Cardiovascular System Question And Answers

Renin-Angiotensin-Aldosterone System

Question 1. Name the drugs acting on the RAAS. Describe the pharmacology of any one of them.
Answer:

• Drugs that interfere with renin angiotensin aldosterone system (RAAS) include
• Direct renin inhibitor
• Angiotensin-converting enzyme inhibitors (ACE-I)
• Angiotensin receptor blockers

Read And Learn More: Pharmacology Question And Answers

Direct Renin Inhibitor:

Aliskiren is a direct renin inhibitor used for the treatment of hypertension. Other indications for it are being explored.

Angiotensin-Converting Enzyme Inhibitors (Ace-I)

Question 2. List the ACE inhibitors. Describe their action, uses, and adverse effects.
Answer:

• Angiotensin-converting enzyme inhibitors are drugs that prevent the convertion of Ang-I to
• Ang-II by inhibiting the ACE. They are captopril, enalapril, lisinopril, ramipril, benazepril,
  fosinopril, quinapril and trandolapril.

ACE inhibitors Pharmacological Actions:

• ACE-I reduces blood pressure → reverses left ventricular hypertrophy
• In CCF, ACE-I increases cardiac output by a reduction in ventricular afterload

ACE inhibitors Pharmacokinetics:

Generally well-absorbed. Except for captopril and lisinopril, all others are prodrugs. They differ in their pharmacokinetic properties. Most ACE inhibitors are excreted through the kidneys → reducing the dose in renal dysfunction.

ACE inhibitors Adverse effects:

ACE inhibitors are well-tolerated. Adverse effects include:

1. Dry cough: Due to increased bradykinin levels; more common in women → may require
   withdrawal of ACE and an ARB may be tried instead.
2. Hypotension: Hypotension on initiation of therapy —‘first dose phenomenon’. Hence, start with small doses and if patients are already on diuretics—temporarily diuretics should be stopped.
3. Hyperkalemia: Significant in patients on K+ sparing diuretics, NSAIDs, beta-blockers or when given with K+ supplements.
4. Dysgeusia: An altered taste sensation is more common with captopril—but, reversible.
5. Angioneurotic edema: Angioedema (0.1% incidence) with swelling in the lips, nose, larynx, and airway obstruction. It may be due to increased bradykinin levels and can be fatal. ACE inhibitors should be immediately withdrawn at the first sign of angioedema.
6. Skin rashes Rare and self-limiting.
7. Teratogenicity: ACE-I are teratogenic.
   • Given in 2 and 3  trimesters → Fetal growth retardation, malformed lungs → death.
   • ACE inhibitors are, therefore contraindicated in pregnancy.
8. Other ADRs: Headache, nausea, abdominal pain, proteinuria and rarely, neutropenia.

Neutropenia is more common in patients with collagen diseases. ACE-I can precipitate acute renal failure in patients with renal artery stenosis.

ACE inhibitors Use:

1. Hypertension: ACE-I are first-line drugs in hypertension of all grades due to all causes

2. Congestive cardiac failure: First-line drugs in CCF.

3. Myocardial infarction: Started within 24 hours ACE-I prevents the development of CCF and reduces mortality. In post-MI patients, ACE-I reduces long-term mortality and prevents ventricular remodeling and the development of cardiac failure.

4. Prophylaxis in coronary artery disease: ACE-I reduces the risk of MI, stroke, heart failure, diabetes, and sudden death. They may prevent reinfarction in post-MI patients.

5. Diabetic nephropathy: Long-term treatment with an ACE-I prevents the progression of renal disease and retards the worsening of renal function. They reduce albuminuria, intraglomerular pressure and reduce hyperfiltration.
6. Chronic renal failure: ACE-I delay the progression of failure in CRF due to causes other than diabetes.

7. Scleroderma renal crisis: ACE-I may be life-saving in these patients as they prevent an increase in BP and deterioration of renal function.

Precautions/Contraindications and Drug Interactions:

Question 3. Mention the contraindication of ACE-I.
Answer:

1. Started with a low dose and gradually increased every 1–2 weeks to the required dose.
2. Contraindicated in pregnancy.
3. At the first sign of angioedema, ACE-I should be stopped.
4. Contraindicated in patients with renal artery stenosis as they can cause renal failure in them.
5. ACE-I + K+ sparing diuretics → ↑ ↑ Hyperkalemia → Avoid combination.
6. ACE-I → ↓ Li+ excretion → Toxicity → Avoid combination.
7. ACE-I → ↑ Digoxin levels → Toxicity → Avoid combination.

Angiotensin Receptor Blockers ( ARBs)

Drugs that block the angiotensin receptors antagonize the effects of angiotensin II. Angiotensin receptor blockers (ARBs) have a high affinity for AT1 receptors—the affinity of Losartan is 1,000 times and valsartan 20,000 times more for AT1 receptors than AT2. On long-term administration of ARBs, plasma renin activity increases.

 ARB’s Advantage:

• No increase in bradykinin levels and its associated adverse effects like dry cough and angioedema.
• ARBs are competitive antagonists of thromboxane A2 → inhibit platelet aggregation.
• ARBs also reduce the proliferation of arteriolar intima.
• ACE-I may stimulate the formation of Ang-II by alternative pathways (for example, Chymase) leading to a reduction in their efficacy. ARBs do not have this disadvantage since they block the receptors.
• ARBs are all given orally. Their bioavailability is generally <50%.

 ARBs  Adverse effects: ARBs are well-tolerated.

• Hypotension and hyperkalemia like ACE-I.
• Angioedema is rare.
• Weakness, headache, dizziness, and epigastric distress are mild.
• ARBs are teratogenic → contraindicated in pregnancy.

ARBs Uses:

1. Hypertension: First-line drugs → alternatives to ACE-I. ARBs can be combined with diuretics.
2. Cardiac failure: Alternatives to ACE-I in cardiac failure and therapeutic benefits are comparable to them.
3. Diabetes mellitus with renal dysfunction: ARBs are drugs of choice—they are ‘renoprotective’ in type 2 diabetes mellitus as they prevent or delay the development of renal failure in such patients.
4. Prevention of stroke: In hypertensive patients with left ventricular (LV) hypertrophy, ARBs reduce the risk of stroke.
5. Atrial fibrillation: Irbesartan used to maintain cardiac rhythm in chronic atrial fibrillation.
6. Portal hypertension: Losartan safe and effective in portal hypertension and cirrhosis.

Calcium Channel Blockers

Question 4. Name the CCBs. Describe their mechanism of action, uses, and adverse effects.
Answer:

There are four types of calcium channels:

1. Voltage-gated Ca⁺ channels.
2. Receptor-operated channels.
3. Stretch-operated channels.
4. Na⁺ Ca⁺ exchange channel.

Calcium Channel Blockers (Ccb) Include: 

CCBs Mechanism of action:

• Depolarization of the cardiac and most smooth muscle cells depends on the entry of extracellular calcium into the cell through the calcium channels along with the release of extracellular calcium from the sarcoplasmic reticulum.
• CCBs inhibit the entry of calcium by blocking the L-type of calcium channels.
• This decreases Ca⁺⁺ current and Ca⁺ entry into the cardiac and vascular smooth muscle cells leading to relaxation. In the heart, the reduced Ca⁺⁺ results in decreased contractility, heart rate and

Actions: CCBs bring about the following effects:

1. Smooth muscle:

1. Vascular smooth muscles:

• Arteriolar smooth muscles are relaxed by CCBs

• Venous beds → effects not significant.
• Dihydropyridine CCBs have prominent effects on the blood vessels compared to the heart, i.e. they are vascular selective.

2. Coronary circulation: CCBs dilate the coronary vessels → increase coronary blood flow → hence they are useful in variant or vasospastic angina.

3. Other smooth muscles:

Skeletal muscles:

Because the skeletal muscle uses intracellular calcium for contraction and does not depend on calcium influx during depolarization, there is no skeletal muscle relaxation with CCBs.

2. Heart:

• CCBs have a negative inotropic effect they depress the myocardial contractility, reduce heart rate, and in higher doses slow AV conduction.
• They reduce cardiac work done and along with decreased PVR, there is a decrease in myocardial oxygen consumption.
• Verapamil and diltiazem depress the SA node—they have more prominent cardiac effects than vascular effects when compared to DHPs.

3. Other effects:

• Verapamil in high doses inhibits insulin release.
• CCBs may interfere with platelet aggregation.
• Verapamil blocks the P-glycoprotein which is involved in the efflux of drugs out of cancer cells.
• This may reverse the resistance of cancer cells to chemotherapy and malarial parasite to chloroquine.

CCBs Pharmacokinetics:

CCBs are well absorbed but undergo extensive first-pass metabolism. They are all highly plasma protein bound (70–99%) and are metabolized in the liver.

Therapeutic Uses:

Question 5. Describe the uses of CCBs.
Answer:

1. Ischemic heart disease:

• Angina pectoris: Verapamil and diltiazem are used for the prophylaxis. In chronic stable angina, ↓ PVR, ↓ HR → ↓ CO → ↓ myocardial O₂ demand. They also inhibit exercise-induced tachycardia and cause coronary vasodilatation.
• Vasospastic angina: CCBs are coronary vasodilators and relieve pain → drugs of choice.
• Unstable angina: Verapamil may be used to reduce cardiac workload (DHPs are contraindicated for the risk of reflex tachycardia).

2. Hypertension:

• Long-acting CCBs like amlodipine may be used. Amlodipine is preferred because of its long half-life, good patient compliance and tolerability.
• CCBs are also suitable for combination with most other antihypertensives. Avoid verapamil + b-blocker → Myocardial depression.
• In hypertensive crises, sublingual nifedipine is used.

3. Arrhythmias: Verapamil is used in PSVT and to control ventricular rate in atrial flutter or fibrillation. IV verapamil and diltiazem are also used in supraventricular tachyarrhythmias

4. Peripheral vascular diseases: In Raynaud’s disease and intermittent claudication for their vasodilator effects.

5. Other uses

• Hypertrophic cardiomyopathy: Verapamil improves diastolic function and exercise performance → relieves symptoms.
• Migraine: Verapamil is useful for the prophylaxis of migraine.
• Subarachnoid hemorrhage: Vasospasm that follows subarachnoid hemorrhage is believed to be responsible for neurological deficits. As nimodipine brings about cerebral vasodilatation, it is used to treat neurological deficits in patients with cerebral vasospasm.
• Atherosclerosis: DHPs may slow the progress of atherosclerosis. In post-MI patients, verapamil reduces mortality and the risk of reinfarction.
• Preterm labor: Nifedipine inhibits uterine contractions → delays preterm labor.
• Cardiac transplantation: Diltiazem suppresses the formation of post-transplant coronary atheroma.
• Diabetic nephropathy:

Smooth muscle hyperactivity: As in achalasia may respond.

Question 6. Write short note on nifedipine/verapamil/amlodipine.
Answer:

Dihydropyridines:

• Dihydropyridines are potent vasodilators and cause a significant fall in BP and evoke reflex tachycardia.
• They block the Ca⁺⁺ channels in the vascular smooth muscles at lower concentrations than that needed to depress the heart.
• Hence they have weak myocardial depressant effects. Nifedipine inhibits platelet aggregation.
• Smooth muscles of the bronchi, ureter, and uterus are relaxed. Nifedipine can be given sublingually, orally, and parenterally.
• Dose: 5–20 mg oral TDS.

Amlodipine:

• Amlodipine has a favorable pharmacokinetic profile. Bioavailability is better (60–70%) compared to other DHPs.
• Absorption is slow and steady because of which the blood levels rise gradually. Hence side effects like flushing, headache, dizziness, and palpitation are much less compared to other DHPs.
• It has a long t½ and is suitable for once daily use. Hence amlodipine is a commonly used CCB.
• Dose: 5–10 mg OD.

Verapamil and Nifedipine:

Nifedipine, Verapamil, Amlodipine Adverse Effects:

DHPs (prominent vascular effects):

• Flushing
• Palpitation
• Dizziness
• Fatigue
• Hypotension
• Leg cramps
• Ankle edema

Verapamil (prominent cardiac depressant effects):

• Bradycardia
• Heart block
• Headache
• Hypotension
• Constipation
• Gum hyperplasia—long-term use

Drug Interactions:

1. Verapamil + b-blocker → ↑ myocardial depression
2. Verapamil → ↓ digoxin excretion → ↑ digoxin levels → toxicity
3. Verapamil inhibits microsomal → ↑ plasma levels of statins, → toxicity enzymes CYP3A4 cyclosporin, sildenafil

Congestive Cardiac Failure

Question 7. Classify drugs used in CCF. Describe the rationale for use of each of them in CCF.
Answer:

In congestive cardiac failure (CCF), the heart is unable to provide adequate blood supply to meet the body’s oxygen demand. Since the pumping ability of the heart is reduced, cardiac output decreases. The drugs used in CCF are:

CCF Classification: 

Aim of treatment—to reduce morbidity and mortality by restoring cardiac output and relieving congestion.

CCF  Diuretics:

Loop diuretics like frusemide are the first-line drugs in CCF.

They have some disadvantages:

1. Long-term diuretic therapy may cause hypokalemia (hence add a K⁺-sparing diuretic).
2. They activate renin–the angiotensin system → deleterious effects on the CVS.
3. Diuretics do not stop the progression of heart failure but only suppress the symptoms.

Hence diuretics are given for short periods as and when required. IV frusemide with an ACE inhibitor is useful in acute heart failure. Long-term frusemide therapy may be needed in more severe diseases.

Spironolactone:

• Spironolactone the K⁺ sparing diuretic, though a weak diuretic, can benefit patients with heart failure because it antagonizes the effects of aldosterone including raised plasma volume and preload.
• It reduces morbidity and mortality when given along with ACE inhibitors in patients with severe heart failure (HF).

CCF Vasodilators:

Vasodilators reduce mortality in patients with cardiac failure.

1. Arteriolar dilators: Arteriolar dilators (for example, Hydralazine)

Arteriolar dilator → Relax arterial smooth → ↓ PVR → ↓ Afterload → ↓ Cardiac workload
muscle

• Hydralazine an arteriolar dilator improves renal function as it causes good renal vasodilatation.
• Hydralazine + Nitrate → Improve long-term survival → Alternative to ACE-I

2. Venodilators: Venodilators (for example, Nitrates)

Venodilators → ↓ Venous return → ↓ Preload → Reduce stretching of the ventricular walls and myocardial oxygen requirements.

Organic nitrates:

• Nitroglycerine and isosorbide dinitrate are good vasodilators with rapid and short action.
• They can be used for short periods to decrease the ventricular filling pressure in acute heart failure. Nitrates may also be combined with hydralazine.

3. Arteriolar and venular dilators reduce both preload and afterload:

1. ACE inhibitors like captopril, enalapril, lisinopril, and ramipril, act by

• Reduction of afterload: Angiotensin II is a powerful vasoconstrictor present in the plasma in high concentrations in cardiac failure. ACE inhibitors prevent the formation of angiotensin II and thereby reduce the afterload.
• Reduction of preload: ACE-I prevents the formation of aldosterone, prevents salt and water retention and thereby reduces the preload. They also prevent bradykinin degradation and increase bradykinin levels which also causes vasodilatation.
• Reversing compensatory changes: Angiotensin II formed locally in the myocardium is responsible for undesirable compensatory changes like ventricular hypertrophy and ventricular remodeling seen in CCF. ACE-I reverses these changes and prolongs survival.

They are thus the most preferred drugs in all patients with CCF. ARBs may be used as alternatives. Direct renin inhibitor aliskiren is also useful.

2. Sodium nitroprusside:  

• It is a powerful vasodilator → dilates both arterioles and venules and reduces both ventricular filling pressure and peripheral arterial resistance.
• It is given IV, has a rapid (30–60 seconds) and short action (3 minutes), hence useful in acute severe heart failure.

3. Prazosin: Is a₁ antagonist, it is a vasodilator—can be used in acute heart failure for longer periods than nitrates.

4. Calcium channel blockers: Not routinely used in heart failure because of their myocardial depressant effect. Amlodipine may be tried when other vasodilators are contraindicated.

CCF Inotropes:

1. Cardiac glycosides: When heart failure does not respond to diuretics and ACE inhibitors, digoxin may be tried. Digoxin improves cardiac performance in the dilated, failing heart. If there is associated atrial fibrillation, digoxin is the preferred drug. Detailed pharmacology of cardiac glycosides is discussed later.

2. β-adrenergic agonists:  

Dobutamine

Dobutamine is a good inotropic agent—it stimulates the cardiac b1-receptors and increases the force of contraction of the heart.

Dobutamine may be given as intermittent infusion which relieves the symptoms and the benefit may persist for several weeks.  Dobutamine infusion is also useful in acute heart failure in cardiac surgeries or MI.

Dose: 2–8 μg/kg/min as temporary support to the failing heart. The development of tachyphylaxis limits its longer use.

Dopamine: 

Dopamine may be used in CCF with associated renal impairment because dopamine increases renal perfusion in addition to increased cardiac output. Dopamine 3– 10 μg/kg/min may be used in cardiogenic shock.

Dopexamine:

• Dopexamine is an agonist at dopamine D₁, D_2, and b₂–  adrenergic receptors → has vasodilator properties—reduces PVR and improves renal blood flow.
• Thus cardiac workload reduces due to reduced afterload. It also has mild inotropic properties by b₁– receptor stimulation. Dopexamine may be useful in heart failure.

3. Phosphodiesterase inhibitors:

• Amrinone and milrinone inhibit the enzyme phosphodiesterase (which degrades cAMP) resulting in increased cAMP levels.
• They increase the force of contraction and also cause vasodilatation. Because of the adverse effects and increased mortality seen with the use of these drugs, they are not preferred.
• Sildenafil inhibits PDE5 which is abundant in the lungs. It is used in patients with pulmonary hypertension and CCF.
• Sildenafil improves cardiac function, hemodynamics of the heart and overcomes ventricular hypertrophy, and enhances exercise capacity.

4. Newer inotropes:

Levosimendan:

In addition to PDE inhibition, levosimendan sensitizes the troponin system to calcium and has inotropic effects. It also has vasodilator properties including coronary vasodilation. It is used in heart failure in some countries. Levosimendan may be used in acute decompensated heart failure as an alternative to dopexamine.

Istaroxime acts as an inotropic agent in two ways—inhibits Na+ K+ ATPase like digoxin and also facilitates the sequestration of calcium in the sarcoplasmic reticulum. It has some advantages over digoxin like being less arrhythmogenic.

CCF Other:

α-adrenergic blockers: Though b-blockers are negative inotropic agents when used carefully along with other drugs, b-blockers can improve long-term survival.

Beta-blockers should be started with a low dose and gradually titrated upwards. The reduced ejection fraction due to reduced contractility may be seen initially but gradually improves after 8–10 weeks of treatment. The beneficial effect could be because of:

1. Opposing the negative effects of sympathetic overactivity including remodeling effects.
2. Upregulation of beta receptors.
3. Decreased heart rate.

Beta-blockers are useful in mild to moderate heart failure with dilated cardiomyopathy and systolic dysfunction. A long-acting preparation like sustained release metoprolol is preferred.

CCF Newer Drugs:

• Ivabradine: Ivabradine selectively blocks the If current in the SA node thereby reducing heart rate without depressing myocardial contractility (see Page 127) → useful in chronic HF.
• Sacubitril: Neprilysin is an enzyme that degrades natriuretic peptides. Sacubitril inhibits neprilysin, thereby increasing levels of natriuretic peptides → useful in heart failure along with valsartan (an ARB).
• Serelaxin: Serelaxin is relaxin-2 which activates VEGF, vascular endothelin B receptor, and also enhances nitric oxide (NO) production, leading to renal and systemic vasodilatation → useful in acute heart failure.
• Ularitide: Ularitide is synthetic urodilatin, a natriuretic peptide that regulates renal sodium and water excretion and has been shown to be beneficial in acute heart failure.

Pharmacology Of Cardiac Glycosides

Question 8. Describe the mechanism of action, uses, and adverse effects of digoxin.
Answer:

Cardiac glycosides are obtained from the plants of the Foxglove family. William Withering, an English physician, first described the clinical effects of digitalis in CCF in 1785.

Source: The word digitalis is used to mean cardiac glycosides.

• Digoxin from leaves of Digitalis purpurea—used clinically
• Digitoxin leaves of Digitalis lanata
• Ouabain seeds of Strophanthus gratus

Chemistry: The glycosides consist of an aglycone attached to sugars.

Digoxin Pharmacological Actions:

• Cardiac actions: The primary effects of digitalis on the heart are:
  • Reduction in heart rate
  • Inotropic effects
  • Cardiotonic Effects
• Inotropic effects: Cardiac glycosides increase the force of contraction of the heart and the inotropic effects are more pronounced on the failing heart.

Cardiac glycosides are cardiotonic drugs.

Short systole and prolonged diastole → more rest to the heart and better coronary filling  ↑ FOC, stroke volume → ↑ CO, ventricles empty better

• Tone: ↑ resting tone of the myocardium
• Heat rate: Digoxin reduces heart rate by:
  • ↑ Vagal tone
  • ↓ Sympathetic overactivity (circulation improved)
  • Direct action on SA and AV nodes
• Coronary circulation: Improves coronary circulation due to: ↑ coronary filling and ↑ CO
• Electrophysiological effects:
  • Depress AV conduction and ↑ AV nodal refractory period
  • ECG changes—T wave inversion, P wave changes, ↑ PR interval, shortened QT interval,
    ↓ ST segment.

Extracardiac Actions:

• Kidney: Diuresis occurs which also relieves edema in CCF patients.
• CNS: High doses stimulate CTZ resulting in nausea and vomiting.

Digoxin Mechanism of action: Cardiac glycosides inhibit the enzyme Na⁺ K⁺ ATPase—also called ‘sodium pump’ present on the cardiac myocytes

 

Digoxin Pharmacokinetics:

The bioavailability of digoxin varies with different manufacturers and because the safety margin is low, in any given patient, preparations from the same manufacturer should be used. Glycosides are cumulative drugs. The therapeutic concentration is 0.5 to 1.4 ng/mL.

Digoxin: Dose 0.125–0.5 mg daily is the slow loading and maintenance dose.

Comparison between digoxin and digitoxin:

Digitalization:

• Response to digoxin develops over 5–7 days with the maintenance dose.
• However, when rapid response is required, rapid digitalization can be done by more frequent dosing with constant monitoring of 0.5– 0.75 mg every 8 hours.

Question 9. Write a short note on the toxicity of digoxin/cardiac glycosides.
Answer:

• Digoxin Adverse effects:
• Cardiac glycosides have a low safety margin and adverse effects are common.
• They inhibit Na⁺ K⁺ ATPase in all excitable tissues—including neurons and smooth muscle cells where spontaneous activity is increased and this action is responsible for toxicity. Toxicity can be cardiac and extracardiac.

 Drug interactions:

Extracardiac:

• Gastrointestinal toxicity—anorexia, nausea, vomiting (directly stimulate the CTZ), and diarrhea are the first symptoms to appear. It is important to recognize these first symptoms of toxicity but vomiting may also be due to CCF itself.
• Neurotoxicity—digitalis can cause vertigo, blurred vision, disturbances of color vision, headache, confusion, neuralgia, disorientation, delirium, hallucinations and rarely convulsions.
• Others: Allergic skin rashes and long-term use can cause gynecomastia as it structurally resembles estrogen. Digoxin crosses the placental barrier and can cause toxicity.

Cardiac Toxicity:

• Arrhythmias of most types
• Extrasystoles
• Bradycardia
• Pulses bigeminy
• AV block
• Ventricular tachycardia or fibrillation
• Paroxysmal atrial tachycardia → rare.

Factors that influence digitalis-induced cardiotoxicity are:

1. Hypokalemia:

• Unfortunately, plasma K+ is not an indicator of myocardial K+ status.
• Vomiting, diarrhea, and diuretic therapy may all result in hypokalemia and potentiate digoxin toxicity.

2. Hypercalcemia:

• ↑ Ca⁺⁺ → Intracellular Ca⁺⁺ stores fill up faster → Digitalis induced arrhythmias, cardiotoxicity
• Rapid digitalization and IV cardiac glycosides are → more toxic.
• Patients with poor cardiac status especially elderly → more prone to digoxin toxicity.

Treatment of Toxicity

• Stop digital
• Oral K⁺ supplements were given (except in the presence of hyperkalemia and AV block).
• When parenteral K⁺ is required, it should be given slowly as a drip with constant ECG monitoring.
• Ventricular arrhythmias are treated with IV phenytoin/lignocaine.
• Bradycardia is treated with atropine and supraventricular arrhythmias with propranolol.
• In severe toxicity, a temporary cardiac pacemaker should be inserted.
• Antidigoxin immunotherapy (Digibind obtained from sheep) anti digoxin antibodies bind cardiac glycosides to reverse their effects and are life-saving in severe toxicity.

Precautions And Contraindications To Digitalis Therapy:

• Hypokalemia → ↑ toxicity
• MI, thyrotoxicosis patients—more prone to arrhythmias
• Patients with acid-base imbalance—more prone to toxicity
• Avoid in myocarditis, elderly, AV block and in renal failure.

Digitalis Therapy Uses:

1. Heart failure:

• Digoxin increases the force of contraction and cardiac output.
• All these effects further improve the performance in the failing heart and relieve the symptoms.
• When the patients do not respond to diuretics and vasodilators, digoxin may be given. If there is associated atrial fibrillation, digoxin is the preferred drug.

2. Cardiac arrhythmias:

• Atrial fibrillation: The dose should be adjusted to get the required ventricular rate (70–
  80/min)

 

• Atrial flutter: Atrial rate of 200–350/min is atrial flutter. Digoxin reduces the ventricular rate as in atrial fibrillation.
• Paroxysmal supraventricular tachycardia (PSVT): Re-entry in the SA and AV nodes leads to supraventricular tachyarrhythmia.

Digoxin → ↓ HR, depress AV conduction → relieves PSVT. Digoxin can be used IV to terminate these arrhythmias and in AV nodal tachycardia. However, adenosine, verapamil and diltiazem are the preferred drugs in PSVT.

Antiarrhythmics

Question 10. Classify antiarrhythmics. Discuss the pharmacology of class IA drugs/quinidine.

An arrhythmia is an abnormality of the rate, rhythm, or site of origin of the cardiac impulse or an abnormality in the impulse conduction.

Class 1: Sodium channel blockers

•  Prolong repolarization:
  • Quinidine
  • Procainamide, disopyramide
  • Moricizine
• Shorten repolarization:
  • Lignocaine, mexiletine phenytoin
• Little effect on repolarization:
• Encainide
• Flecainide, propafenone

Class 2:

• β-adrenergic blockers
• Reduce sympathetic tone
  • Propranolol, acebutolol, esmolol, etc.

Class 3:

• K⁺ channel blockers
• Prolong repolarization
  • Amiodarone
  • Dronadarone
  • Vernakalant
  • Bretylium
  • Sotalol
  • Dofetilide
  • Ibutilide

Class 4:

• Ca⁺⁺ channel blockers
• Prolong conduction and refractoriness in SA and AV nodes
  • Verapamil
  • Diltiazem

Class IA Drugs Sodium Channel Blockers:

Mechanism of action: Antiarrhythmics could:

• Suppress the generation of abnormal impulses or
• Alter the re-entry circuits.

Class IA drugs are sodium channel blockers. They preferentially bind Na+ channels in the open and inactivated state block them and preventing the inward movement of Na+ ions.

Blockade of sodium channels results in:

• Depression of phase 0 depolarization
• Prolonged ERP
• Slowing of conduction velocity
• Suppression of abnormal automaticity.
• Class IA drugs decrease the slope of phase 4 depolarization in pacemaker cells particularly when it is from an ectopic focus. They also prolong repolarization by blocking the K+ channels

 Quinidine:

Quinidine is the D-isomer of quinine obtained from the cinchona bark.

 Quinidine Pharmacological actions:

• By blocking Na⁺ channels, quinidine depresses all cardiac properties—automaticity, excitability, and conduction velocity and prolongs repolarization quinidine thus has membrane-stabilizing activity, i.e. it inhibits the propagation of the action potential.
• By reducing automaticity in the Purkinje fibers and ectopic foci, quinidine overcomes extrasystoles.
• Quinidine has vagolytic (atropine-like) and a-blocking properties. It is also a skeletal muscle relaxant.

 Quinidine Pharmacokinetics:

Given orally quinidine is rapidly absorbed, 90% bound to plasma proteins, metabolized in the liver, and excreted in the urine.

Sodium Channel Blockers  Adverse effects: Quinidine is not well–tolerated due to adverse effects:

1. Cardiac: Quinidine itself can cause arrhythmias and heart block (most antiarrhythmics can themselves cause arrhythmias). Quinidine can also cause hypotension, prolongation of QT interval and torsades de pointes. Hence, treatment should be monitored .
2. Noncardiac: Diarrhea, nausea, vomiting, and hypersensitivity reactions including thrombocytopenia and rarely bone marrow depression, hepatitis, and idiosyncratic reactions can occur. Higher doses can cause cinchonism like quinine.

 Choice of drugs in cardiac arrhythmias:

 Quinidine Drug Interactions:

• Quinidine (microsomal enzyme inhibitor) + Propafenone → ↑ propafenone levels
• Quinidine + Phenytoin/phenobarbitone → ↑ quinidine metabolism → therapeutic failure (enzyme inducers)
• Quinidine → ↓ digoxin clearance → toxicity
• Quinidine → Potentiate skeletal muscle relaxants (SMRs)
• Quinidine + b-blocker/K+/verapamil → ↑ myocardial depression → cardiac arrest

1. Procainamide: An amide derivative of the local anesthetic procaine.

Advantages over Quinidine:

• Weak vagolytic properties.
• Not an a-blocker.
• Better tolerated than quinidine.

Procainamide is partly metabolized by acetylation and people can be fast or slow acetylators. Procainamide can cause nausea, vomiting and hypersensitivity reactions including systemic lupus syndrome (more common in slow acetylators). Higher doses can cause hypotension, flushing, heart block, and Torsades de pointes.

2. Disopyramide: Has prominent anticholinergic actions and can also cause myocardial depression.

Uses Of Class IA Drugs:

• Effective in almost all types of arrhythmias to prevent recurrences.
• They are used in atrial fibrillation and atrial flutter and in ventricular arrhythmias to prevent recurrence. Because of the adverse effects, they are not preferred.

Class IB Drugs:

Explain the rationale for use of lignocaine in ventricular arrhythmias. Class IB drugs block the sodium channels in the open and inactivated state and also shorten repolarization. They decrease APD and can be used only in ventricular arrhythmias.

Lignocaine: Lignocaine, the local anesthetic:

• Raises the threshold for action potential and reduces automaticity in the ectopic foci.
• Suppresses the electrical activity of the arrhythmogenic tissues, while the normal tissues are not much affected.
• Decreases the APD in ventricles and in the Purkinje fibers (but not in the atria).
• Suppresses the re-entry in the ventricular muscle by converting the one-way block to a two-way block or by abolishing the one-way block.
• Given orally, lignocaine undergoes high first-pass metabolism and has a short t½—hence used parenterally. It may cause drowsiness, hypotension, blurred vision, confusion, and convulsions.

IB Drugs Uses:

• Ventricular arrhythmias—particularly that caused by acute myocardial infarction or open heart surgery and in digitalis-induced arrhythmias.
• Lignocaine is not useful in atrial arrhythmias because atrial action potentials are so short that the sodium channel is in the inactivated state only for a very short period.
• Hence, lignocaine does not modify the refractory period or action potential duration of the atria.
• Phenytoin: An antiepileptic is also useful in digitalis-induced arrhythmias.
• Mexiletine: A congener of lignocaine that is orally effective and used as an alternative to lignocaine in ventricular arrhythmias.

Class IC Drugs:

• Class IC drugs including flecainide, propafenone, and moricizine are the most potent sodium channel blockers.
• Because of the risk of cardiac arrest, sudden death, and other adverse effects, they are not commonly used.
• They are tried in refractory supraventricular arrhythmias and to maintain sinus rhythm in atrial fibrillation.

Class 2 Drugs:

β-blockers: b-blockers like propranolol exert antiarrhythmic effects due to the blockade of cardiac b-receptors. They:

• Depress myocardial contractility, automaticity, and conduction velocity.
• Depress AV conduction by prolonging the refractory period of the AV node.
• Suppress extrasystoles due to catecholamines.
• In higher doses, they also have membrane-stabilizing activity like class IA drugs.

Class 2 Drugs Uses :

• b-blockers like propranolol, atenolol, and metoprolol are used in the treatment and prevention of supraventricular arrhythmias especially those associated with exercise, emotion
  or hyperthyroidism and adrenergic stimulation (for example, Pheochromocytoma).
• Propranolol is used to suppress sinus tachycardia, atrial and nodal extrasystoles, and digitalis-induced arrhythmias. Propranolol is the drug of choice in patients with congenital long QT syndrome.
• Esmolol (IV): Esmolol is rapid and short-acting and can be used to treat arrhythmias during surgeries, due to anesthesia, following myocardial infarction, and to control the ventricular rate in atrial fibrillation and flutter.
• Sotalol: Though sotalol is a beta blocker, it has prominent actions of class 3 drugs.

Class 3 Drugs:

Potassium channel blockers: Prolong the action potential duration (APD), and refractory period and delay the repolarization by blocking the potassium channels.

Question 11. Write a short note on amiodarone.
Answer:

Amiodarone: Amiodarone an analog of the thyroid hormone is an iodine-containing compound.

It is a powerful antiarrhythmic and acts by multiple mechanisms which are as follows:

Prolongs ERP—prolongs repolarization and refractoriness in all cardiac tissues.

Amiodarone Vasculature:

Relaxes vascular smooth muscles. Peripheral vasodilatation decreases the preload, myocardial workload, and thereby oxygen consumption

 

Amiodarone  Pharmacokinetics: Amiodarone has complex pharmacokinetic properties.

• Oral bioavailability is variable (35–65%), the onset of action is slow → 2–3 days to several weeks, t½ may range from weeks to months.
• Metabolized in the liver by microsomal enzymes and excreted through the gut.

Amiodarone  Drug interactions:

Amiodarone inhibits certain microsomal enzymes → increasing plasma levels of drugs like digoxin and warfarin.

Amiodarone  Adverse Effects:

1. Cardiac effects: Heart block, cardiac failure, QT prolongation, hypotension (particularly IV injections), bradycardia and myocardial depression.

2. Extracardiac effects:

• Thyroid function: Amiodarone can cause hypo as well as hyperthyroidism.

• Nausea, gastrointestinal disturbances and hepatitis.
• Pulmonary fibrosis may be fatal but uncommon.
• Photosensitization, bluish discoloration of the skin, requires a long time for regression after withdrawal of the drug.
• Peripheral neuropathy with weakness of the muscles in the hip.
• Corneal microdeposits (reversible) → visual blurring and halos.

Amiodarone Uses: Amiodarone is useful in many arrhythmias (broad-spectrum antiarrhythmic) but requires constant monitoring.

• Intravenous amiodarone treatment and prophylaxis of recurrent and resistant ventricular fibrillation and ventricular tachycardia.
• To maintain sinus rhythm in paroxysmal atrial fibrillation and in other atrial tachyarrhythmias.
• Postoperative junctional ectopic tachycardia.

Dronedarone:

• Dronedarone an analog of amiodarone, has no iodine atoms in structure → hence no adverse effects on thyroid function.
• Longer-acting—t½ 24 hours; useful in patients with atrial flutter and atrial fibrillation.

Vernakalant:

• Vernakalant is another multi-ion channel blocker → blocks K+ and Na+ channels, prolong the atrial ERP, and slows AV conduction.
• Used in atrial fibrillation (IV) to convert to normal sinus rhythm. Sotalol is a nonselective beta blocker and also a blocker of the potassium channels.
• It prolongs the APD (hence class 3) and ERP in the atria, ventricles, and the Purkinje tissue. By its beta-blocking effects, sotalol depresses the SA and AV nodes.

Amiodarone Adverse effects:

Bradycardia, ventricular fibrillation, torsades de pointes, fatigue, headache, nausea and vomiting.

Uses: Ventricular and supraventricular arrhythmias and for maintaining sinus rhythm in atrial fibrillation and atrial flutter. It is preferred when a beta blocker is needed.

Ibutilide:   an analog of sotalol, is a K+ channel blocker used as an IV infusion to quickly convert atrial flutter and fibrillation to sinus rhythm. It can cause torsades de pointes.

Dofetilide:

• Selective K⁺ channel blocker in the myocardial tissues (pure K⁺ channel blocker).
• Prolongs APD and refractory period.
• Diuretics that cause hypokalemia potentiate the antiarrhythmic effects of dofetilide.
• Has a good bioavailability (~100%).
• Well tolerated—can cause Torsades de pointes due to QT prolongation.
• Used orally in atrial fibrillation to convert and maintain sinus rhythm.

Class 4 Drugs:

Calcium channel blockers: 

• Reduce contractility, automaticity and AV nodal conduction.
• CCBs block the L-type of calcium channels in the myocardium leading to bradycardia and abolish extrasystoles and after depolarizations.
• Verapamil and diltiazem, have prominent cardiac effects because they block the Ca⁺⁺ channels in the cardiac cells in therapeutic doses.

Verapamil is used:

• To terminate paroxysmal supraventricular tachycardia (PSVT). 5 mg is given IV slowly over 2– 3 minutes. It can also be given orally 80–120 mg TDS.
• To control ventricular rate in atrial flutter or fibrillation because it depresses the AV nodal conduction.

Drug interactions:

• Verapamil displaces digoxin from tissue binding sites and also reduces its renal clearance resulting in digoxin toxicity → dose of digoxin should be reduced.
• Diltiazem can be used but the effects are milder.

Other Antiarrhythmics: These drugs are not included in Vaughan William’s classification.

Question 12. Write short note on adenosine.
Answer:

Adenosine  is a purine nucleotide having rapid and short antiarrhythmic action. It is an endogenous substance formed in the metabolism of adenosine triphosphate.

Adenosine:

• Suppresses automaticity and AV conduction.
• Dilates the coronaries.
• Shortens the APD and may cause an AV block within 10–20 seconds of an IV dose.

Adenosine  Mechanism of Action:

• Is not exactly known. Adenosine could act as a potassium channel opener by binding to specific adenosine receptors which are present on the atria, SA and AV nodes.
• These are G-protein-coupled receptors and activation of them opens the outward potassium currents leading to hyperpolarization.
• The action of adenosine is specific for the atria and has no effect on the ventricles because there are no adenosine-stimulated potassium channels in the ventricles.
• Adenosine has a very short t½ of about 10 seconds and is given as a bolus injection. The duration of action is just 10–20 seconds. Dose: 6–20 mg. Theophylline blocks adenosine receptors and inhibits the action of adenosine.

Adenosine Adverse effects:

Bronchospasm and dyspnea can be quite profound in asthmatic patients and may take about 30 minutes to subside.

Adenosine Uses:

• Drug of choice for acute termination of PSVT including AV nodal re-entrant tachycardia.
• The action of adenosine is so specific to the atria that it can be used for the diagnosis of atrial flutter/arrhythmias.
• Its brief duration of action is an added advantage for this purpose.

Adenosine Ivabradine:

Selectively blocks the If current in the SA node thereby reducing heart rate without depressing myocardial contractility—direct bradycardiac agent.

Antianginal Drugs

Question 13. Classify the drugs used in angina pectoris. Describe briefly the mechanism of action, adverse effects, and uses of nitrates.
Answer:

Drugs are used to improve the balance between oxygen supply and demand either by increasing oxygen supply to the myocardium (coronary dilation) or by reducing the oxygen demand.

Angina pectoris Classification:

Nitrates:

Nitroglycerin was introduced for the treatment of angina in 1879.

Mind Map Antiarrhythmics:

 

Angina pectoris  Mechanism of action: Nitrates are vasodilators. They are converted to nitric oxide (NO) by the enzymes mitochondrial glutathione-S-transferase and aldehyde reductase. NO activates vascular guanylyl cyclase which in turn increases the synthesis of cGMP.

• This cGMP brings about dephosphorylation of protein kinases (prevents interaction of actin with myosin).
• It also reduces free cytosolic calcium by preventing calcium release from the sarcoplasmic reticulum or by increasing Ca⁺⁺ efflux.
• These effects result in relaxation of smooth muscles including vascular smooth muscles. Thus it causes vasodilation and also relaxation of other smooth muscles

Angina pectoris  Pharmacological Actions:

1. CVS:

• Reduction in preload: Nitrates are venodilators → cause is pooling of blood in the veins leading to less venous return. When the blood reaching the heart is reduced, the preload and thereby the myocardial workload are reduced. Thus nitrates reduce the oxygen requirement.
• Reduction in afterload: Nitrates also cause some arteriolar dilatation → reduce the peripheral vascular resistance leading to a reduction in afterload.
• Coronary vasodilation: Mild coronary vasodilation → ↑ ↑ coronary blood flow in a normal person but in presence of atherosclerotic coronary artery disease, → not much increase.
• In angina: The beneficial effects of nitrates are
  • In stable angina—due to their vasodilator properties—causing decrease in the myocardial workload resulting in a decrease in the myocardial oxygen demand.
  • In variant angina—relief from coronary vasospasm due to the coronary vasodilation.

2. Other vasculature: Dilatation of blood vessels in the skin—resulting in flushing; dilatation of the meningeal vessels leading to throbbing headache.

Other smooth muscles: Nitrates relax the—

• Bronchial
• GI smooth muscles including biliary ducts and sphincter of Oddi
• Genitourinary smooth muscles including the uterus
• Chest pain due to esophageal spasm is relieved by esophageal smooth muscle relaxation.

3. Platelets: Nitric oxide from nitrates inhibits platelet aggregation by activating platelet guanylyl cyclase.

Angina pectoris  Pharmacokinetics:

Nitrates have good lipid solubility and are well absorbed orally but they undergo extensive first pass metabolism (Table 4).

Some nitrates used in angina pectoris:

Angina pectoris Adverse Effects:

• Headache is common
• Flushing, sweating, palpitation, weakness, postural hypotension, and rashes can occur.

Question 14. Write a short note on tolerance to nitrates.
Answer:

• Tolerance develops on repeated long-term use particularly when continuous high plasma nitrate levels are present.
• Activation of compensatory responses like tachycardia, salt and water retention, may contribute to the development of tolerance. By adopting a proper dosing schedule, tolerance can be avoided.
• The patient must be free of nitrates for at least 8 hours of the day to prevent the development of tolerance.
• Tolerance can also be minimized by a twice/thrice daily dosing schedule instead of sustained-release preparations.

Monday morning disease:

• Nitrates are used in factories where explosives are manufactured.
• Workers joining duty in such factories initially experience headaches, flushing, and palpitations but soon develop tolerance.
• When they are away at weekends and join back on Monday morning, the symptoms recur, called ‘Monday morning disease/sickness’.

Withdrawal:

• Nitrates should not be abruptly or suddenly withdrawn after long-term use because they can precipitate acute angina and spasm of the vascular and other smooth muscles.
• Thus nitrates are said to cause a sort of dependence.

Tolerance to nitrates Drug Interactions:

Nitrates and Sildenafil:

• Cyclic GMP is metabolized by phosphodiesterase. Sildenafil (viagra), a drug used in erectile dysfunction, is a PDE inhibitor.
• It thus increases cGMP activity resulting in relaxation of the cavernosal as well as vascular smooth muscles.
• Vasodilation also results in hypotension. Sildenafil potentiates the action of nitrates and together they cause severe hypotension with reflex tachycardia resulting in MI and sudden death.

Uses Tolerance to nitrates:

1. Exertional angina:

Acute attack:

• Sublingual nitroglycerin is the drug of choice and relieves pain in 2–5 minutes. If the pain is not relieved, dose may be repeated—up to 3 tablets in 15 minutes.
• Isosorbide dinitrate is slower acting than sublingual NTG.
• The patient should be advised to take the tablet in a sitting position because the sudden reduction in BP can result in failure to syncope.

Prophylaxis:

• Acute prophylaxis—when the patient is expected to have a known exertion like walking uphill, a tablet of sublingual NTG can be used for the prevention of angina.
• Longer-acting nitrates are used orally for long-term prophylaxis but patients can develop tolerance to nitrates.
• Nitroglycerin ointment is applied over the chest and transdermal patch for 24 hours.

2. Vasospastic angina: Nitroglycerin relieves pain by relieving coronary vasospasm.

3. Unstable angina: Both reduction in cardiac workload and coronary vasodilation may be of value in such patients. NTG is started (IV) with 5–10 mcg/min and gradually titrated up to 20 mcg/min depending on the requirement.

4. Cardiac failure:

• Nitrates are useful due to their vasodilator property
• Nitroglycerin given SL or IV helps patients with acute LVF by reducing the preload which in turn reduces the cardiac workload. Constant monitoring is required.

5. Myocardial infarction:

• IV nitroglycerin is used by many physicians to reduce cardiac workload.
• The dose should be carefully adjusted to avoid tachycardia and hypotension.

6. Cyanide poisoning:

• Cyanide rapidly binds to cytochrome oxidase and other vital enzymes resulting in inhibition of cellular respiration and blocking the utilization of oxygen.
• It requires immediate treatment.
• Amylnitrite is given by inhalation and sodium nitrite by IV injection (10 mL of 3% solution).
• Sodium thiosulfate is given IV (50 mL of 25% solution). It thus protects the important enzymes from binding to cyanide. Early treatment is very important.

7. Esophageal spasm: Sublingual NTG is taken just before meals to relieve the spasm.

8. Sublingual nitroglycerin is also useful as a spasmolytic to relieve biliary colic.

Calcium Channel Blockers

• Calcium channel blockers (see Page 109) relax the arterioles leading to a decrease in the peripheral vascular resistance and a reduction in the afterload.
• Some reflex tachycardia can occur particularly with dihydropyridines.
• Verapamil and diltiazem also depress the myocardial contractility thereby reducing the heart rate and force of contraction.
• This results in reduced cardiac workload and oxygen consumption. CCBs also dilate the coronaries thereby increasing the coronary blood flow. CCBs are used for the prophylaxis of exertional angina.
• They can be combined (except verapamil) with beta-blockers like propranolol. CCBs are preferred over nitrates in vasospastic angina since they dilate the coronaries and relieve vasospasm.

Β-Blockers

• b-blockers reduce the frequency and severity of attacks of exertional angina and are used in the prevention of angina.
• Exercise, emotion and similar situations increase sympathetic activity leading to increased heart rate, force of contraction, and BP, thereby increasing O2 consumption by the heart.
• b-blockers prevent angina by blocking all these actions and thereby prevent an increase in the myocardial workload and oxygen demand.
• b-blockers improve exercise tolerance.
• They are used for the long-term prophylaxis of classical angina and may be combined with nitrates.
• b-blockers are also useful in unstable angina when judiciously used. b-blockers should always be tapered after prolonged use. b-blockers are not useful in variant angina.

Potassium Channel Openers

Question 15. Write a short note on nicorandil/K+ channel openers/drugs acting on K+ channels.
Answer:

Like the calcium channels, there are several types of potassium channels, viz:

• Voltage-dependent
• ATP sensitive
• Receptor operated
• Ca⁺⁺ and Na⁺ activated potassium channels.

Nicorandil, pinacidil, and cromakalim are potassium channel openers. Minoxidil and diazoxide also open up K⁺ channels and are used in hypertension.

Sulfonylureas block the K⁺ channels in the pancreatic b-cells thereby increasing insulin release. Amiodarone blocks K+ channels in the heart and prolongs APD— used in arrhythmias.

Nicorandil:

• Nicorandil is an arterial and venous dilator.
• Opening of the ATP-sensitive K⁺ channels results in the efflux of K⁺ leading to hyperpolarization and therefore relaxation of the vascular smooth muscles.
• In addition, like nitrates it also acts through nitric oxide and reduces the preload and afterload. It also causes coronary vasodilation.

Nicorandil also relaxes other smooth muscles like the bronchi and uterus for which it may have therapeutic applications.

• Nicorandil Uses: In angina as an alternative to nitrates.
• Nicorandil Adverse effects: Headache, flushing, palpitation, dizziness, and hypotension.
• Nicorandil Pinacidil:  Pinacidil is similar to nicorandil → useful in hypertension.

Miscellaneous Drugs

Cytoprotective Drugs:

Question 16. Trimetazidine/Ranolazine is used in angina pectoris. Give reason.
Answer:

1. Trimetazidine:

• It is claimed to have a protective effect on the ischemic myocardium and to maintain left ventricular function.
• It is a pFOX inhibitor (Partial inhibitor of fatty acid oxidation), i.e. trimetazidine inhibits the enzyme involved in the fatty acid oxidation pathway in the myocardium.
• It also inhibits the superoxide induced cytotoxicity of the myocardial cells.
• It thus modulates the metabolism in the myocardium and protects the myocardium from ischemic damage.
• It is also a calcium channel blocker. It is orally effective and well-tolerated with occasional gastric irritation, fatigue, and muscle cramps.

Cytoprotective Drugs Uses: As an add-on drug along with other antianginal drugs.

Dose: 20 mg TDS or 35 mg sustained release BD with food.

Ranolazine:

• Ranolazine is a recently introduced trimetazidine congener with cardio-protective properties.
• It inhibits the late sodium current (INa) in the myocardium which indirectly facilitates Ca⁺⁺ entry, and also prevents calcium overload in the myocardium during ischemia. It thus reduces myocardial oxygen demand.
• Ranolazine is approved as add-on therapy in patients who do not respond to first-line drugs.
• It prolongs QT interval and therefore, should be avoided with other drugs that prolong QT interval.
• It can also cause weakness, postural hypotension, dizziness, headache, and constipation.

Dose: 500 mg sustained release tablets BD.

2. Antiplatelet Drugs:

• Dipyridamole: Dipyridamole is a coronary vasodilator but it diverts the blood from the ischaemic zone—‘coronary steal syndrome’ and is, therefore, not beneficial. It inhibits platelet aggregation for which it is used in post-MI and poststroke patients for prevention of coronary and cerebral thrombosis.
• Aspirin: Long-term administration of low-dose aspirin is recommended to prevent myocardial infarction. Aspirin inhibits platelet aggregation and thereby prevents MI in patients with angina.
• Clopidogrel: Clopidogrel is an ADP antagonist (see Page 260) which blocks the ADP receptors on platelets and prevent their activation. The antiplatelet effects are additive with aspirin and is used with aspirin in acute coronary syndrome.
• Others: Ivabradine.

Combination of Drugs in Angina:

1. Nitrates + b-blockers: Very effective in exertional angina.

• Reflex tachycardia due to nitrates → countered by b-blockers.
• Ventricular dilatation due to b-blockers → opposed by nitrates.

2. Nifedipine + b-blockers: Antianginal effects are additive. Reflex tachycardia due to nifedipine is countered by b-blockers.

3. Nitrates + CCBs: Nitrates decrease preload, CCBs reduce afterload and the combination reduces cardiac workload.

4. CCBs + b-blockers + nitrates: In severe angina, 3 drugs can be used.

Vasospastic angina:

Nitroglycerine and sublingual nifedipine are effective in relieving pain.

Unstable angina:

Patients with unstable angina are at a high risk of developing MI or sudden death. They need hospitalization and rigorous treatment with aspirin, or other antiplatelet drugs, heparin, nitrates, and drugs to reduce myocardial workload are used.

Drugs Used In Myocardial Infarction

Immediate Treatment:

1. Analgesics and antianxiety drugs:

• Pain due to myocardial ischemia produces anxiety which results in sympathetic overactivity.
• This could be dangerous to the heart. An analgesic like morphine 10 mg is given intravenously through an IV cannula.
• It relieves pain and thereby reduces anxiety.
• The problems of sympathetic overactivity are reduced. Diazepam may also be given to reduce anxiety and produce sedation.

2. Thrombolytics:

• Can limit the extent of damage and reduce mortality, if started at the onset of symptoms (within 6–12 hours). Streptokinase (1.5 million units infusion). Urokinase or alteplase may be given.
• Anistreplase is convenient to use because it is long-acting and therefore, can be used as a single IV injection. Alteplase is expensive.
• Thrombolytics should be started at the earliest possible (within 6–12 hours) because they can limit the extent of damage and reduce mortality.

3. Antiplatelet drugs: 300 mg of soluble aspirin should be given orally immediately at the onset of symptoms. It reduces mortality and improves the effect of thrombolysis. Aspirin should be continued for long term (75–150 mg/day). Patients allergic to aspirin may be given oral clopidogrel.

4. Anticoagulants: Heparin may be given to prevent the extension of the thrombus and also to prevent deep vein thrombosis.

5. Oxygen: High-flow oxygen should be given by inhalation.

6. Vasodilators: Nitroglycerine or sodium nitroprusside IV infusion to reduce the cardiac workload and decrease mortality. Care should be taken to avoid reflex tachycardia.

7. Other drugs:

• b-blockers: IV atenolol 5–10 mg or metoprolol 5 mg should be given at the earliest possible unless contraindicated in asthma, heart block, or heart failure. b-blockers limit the infarct size, reduce the incidence of arrhythmias and decrease mortality. Later oral bblockers should be continued.
• ACE inhibitors: Started within 24 hours and continued for long periods provide long-term survival benefits. They prevent ventricular remodeling and reduce the progression of heart failure.
• Inotropic drugs: Dobutamine or dopamine may be given to support cardiac function.
• Antiemetics: An antiemetic may be given intravenously if required (pheniramine 25 mg)
• Antiarrhythmics: Arrhythmias are common in acute MI; suitable antiarrhythmics should be used depending on the arrhythmia.

Long-Term Treatment:

Once the patient is stabilized, certain drugs are needed for the prevention of further ischemic events.

• A stool softener may be given to avoid straining at stools.
• Low-dose aspirin, a B-blocker, and an ACE inhibitor are useful in reducing long-term mortality.

Risk Factor Management:

• Smoking should be stopped.
• Hyperlipidemia, if any, should be controlled.
• Body weight should be reduced.
• Regular moderate exercises should be advised.
• Adequate control of diabetes and hypertension, if any.

Other Drugs:

Pentoxifylline:

• Pentoxiphylline is a phosphodiesterase inhibitor.
• It reduces the viscosity of the blood and enhances blood flow to the ischemic areas.
• It is also claimed to improve the flexibility of the
• RBCs (called hemorheological action) result in an improvement of microcirculation and does not produce coronary steal syndrome. It potentiates the action of anticoagulants.

Uses:

• Pentoxiphylline is used in transient ischemic attacks, non-hemorrhagic stroke, chronic cerebrovascular insufficiency, trophic leg ulcers, gangrene, and intermittent claudication (which= could be due to diabetes, atherosclerosis or inflammatory vascular disease).
• Pentoxiphylline is also used in AIDS patients with increased TNF (because pentoxiphylline inhibits the production of TNF-a) and to improve sperm motility.

Antihypertensive Drugs

Hypertension is an increase of systolic and/or diastolic BP above 140/90 mm of Hg. Blood pressure is determined by cardiac output (CO) and total peripheral vascular resistance.

Antihypertensives may be classified as follows:

Antihypertensive Drugs Classification: 

1. Diuretics:

• Thiazides: Hydrochlorothiazide, chlorthalidone, indapamide
• Loop diuretics: Frusemide, bumetanide, torsemide
• K⁺ sparing diuretics: Spironolactone, amiloride, triamterene

2. Drugs acting on renin-angiotensin-aldosterone system:

• Angiotensin-converting enzyme inhibitors: Captopril, enalapril, lisinopril, ramipril, perindopril, fosinopril, trandolapril, quinapril, benazepril
• Angiotensin 2 receptor blockers: Losartan, candesartan, valsartan, eprosartan, irbesartan, olmesartan
• Direct renin inhibitor: Aliskiren

3. Sympatholytics:

• Centrally acting drugs: Clonidine, methyldopa, guanabenz, guanfacine
• Ganglion blockers: Trimethaphan
• Adrenergic neuron blockers: Guanethidine, reserpine
• Adrenergic receptor blockers:
  • a-blockers—prazosin, terazosin, doxazosin, phenoxybenzamine, phentolamine
  • b-blockers propranolol, atenolol, esmolol, metoprolol
  • Mixed α and β blockers: Labetalol, carvedilol
• Ca⁺⁺ channel blockers: Nifedipine, nicardipine, nimodipine, amlodipine, verapamil
• Vasodilators:
  • Arteriolar dilators: Hydralazine, minoxidil, diazoxide
  • Arteriolar and venular dilators: Sodium nitroprusside

Diuretics

Question 17. Explain the rationale for use of the following in hypertension:

1. Diuretics
2. Enalapril
3. ARBs/losartan
4. Clonidine
5. Methyldopa
6. Propranolol/atenolol
7. Verapamil/CCBs
8. Vasodilators
9. Sodium nitroprusside

Answer:

• Antihypertensive effects of diuretics are mild—BP falls by 15–20 mm Hg over 2–4 weeks.
• Diuretics act as antihypertensives as follows: Diuretics increase the excretion of sodium and water resulting in reduced plasma volume → ↓ CO→ ↓ BP.
• Though initially, the fall in BP is due to reduced plasma volume and cardiac output, after about 6–8 weeks, CO returns to normal due to compensatory mechanisms. It is then that the
• PVR declines. Reduction in body sodium stores results in low intracellular sodium levels. Such low sodium in vascular smooth muscle cells leads to the relaxation of vasculature and decreased peripheral vascular resistance.
• Restriction of dietary salt intake will reduce the dose of the diuretic needed. On long-term treatment with diuretics, PVR is reduced but CO and heart rate are not altered.
• Dose: 12.5–25 mg/day hydrochlorothiazide/chlorthalidone.

Status in hypertension:

• Thiazides are the first-line antihypertensives.
• Are inexpensive.
• Are suitable for combination with other antihypertensives particularly those causing salt and water retention as a side effect and the antihypertensive action is synergistic.
• Thiazide + K+ sparing diuretic (spironolactone/amiloride/triamterene)
  • Additive diuretic effect
  • Avoids hypokalemia due to thiazides
  • Amiloride : Thiazide → 1 : 10 ratio → 12.5 mg : 125 mg.
• Indapamide related to thiazides is often preferred in hypertension because it:
  • Lowers BP in sub diuretic doses.
  • May have additional vasodilator properties.
  • Can be administered once daily—long-acting.
  • Causes milder electrolyte disturbances.

Loop Diuretics:

• Although loop diuretics, like frusemide, are powerful diuretics, their antihypertensive action is weaker than thiazides.
• Frusemide is short-acting and the loss of salt and water are compensated quickly by an increased reabsorption of Na+ and water. Hence uniform reduction in vascular resistance cannot be achieved.
• Side effects like electrolyte disturbances are more severe with loop diuretics.

Loop Diuretics Uses:

Only in hypertension with chronic renal failure or congestive heart failure and in hypertensive crisis to rapidly lower the BP.

Drugs Acting On Renin-Angiotensin-Aldosterone System

Drugs act at different levels in the renin-angiotensin-aldosterone system (RAAS) to reduce BP

Angiotensin-Converting Enzyme (Ace) Inhibitors:

• Angiotensin 2 is a powerful vasoconstrictor. Aldosterone also raises the BP by increasing the plasma volume.
• ACE inhibitors prevent the formation of angiotensin 2 and (indirectly) aldosterone. There is vasodilation and a decrease in PVR resulting in a fall in BP.
• ACE also degrades bradykinin and ACE inhibitors raise the bradykinin levels which is a potent vasodilator.
• This also contributes to the fall in BP.

Status in Hypertension:

• ACE inhibitors are first-line antihypertensives.
• Useful in the treatment of hypertension of all grades due to all causes.
• The addition of a diuretic potentiates their antihypertensive efficacy.
• They are generally combined with thiazides without a K ⁺ sparing diuretic because there can be significant hyperkalemia when an ACE-I is combined with a K+ sparing diuretic.
• ACE inhibitors are well tolerated.
• Specially indicated as antihypertensives in:
  • Hypertension with left ventricular hypertrophy (LVH) because hypertrophy is gradually reversed by ACE inhibitors.
  • Diabetes mellitus because ACE-I slow the development of nephropathy.
  • Renal diseases with hypertension—ACE inhibitors slow the progression.
  • Patients with coexisting IHD including post-MI patients.
  • In severe hypertension, with other antihypertensives like b-blockers, CCBs or diuretics.

Angiotensin 2 Receptor Blockers (Arbs)

Losartan, candesartan, irbesartan, valsartan and telmisartan ARBs have high affinity for AT₁ receptors and by blocking AT₁ receptors, ARBs block the effects of angiotensin II. They thus relax vascular smooth muscles, promote salt and water excretion and reduce the plasma volume.

Advantage of ARBs over ACE inhibitors:

• No increase in bradykinin levels and its associated adverse effects like dry cough and angioedema.
• Blood flow to the kidneys, brain and heart increases due to selective vasodilation and thus maintains blood supply to these vital organs.

Arbs Adverse effects: ARBs are well-tolerated.

1. Hypotension and hyperkalemia like ACE inhibitors.
2. Angioedema—rare.
3. Contraindicated in pregnancy → teratogenic potential.

Status in hypertension:

As alternatives to ACE inhibitors → first-line drugs in hypertension. ARBs can be usefully combined with diuretics.

Direct Renin Inhibitor

• Aliskiren is a direct renin inhibitor or renin antagonist that blocks the effects of renin, thereby reducing blood pressure.
• The use of drugs like ACE inhibitors, ARBs and diuretics, tends to bring about a compensatory rise in plasma renin levels.
• Because aliskiren blocks the effects of renin, its action is synergistic with these drugs. It can also be used as monotherapy and is orally effective.
• Aliskiren is contraindicated in pregnancy. Adverse effects include hyperkalemia, angioedema, hypotension, dizziness, and rashes.
• Dose: 150–300 mg OD.

Sympatholytics

Sympatholytic drugs may be used to interfere with sympathetic activity at different levels including centrally, at the ganglia, neurons and receptors.

Drugs Acting Centrally:

Clonidine:

• Clonidine an imidazoline derivative, is a selective a2-agonist.
• Stimulation of a₂ autoreceptors in the CNS (in the vasomotor center and hypothalamus) decreases central sympathetic outflow and blocks the release of noradrenaline from the nerve terminals leading to a fall in BP and bradycardia.
• There is a reduction in heart rate, cardiac output, and a decrease in PVR but an increase in renal blood flow.

Dose: 100–300 micrograms BD. A transdermal patch is effective for 7 days applied over the arm once a week. Adverse effects are milder with the transdermal preparation.

Clonidine Adverse Effects

• Drowsiness
• Dryness of mouth, nose, and eyes
• parotid gland swelling and pain constipation
• Impotence
• Sudden withdrawal of clonidine will lead to rebound hypertension , Headache, tremors, sweating, and tachycardia.
• Hence dose should be tapered

Clonidine Uses:

1. Hypertension:  Clonidine is used in mild to moderate hypertension.
2. Other uses:
3. In opioid withdrawal: Most withdrawal symptoms in opioid addicts are of sympathetic overactivity and can be reduced by treatment with clonidine.
4. Diabetic neuropathy: Clonidine controls diarrhea by improving the absorption of NaCl and water in the gut by stimulation of  a₂ receptors in the intestines.
5. With anesthetics: Clonidine reduces the dose of the general anesthetic needed due to its analgesic effects.

Clonidine  Alpha methyldopa:

• Alpha methyldopa, an analog of dopa, is a prodrug. Metabolized to a methyl norepinephrine,m which is an a₂-agonist and acts like clonidine.
• It reduces central sympathetic outflow leading to a fall in BP.
• Renin levels also fall but renal blood flow is well maintained. Left ventricular hypertrophy is reversed in about 12 weeks.

Clonidine  Adverse effects:

• Sedation, dryness of mouth and nose, nightmares, depression, vertigo, extrapyramidal signs, raised prolactin levels, headache, postural hypotension, and impotence.
• On prolonged use, salt-and water retention may reduce the antihypertensive effect (called pseudo tolerance) and needs a diuretic to be added 250–750 mg BD.

Clonidine  Uses:

Mild to moderate hypertension along with a diuretic. It is preferred in hypertension during pregnancy as it is safe in them.

Adrenergic Receptor Blockers

α-blockers:

• Nonselective a-blockers like phenoxybenzamine and phentolamine are used in the treatment of hypertension due to pheochromocytoma.
• Selective a₁-blockers like prazosin, terazosin and doxazosin block the a1-receptors in arterioles and venules and thereby dilate both arterioles and venules.
• Peripheral vascular resistance is decreased leading to a fall in BP with only mild tachycardia.
• α₁-blockers are used in mild to moderate hypertension – particularly suitable in hypertensive men who also have BPH because they help both.

β-blockers:

• b-blockers are mild antihypertensives. Blockade of cardiac b1 receptors results in decreased myocardial contractility and cardiac output. Thus they reduce the BP due to a fall in the cardiac output.
• They also lower plasma renin activity and have an additional central antihypertensive action. b-blockers are well-tolerated and are of special value in patients who also have arrhythmias or angina.
• They may be used alone but are also suitable for combination with other antihypertensives, particularly with drugs that cause tachycardia as their side effect (for example,Vasodilators).
• They are thus the first-line antihypertensive drugs in mild to moderate hypertension. b-blockers should always be tapered while withdrawing.
• Atenolol or Metoprolol are used. Esmolol is a short-acting b1-blocker (t½ 10 min) used in hypertensive emergencies.

α- and β-blockers:

Labetalol and carvedilol block a1- and b-receptors → used IV for hypertension in pheochromocytoma and in hypertensive emergencies.

Calcium Channel Blockers

• CCBs are another important group of antihypertensives. They dilate the arterioles resulting in reduced peripheral vascular resistance.
• Nifedipine and other dihydropyridines (DHPs) produce some reflex tachycardia but this is not seen with verapamil and diltiazem as they are cardiac depressants.
• Fluid retention is negligible, unlike other arteriolar dilators. CCBs should be avoided in patients with left ventricular hypertrophy and previous myocardial infarction.
• Short-acting (DHPs) produce frequent changes in BP and sympathetic activity → should be avoided in hypertension.

Use In Hypertension:

• CCBs are well-tolerated and effective.
• Particularly effective in elderly patients.
• May be used as monotherapy or along with other antihypertensives.
• In HT emergencies, short-acting DHPs can be used parenterally because sublingual
  nifedipine may not achieve quick therapeutic plasma levels.
• Short-acting CCBs may be associated with increased mortality and risk of sudden death.
• Hence sustained release or long-acting dihydropyridine CCBs may be used for smoother control of BP.
• IV clevidipine can be used when parenteral CCB is needed for quick reduction of BP.

Vasodilators:

Question. Explain why (i) hydralazine is used in hypertension, (ii) vasodilators are used in hypertension.
Answer:

Vasodilators used in hypertension are:

1. Arteriolar dilators: Hydralazine, minoxidil, diazoxide.
2. Arteriolar and venular dilator: Sodium nitroprusside.

Vasodilators relax the vascular smooth muscles thus reducing BP due to decreased peripheral vascular resistance. Salt and water retention and reflex tachycardia are common with vasodilators.

1. Hydralazine:

Hydralazine is a directly acting arteriolar dilator. The fall in BP is associated with tachycardia,
renin release and fluid retention. Coronary, cerebral, and renal blood flow are increased.

• Hydralazine is well absorbed but first-pass metabolism is extensive (25% bioavailability).
• Metabolized by acetylation in the liver (like INH) and the rate of acetylation is genetically determined—people may be fast or slow acetylators.
• Fast acetylators have lower bioavailability and therefore, poorer antihypertensive effects. Dose: 25–50 mg OD-TDS.

Hydralazine Adverse effects:

• Headache, dizziness, flushing, palpitation, nausea, anorexia, hypotension, and salt and water retention.
• It may precipitate angina and arrhythmias in some patients because of increased O₂ demand due to reflex tachycardia and decreased myocardial blood supply due to peripheral vasodilatation.
• Hydralazine can cause hypersensitivity reactions with drug fever, peripheral neuropathy, and serum sickness.
• A syndrome resembling lupus erythematosus (arthralgia, fever, myalgia, pleuritis, pericarditis) may occur with high doses of hydralazine and is more common in slow acetylators.
• It is reversible on withdrawal of hydralazine.

Hydralazine  Uses: In moderate hypertension hydralazine is used in combination:

1. Hydralazine + b-blocker/diuretic
2. Hydralazine + a nitrate → HT with cardiac failure
3. Hypertension in pregnancy (2nd and 3rd trimesters).

Minoxidil:

Question 19. Write a short note on minoxidil. Role of minoxidil in baldness.
Answer:

Minoxidil is a directly acting arteriolar dilator.

• Minoxidil is a prodrug converted to minoxidil sulfate which opens up the potassium channels in the smooth muscles.
• Opening of the K⁺ channels causes efflux of K⁺ resulting in hyperpolarization and smooth muscle relaxation.
• Minoxidil can cause sodium and water retention leading to edema, it can also cause palpitations, anginal episodes, headache and,sweating→ combined with a diuretic and b-blocker.
• Hypertrichosis or increased hair growth on the face, arms, legs, and back make it unacceptable in women.

Minoxidil Uses:

1. Hypertension: Minoxidil + a diuretic → as a reserve drug—in severe hypertension—started with 5 mg daily and gradually increased to 40–50 mg.
2. Baldness: Minoxidil directly stimulates the growth of hair on prolonged use. Minoxidil → Activates relevant gene → Stimulates maturation and growth of hair shaft cells

It is used topically (2% solution) in alopecia—young men with relative alopecia are more likely to respond. Continued use of minoxidil is needed in patients who respond because stopping treatment may result in hair fall. Topical minoxidil can rarely cause dermatitis.

Diazoxide: 

• Diazoxide Is an arteriolar dilator like minoxidil but also causes an increase in blood glucose levels like thiazides (related to thiazide diuretics).
• It is used IV in hypertensive emergencies when monitoring infusion is not possible, because diazoxide is long-acting (24 hours).

Sodium Nitroprusside

Question 20. Short note: Sodium nitroprusside. Describe briefly the rationale for the use of sodium nitroprusside in hypertension.
Answer:

• Sodium nitroprusside is a rapidly acting vasodilator and it relaxes both arterioles and venules.
• Both peripheral resistance and cardiac output are reduced resulting in lower myocardial oxygen consumption.
• Mechanism of action—Nitroprusside acts through the release of nitric oxide which activates guanylyl cyclase, resulting in the formation of cGMP which relaxes the vascular smooth muscles.
• On IV administration, it is rapid and short-acting (3 minutes) allowing rapid titration of the dose. Suitable for hypertensive emergencies with close monitoring and in severe heart failure.
• Sodium nitroprusside is taken up into the RBCs and cyanide is released. The cyanide is metabolized by the mitochondrial enzyme and a sulfur group is added to get thiocyanate which is gradually excreted by the kidneys.

The following are to be noted in using sodium nitroprusside:

• Acts quickly (<30 seconds) → BP should be monitored constantly.
• Sodium nitroprusside is light-sensitive. The infusion bottle and the tubing must be protected
  from light by an opaque wrapping. Fresh solutions should be made before each use.
• If the color changes, the infusion should be discarded.
• If an infusion is prolonged, blood levels of cyanide and thiocyanate levels should be checked.
• Used for emergency control of BP and in severe heart failure—not more than 2–3 days.

Nitroprusside Adverse reactions:

Palpitations, sweating, weakness, nausea, vomiting, and hypotension.

In higher doses—nitroprusside gets converted to cyanide and thiocyanate. Accumulation of thiocyanate can result in symptoms of toxicity like nausea, anorexia, weakness, disorientation, psychosis, muscle spasm, and convulsions.

High doses → severe hypotension, metabolic acidosis, arrhythmias, and death.

• Sodium thiocyanate + nitroprusside → prevent cyanide accumulation
• Hydroxocobalamin + cyanide → nontoxic cyanocobalamin

Methemoglobinemia is also known following infusion of nitroprusside:

Nitroprusside  Uses:

• Drug of choice in hypertensive emergencies—started with 0.5 mg/kg/min infusion and may be gradually increased up to 10 mg/kg/min.
• The BP should be constantly monitored.
• In situations where short-term reduction of myocardial workload is required as in severe heart failure and myocardial infarction.

Hypertension In Pregnancy:

• Methyldopa orally for maintenance and hydralazine parenterally for reduction of BP in
• emergencies used only after the first trimester.
• Dihydropyridine CCBs like nifedipine may be used but should be withdrawn during labor as they may inhibit uterine contractions.
• Other drugs like prazosin and clonidine can also be used.
• Cardioselective β-blockers like atenolol and acebutolol may be used in pregnancy but nonselective b-blockers should be avoided as they may reduce blood supply to the placenta leading to reduced size of the placenta and low birth weight.

Drug interactions of Antihypertensives:

• Sympathomimetics, tricyclic antidepressants → ↓ effects of sympatholytics.
• NSAIDs salt and water retention → ↓ Effect of antihypertensives Cause

Plasma Expanders

Question 21. Write short notes on plasma expanders.
Answer:

When there is sudden loss of blood or plasma as seen in conditions like extensive bleeding, the reduction in blood volume results in underperfusion of tissues and can be rapidly fatal. To restore the intravascular volume, the component that is lost should ideally be replaced like plasma in burns and blood after hemorrhage. Plasma expanders are used for immediate volume replacement.

Dextrans:

• Dextrans are polysaccharides obtained from sugar beet.
• Their osmotic pressure is similar to that of plasma proteins. Dextran 70 (mol wt 70,000)expands the plasma volume for almost 24 hours.
• It interferes with coagulation, blood grouping, and cross-matching. It is slowly excreted by glomerular filtration and partly metabolized over weeks by oxidation.
• Dextran (mol wt 40,000) is faster but has shorter acting. It can improve microcirculation in shock by preventing rouleaux formation of RBCs and have an anti sludging effect. It can clog renal tubules resulting in renal failure—though rare should be watched for.
• Allergic reactions are common.
• Dextrans have a long shelf-life (10 years) and can be easily sterilized.
• Commonly used plasma expanders—dextran 70–500 mL in normal saline or 5% dextrose.

Gelatin products:

• Gelatin polymers can remain stable for almost 3 years at a pH of 7.2–7.3.
• They do not interfere with coagulation, blood grouping and cross-matching. They are not antigenic and can rarely cause allergic reactions and bronchospasm.
• Degraded gelatin polymer has a long shelf-life and is excreted gradually by the kidneys. It is used for priming the heart-lung and dialysis machines.

Hydroxyethyl starch (Hetastarch):

• Maintains blood volume for a long period. It is derived from starch and is used as 6% solution for infusion, it expands blood volume and stabilizes it for almost 24 hours. It does not interfere with coagulation and blood grouping.
• Flu-like symptoms— fever, chills, vomiting, and anaphylactoid reactions can occur.
• Used in shock to expand the plasma volume, in burns, and in other conditions associated with extensive fluid loss.

Polyvinylpyrrolidone (PVP):

• Polyvinylpyrrolidone is a synthetic, water-soluble polymer used as a 3.5% solution. It is partly excreted through the kidneys and part of it is stored in reticuloendothelial cells, Kupffer cells in the liver, skeletal muscles, and skin for a long period.
• PVP binds penicillin and insulin in the plasma. It is not preferred due to various disadvantages like—it provokes histamine release and interferes with blood grouping.

Human albumin:

• Human albumin is obtained from pooled human plasma. Given as 5–20% solution. 100 mL of the 20% solution is osmotically equivalent to 800 mL of whole blood.
• It is nonantigenic, and does not interfere with coagulation, blood grouping, or cross-matching. It also does not carry the risk of transmitting serum hepatitis as the preparation is heat treated. It is expensive.
• Human albumin is used in edema, burns, hypovolemic shock, hypoproteinemia, acute liver failure, and in dialysis. Allergic reactions and fever can occur though rarely.

Plasma Expanders Uses:

• As plasma substitutes in hypovolemic shock, burns, and in extensive fluid loss—as an emergency measure to restore plasma volume.
• Contraindications of plasma expanders are—cardiac failure, pulmonary edema, renal failure, and severe anemia.

Intravenous Fluids

• Intravenous fluids are sterile solutions meant for intravenous administration. The content and quantity of solute varies.
• Intravenous fluids are used for the replacement of fluid, electrolytes, and nutrition.
• There are different types of IV fluids to be given depending on the patient’s requirements.

Types of IV Solutions:

Intravenous solutions are of 3 types depending on osmolality. Fluids having an osmolality nearly equal to that of extracellular fluid (ECF) or if the electrolyte content (cations + anions) is nearly equal to 310 mEq/L—are considered isotonic.

• Isotonic fluids (electrolyte content = 310 mEq/L). For example, normal saline, lactated ringer
• Hypotonic fluids (electrolyte content <250 mEq/L). Half normal saline
• Hypertonic fluids (electrolyte content >375 mEq/L). For example, dextrose (5%) in normal saline.

Plasma osmolality is nearly equal to 300 mmol/L. The osmolality of 10% dextrose is 505 mmol/L.

Intravenous fluids may also be grouped as:

• Maintenance fluids—5% dextrose in half-normal saline
• Replacement fluids—normal saline, dextrose saline (DNS), ringer lactate, Isolyte—M, P, G, and E
• Special fluids (for special indications)—25% dextrose, sodium bicarbonate, potassium chloride.

Pharmacotherapy Of Shock

Shock is an acute circulatory failure with under perfusion of tissues. It needs immediate treatment and can be rapidly fatal, if not appropriately taken care of.

Shock Clinical Features:

In shock, symptoms of sympathetic overactivity are generally seen like pallor, sweating, cold extremities, and tachycardia. Shock may be of different types and causes:

Hypovolemic shock:

• Decreased blood volume due to sudden loss of plasma or blood as in hemorrhage, burns, or dehydration can result in hypovolemia and underperfusion of all tissues including vital organs.
• Treatment of hypovolemic shock is by prompt replacement of fluids and electrolytes. Blood pressure should be monitored.

• Septic shock:
  • Septic shock is precipitated by severe bacterial infection and may be due to the release of bacterial toxins.
  • These trigger the release of inflammatory cytotoxic mediators including interleukins, PGs, TNF-a, PAF, cytokines, and others, resulting in vasodilation.
  • It is called warm shock since the skin is warm due to peripheral vasodilation.
  • Treatment:
    • Immediate treatment of shock is as important as controlling the infection.
    • General measures include correction of acidosis, blood volume, maintenance of BP, and appropriate antibiotics in adequate doses. Ventilatory support may be given if required.
• Cardiogenic shock:
  • Cardiogenic shock is due to failure of pumping of the blood by the heart as in myocardial infarction or acute myocarditis.
  • IV morphine is the drug of choice to relieve pain and anxiety.
• Anaphylactic shock:
  • Anaphylactic shock is a type I hypersensitivity reaction.
  • Antigen–antibody reaction on the surface of mast cells and basophils triggers the release of massive amounts of histamine and other mediators of inflammation.
  • The important clinical features are hypotension, bronchospasm, and laryngeal edema. It can be rapidly fatal and therefore, needs to be treated immediately.
• Treatment:
• Adrenaline: 0.3–0.5 mL of 1:1,000 solution is injected intramuscularly; it promptly reverses the symptoms because it is the physiological antagonist of histamine and can be life-saving. If needed, another dose may be repeated after 15–20 minutes.
• The airway should be maintained. Salbutamol nebulization may be given to relieve bronchospasm.
• The foot end of the bed should be elevated to improve BP. Suitable plasma expanders and vasopressors like norepinephrine or dopamine may be needed.
• Hydrocortisone hemisuccinate 100 mg may be given intravenously. Once the patient
  recovers, a short course of oral prednisolone may be given. Antihistamines chlorpheniramine 20 mg may be injected by slow IV injection. It may take care of some of the manifestations of allergy.
• Neurogenic shock: Neurogenic shock is due to venous pooling as following spinal anesthesia, severe head injury, spinal cord injury, and abdominal or testicular trauma (vagal inhibition).
• Treatment: Blood volume replacement should be done. A vasopressor like noradrenaline, may be given intravenously to improve the vascular tone.

General guidelines for the treatment of shock:

• The cause should be identified and treated.
• BP and plasma volume should be maintained with appropriate IV fluids.
• The foot end of the bed should be elevated.
• This increases venous return which raises the BP to some extent based on the requirement.
• Vasopressors like dopamine may be given IV when the BP cannot be brought up by IV fluids.
• Plasma expanders may maintain the plasma volume when there is severe hypovolemia.
• Acid-base and electrolyte disturbances should be corrected.
• Adequate urine output should be ensured.
• Ventilatory support and oxygen administration may be given if required.