Drug

Pharmacodynamics

Pharmacokinetics

Unwanted effects

Clinical Use

Calcium channel blockers:

·          Verapamil

·          Nifedipine

·          Diltiazem

Mechanism of action:

·          Block entry of Ca²⁺ into autorhythmic & excitable cells.

·          Cytoplasmic free Ca²⁺ determines contractility of cardiac & smooth muscle.

·          Use dependence: more active receptor, greater efficacy of drugs.

·          Voltage dependence: different potency in different membrane potentials.

·          Skeletal muscle is not affected.

Vasculature:

·          Arterial vasodilation

·          Nifedipine > Diltiazem > Verapamil

Nodal & conducting tissue:

·          Decrease rate of nodal discharge & conduction.

·          Prolong AV nodal refractory period.

·          Verapamil > Diltiazem

Myocardium:

·          Decrease myocardial contractility.

·          Verapamil > Diltiazem.

·          Well absorbed orally.

·          High protein binding (90%)

·          Extensively metabolized by the liver with active metabolites.

·          Short half-lives: 4-6hrs

·          Little excreted unchanged.

·          High first pass effect: verapamil (80%), diltiazem (45%), nifedipine (40%)

Verapamil:

·          (-) isomer 10 x active than (+)

·          Bioavailability of (-) isomer only 15% of (+) isomer

Nidedipine:

·          Wide interindividual variability

·          Metabolized by CYP3A4 enzyme in liver.

·          Inhibited by ketoconazole, grapefruit

Verapamil:

·          Constipation

·          Headache

·          Pruritus

·          Mild nausea

·          Nervousness

·          Peripheral edema

·          Hypotension

Nifedipine:

·          Flushing

·          Palpitations

·          Headache

·          Hypotension

·          Peripheral edema

·          Compensatory tachycardia may precipitate angina

Diltiazem: same as verapamil but lower incidence

Angina pectoris:

·          All three are effective.

·          Dilation of coronary vessels improves perfusion.

·          Arterial vasodilation decreases afterload & decrease heart rate.

·          Decreased contractility decreases myocardial oxygen demand.

Variant angina & peripheral vascular disease:

·          Nifedipine relieves coronary artery spasm in Printzmetal angina.

·          Also useful in Raynaud’s phenomenon.

Hypertension:

·          Nifedipine has the greatest vasodilator & least cardiac effects.

·          Used in emergency treatment of severe hypertension.

Congestive heart failure:

·          Arterial vasodilation  decreases afterload.

·          Higher doses produce suppression of cardiac contractility & heart rate.

Antiarrhythmia:

·          Effects of verapamil on AV nodal conduction useful in AV tachyarrhythmias:

·          Paroxysmal supraventricular tachycardia

·          Wolff-Parkinson-White syndrome

Ischaemic heart disease:

·          Prolong survival of ischaemic heart muscle by preventing damage due to intracellular accumulation of Ca²⁺ in anoxia.

Cardiac surgery:

·          Included in cardioplegic solutions used in cardiac surgery.

Anticalcinotic vascular protection:

·          Useful in protecting vessel walls from damage by intracellular accumulation of Ca²⁺.

Nitrates:

·          Amyl nitrate

·          Glyceryl trinitrate

·          Isosorbide dinitrate

Mechanism of action:

·          Denitrated in smooth muscle to release NO.

·          NO activates guanylyl cyclase & increase cGMP which acitvates a cGMP-dependent protein kinase.

·          Eventual dephosphorylation of myosin light chain kinase causes smooth muscle relaxation.

Desired effects:

·          Venodilation decreases venous return.

·          Arteriolar dilation decreases afterload.

·          Poor bioavailability

·          Sublingual administration for rapid action

·          Oral or transcutaneous route for longer duration.

·          Metabolites of glyceryl trinitrate & isosorbite dinitrate are active after denitration.

Administration:

·          Amyl nitrate: crushable ampoule for inhalation.

·          Rest: sublingual or chewable tablet.

Onset of action:

·          Amyl nitrate: 10min

·          Glyceryl trinitrate: 30min

·          Isosorbide nitrate: chewable & sublingual – 1hr; oral substained release – 6-12hr

·          Isosorbide-5-mononitrate (oral): 12hr

·          Orthostatic hypotension

·          Dizziness

·          Throbbing headache due to meningeal artery pulsations

·          Palpitations

·          Methaemoglobinemia

Reflex tachycardia:

·          Due to compensatory increase in heart rate & contractility.

·          Reduces therapeutic effect by increasing oxygen demand & decreasing perfusion time.

Tolerance:

·          Tends to occur esp. with high doses of long-acting nitrates which give steady plasma concentration.

·          Cross-tolerance between different nitrates.

·          Avoid using intermittent dosing.

Contraindicated in:

·          Ventricular outflow obstruction

·          Low output heart failure

·          Raised intracranial pressure

·          Glaucoma

·          Mitral valve prolapse

Choice of preparation:

·          Sublingual glyceryl trinitrate is the most frequently used preparation for relief of anginal symptoms because of its ease of administration & rapid onset of action.

·          It is not suitable for maintenance therapy because of its short duration of action.

ACE Inhibitors:

·          Captropril

·          Enalapril

·          Inhibits angiotensin-converting enzyme

·          ACE is bound to membrane of vascular endothelial cells.

·          It converts angiotensin I to angiotensin II & inactivates bradykinin

·          Lowers peripheral vascular resistance.

·          Well absorbed orally.

Captopril:

·          Half-life: 3hrs

·          Metabolized to disulphide conjugates.

·          Less than 50% of an oral dose is excreted unchanged by kidneys.

Enalapril:

·          A prodrug, de-esterified to active metabolite enalaprilat.

·          Peak concentration after 3-4hrs.

Captopril:

·          Bone marrow suppression

·          Neutropenia

·          Nephrotoxicity

·          Macular rash

·          Altered taste

·          Dry cough

·          Severe hypotension in hypovolemic patients

Drug interactions:

·          Potassium-sparing diuretics: precipitate hyperkalemia

·          Effective blood pressure lowering in 70% of patients; up to 90% if used with diuretics.

·          Initial hypotension may be substantial, hence first dose is usually given at night.

·          Greater fall in blood pressure in high renin states but has effect even in low renin states.

Iosartan:

·          Competitive angiotensin I receptor antagonist

·          Short half-life: 2hrs

·          Active metabolite, non-competitive antagonist with longer half-life.

Vasodilators:

·          Hydralazine

·          Minoxidil

·          Diazoxide

Hydralazine:

·          May act through guanylate cyclase.

·          Arteriolar dilation

·          Increase heart rate & stimulation of renin-angiotensin-aldosterone system

Minioxidil:

·          Opening of K⁺ channels.

·          More potent than hydralazine

Diazoxide:

·          Chemically similar to the thiazides.

·          No diuretic action

·          Tend to cause fluid retenion

Sodium nitroprusside:

·          Cyanonitroso-complex of iron

·          Dilates both arteries & veins

Hydralazine:

·          Well absorbed orally

·          Bioavailability: 25%

·          Metabolized in part by acetylation, a pathway subject to genetic polymorphism.

·          Half-life: 2-3hrs

·          Duration of effect: 6-8hrs

Minoxidil:

·          Well absorbed orally

·          Metabolized by glucuronide conjugation

·          Not protein bound

·          Half-life: 4hrs

·          Duration of action: 1-3 days

Diazoxide:

·          Extensively bound to plasma protein & vascular tissue.

·          Metabolized & excreted unchanged.

Sodium nitroprusside:

·          Administered parenterally

Hydralazine:

·          Toxicity is more common in slow acetylators receiving high doses.

·          SLE-like syndrome

·          Arthralgia

·          Myalgia

·          Fever

·          Skin rash

·          Diarrhea

·          Constipation

·          Flushing

Minoxidil:

·          Headache

·          Sweating

·          Excessive hair growth

·          Cardiotoxicity

·          Autoimmune reaction

Diazoxide:

·          Hyperglycaemia

·          Hyperosmolarity

Sodium nitroprusside:

·          Thiocyanate toxicity

·          Disorientation

·          Psychosis

·          Muscle spasms

·          Convulsions

Hydralazine:

·          Compensatory tachycardia & fluid retenion

·          Used in combination with a beta-blocker or a diuretic.

Minoxidil:

·          Topical minoxidil is used to stimulate hair growth to counter baldness.

·          Compensatory effects more marked than hydralazine; must be combined with a beta-blocker or diuretic.

Diazoxide:

·          High efficacy arteriolar dilator used in hypertensive emergencies.

·          Administered parenterally with onset of hypotensive effect within 5 minutes & lasts for several hours.

·          Excessive dosing has resulted in stroke, angina or myocardial infarction induced by profound hypotension.

Sodium nitroprusside:

·          Administered by intravenous infusion & in hypertensive emergencies its extremely rapid action & short duration of action require constant titration of infusion rate against fall in blood pressure.

Central Sympathoplegics:

·          Methyldopa

·          Reduce sympathetic outflow from vasopressor centers in the brainstem.

·          Methyldopa: taken up into central & peripheral adrenergic terminals & converted to an a-receptor agonist, a-methylnonepinephrine

Methyldopa:

·          Bioavailability: 25%

·          Extensive first-pass conjugation by GI mucosa.

·          Half-life: 2hrs

·          Limited maximal efficacy in lowering blood pressure.

Clonidine:

·          Bioavailability: 75%

·          Half-life: 8-12hrs

·          Lipid-soluble: rapidly enters brain.

·          Given twice a day.

Methyldopa:

·          Overt sedation

·          Mental lassitude

·          Impaired mental concentration

·          Nighmares

·          Mental depression

·          Vertigo

·          Extrapyramidal signs

·          Lactation

·          Positive Coombs test

Clonidine:

·          Dry mouth

·          Sedation

·          Mental depression

·          Tricyclic antidepressants block effects.

Methyldopa:

·          Useful in treatment of mild to moderately severe hypertension.

·          Lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate & cardiac output.

·          Advantage: causes retention in renal vascular resistance.

Clonidine:

·          Reduction of cardiac output due to decreased heart rate.

Ganglion-blocking agents:

·          Administered IV.

·          Orthostatic hypotension

·          Sexual dysfunction

·          Constipation

·          Urinary retention

·          Glaucoma

·          Blurred vision

·          Except trimethapan, drugs of this class are no longer used clinically due to intolerable toxicities.

·          Hypertensive emergencies.

Adrenergic neuron-blocking agents:

·          Guanethidine

·          Lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons.

Guanethidine:

·          Inhibits release of norepinephrine from sympathetic nerve endings.

·          Cause a gradual depletion of nonepinephrine stores in the nerve ending.

Reserpine:

·          Blocks ability to transmitter vesicles to take up & store biogenic amines.

Guanethidine:

·          Bioavailability is variable.

·          50% cleared by kidney.

·          Long half-life: 5 days.

·          Onset of effect is gradual with constant daily dosing.

Reserpine:

Guanethidine:

·          Postural hypotension

·          Hypotension following exercise

·          Decreased blood flow to heart & brain

·          Shock

·          Delayed or retrograde ejaculation

·          Diarrhea

·          TCAs decrease effects

Reserpine:

·          Sedation

·          Lassitude

·          Nightmares

·          Severe mental depression

·          Mild diarrhea

·          Gastrointestinal cramps

Guanethidine:

·          High maximal efficacy.

·          Mainstay of outpatient therapy of severe hypertension.

Reserpine:

·          Lowers blood pressure by decreased cardiac output & decreased peripheral vascular resistance.