Hyperuricemia
Acute gouty arthritis
Nausea
Vomiting
Anorexia
Drug fever
Malaise
Avoided in pregnancy
ETHAMBUTOL
MECHANISM OF ACTION
It inhibits arabinosyl transferase
Hence polymerization of arabinoglycan is prevented
Arabinoglycan essential constituent of mycobacterial cell wall ADVERSE EFFECTS
Retrobulbar neuritis impairing visual acuity and red-green colour discrimination
Dose of 25 mg/kg/day for more than 9 months
Avoided in children
Decreases renal excretion of urates → precipitate gouty arthritis
Mild gastrointestinal intolerance
Rashes
Fever
Dizziness
GOALS OF ANTI-TUBERCULAR CHEMOTHERAPY 1) Kill dividing bacilli
Drugs with bactericidal action rapidly reduce bacillary load in the patient and achieve quick sputum negativity so that patient is non-contagious to the community
2) Kill persisting bacilli To cure tuberculosis and prevent relapse
3) Prevent emergence of resistance So that the bacilli remain susceptible to the drugs
SHORT COURSE CHEMOTHERAPY OF NEW SPUTUM POSITIVE PULMONARY TUBERCULOSIS (CATEGORY I TB)
Two phases involved: intensive phase, then followed by continuation phase
For both phases, all drugs are given thrice weekly under DOT scheme
Intensive phase: Lasts for 2 months Aimed to rapidly kill the bacteria, to minimize the chances for developing resistance
and to bring about sputum conversion and symptomatic relief Drug regimen: Isoniazid + Rifampicin + Pyrazinamide + Ethambutol
Continuation phase: Lasts for 4 months Aimed to eliminate the remaining bacilli to minimize the chances of relapse Drug regimen: Isoniazid + Rifampicin
ANTI-LEPROTIC DRUGS
LEPROSY
Leprosy is a chronic granulomatous infection caused by an Mycobacterium leprae
Cannot be grown on culture media, so drug sensitivity testing in vitro is not possible
Mycobacterium leprae lie within macrophages and remain dormant but alive
Large number of persons may be infected by the bacteria but only a few suffer clinically
Clinical leprosy is a consequences of deficient CMI in susceptible individuals
Transmission: person-to-person when bacilli are shed from the nose and skin lesions of the infected patients
Affects the peripheral nervous system, the skin and various tissues
Leprosy is classified based on its chemotherapy which are paucibacillary leprosy and multibacillary leprosy
PAUCIBACILLARY LEPROSY
Noninfectious leprosy with few bacilli
Also called tuberculoid leprosy
Important features: Less than 5 hypoaesthetic skin lesions Normally or only partially deficient cell mediated immunity Bacilli are rarely found in biopsies Lepromin test: positive There are prolonged remissions with periodic exacerbations
MULTIBACILLARY LEPROSY
Infectious leprosy with numerous bacilli
Mainly a lepromatous leprosy
Important features: More than 5 hypoasthetic but diffused skin lesions with mucous membrane
infiltrations Cellular immunity is largely deficient Skin and mucous membrane have numerous bacilli Lepromin test: negative Disease later progresses to anesthesia of distal parts and wounds
CLASSIFICATION OF ANTI-LEPROTIC DRUGS
Sulfones: Dapsone
Phenazine derivatives: Clofazimine
Anti-tubercular drug: Rifampicin
Antibiotics: Fluoroquinolones: Ofloxacin, Sparfloxacin, Pefloxacin Macrolides: Clarithromycin Tetracyclines: Minocycline
DAPSONE
Closely related to Sulfonamides and shares a common mechanism of action, ie. inhibition of bacterial folic acid synthesis
Thus, it is leprostatic
Mechanism of action: Dihydropteridine + PABA
Dihydropteroic acid
Dihydrofolic acid
Most widely used sulfone for long-term therapy of both types of leprosy
However, resistance emerges in some population of Mycobacterium leprae especially in lepromatous leprosy patients if it used as a monotherapy
Therefore, combination of Dapsone with Rifampicin and/or Clofazimine is recommended
Well absorbed after oral administration
Widely distributed throughout body fluids and tissues
Tends to remain in skin, muscle, kidney and liver upto 3 weeks after therapy is stopped
Skin which is heavily infected with Mycobacterium leprae may contain 10-15 times as much Dapsone as normal skin
CLOFAZIMINE
A phenazine dye which binds preferentially to mycobacterial DNA to inhibit mycobacterial growth
It is a leprostatic drug with anti-inflammatory properties
This is a major advantage of Clofamizine over other anti-leprotic drugs and therefore it has a valuable pace in the management of lepra reaction (erythema nodosum leprosum)
Is used for Dapsone-resistant leprosy or in patient intolerant to Dapsone
Anti-leprotic effect of Clofazimine has biological lag of 6-7 weeks
Oral absorption
Major elimination is through faeces
Plasma half-life is 60-70 hours
Widely distributed in tissues including phagocytes
Adverse effects: Usually well tolerated Non-haemolytic anaemia and methaemoglobinaemia in persons having G6PD
deficiency Mild side effects: nausea, loss of appetite, pruritis, drug fever, reversible neuropathy
and hepatotoxicity
Dihydropteroic acid synthase Dapsone
WHO REGIMEN A) Multibacillary (lepromatous) leprosy
Dapsone 100 mg daily + Clofazimine 50 mg daily for 29 days and 300 mg on 30th day + Rifampicin 600 mg once a month for 24 months
B) Paucibacillary (tuberculoid) leprosy
Dapsone 100 mg daily + Rifampicin 600 mg once a month (6 months)
If Dapsone is not tolerated, Clofazimine 50 mg daily for 29 days and 300 mg on 30th day
C) Alternative regimens for multibacillary leprosy
1. If Rifampicin is unsuitable because of resistance or intolerance:
Clofazimine 50 mg daily + Ofloxacin 400 mg daily + Minocycline 100 mg daily for first 6 months
And thereafter, Clofazimine 50 mg daily + Ofloxacin 400 mg daily (or Minocycline 100 mg daily) for further 18 months
2. If Clofazimine cannot be given because of unacceptable skin pigmentation or abdominal pain:
Dapsone 100 mg daily + Ofloxacin 400 mg daily (or Minocycline 100 mg daily) + Rifampicin 600 mg once a month for 24 months
DRUGS USED IN TREATMENT OF LEPRA REACTION
During Dapsone therapy, some reactive episodes might occur this is known as lepra reaction
There are two types namely type 1 lepra reactions and type 2 lepra reaction
Type 1 lepra reaction: Delayed hypersensitivity reactions against Mycobacterium leprae antigens (type IV
hypersensitivity) This is characterized by cutaneous ulceration and multiple nerve involvement It can be treated with Corticosteroids (Glucocorticoids and Mineralocorticoids drugs)
Type 2 lepra reaction: Also known as nodosum leprosum Humoral antibody response (type III hypersensitivity) This is characterized by enlarged lesions, become red, inflammed and painful It can be treated with Clofazimine, Thalidomide and Corticosteroids Clofazimine does not react as rapidly as Corticosteroids and Thalidomide