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Drugs used in hypertension

Drugs used in hypertension. Dr. R. Pilviniene. DEFINITION. Hypertension is defined as sustained elevation of resting systolic blood pressure (SBP) of 140 mmHg or greater, diastolic blood pressure (DBP) of 90 mmHg or greater, or taking antihypertensive medication.

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Drugs used in hypertension

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  1. Drugs used in hypertension Dr. R. Pilviniene

  2. DEFINITION • Hypertension is defined as sustained elevation of resting systolic blood pressure (SBP) of 140 mmHg or greater, diastolic blood pressure (DBP) of90 mmHg or greater, or taking antihypertensive medication. The Merck Manual, Eighteenth edition, 2006

  3. TYPES OF HYPERTENSION • Primary hypertension (formerly essential) • Most common (90%) • Specific cause cannot be established • Secondary hypertension • Hypertension with identified cause

  4. CAUSES OF SECONDARY HYPERTENSION • Renal • Renal parenchymal diseases (glomerulonephritis) • Renovascular diseases • Endocrine • Pheochromacytoma • Hypertiropidism • Primary hyperaldosteronism • Drugs • Contraceptives • Sympathomimetics • Corticosteroids • Cocaine • Unknown

  5. HYPERTENSION: PREDISPOSING FACTORS • Age > 60 years. • Sex (men and postmenopausal women). • Family history of cardiovascular disease. • Smoking. • High cholesterol diet. • Co-existing disorders such as diabetes, obesity and hyperlipidaemia. • High intake of alcohol. • Sedentary life style.

  6. Major factors controlling blood pressure Arteriolar volume ARTERIAL BLOOD PRESSURE CARDIAC OUTPUT PERIPHERAL RESISTANCE ~ ~ X Blood volume Heart rate Filling pressure Venous tone Contractility

  7. TREATMENT STRATEGIES • Reduction of blood volume. • Reduction symphathetic tone. • Reduction smooth vascular tone. • Reduction of angiotensin effects.

  8. Compensatory responses to decreased blood pressure when treating hypertension Hypertension Treatment Decreased blood pressure Sympathetic outflow Renin release Diuretics AKF inh. - - Betablockers, reserpine Salt and H2O retension Tachycardia Increased blood pressure

  9. Drugs Used in Hypertension Angiotensin antagonists Sympatoplegics- adrenoblockers Vasodilators Diuretics Older oral AT receptors blockers ACE inhibitors CNS sympathetic outflow Ganglia Ca2+ blockers Nerveterminal α ir β receptors Parenteral

  10. SYMPATHOLYTICS-ADRENOBLOCKERS • Centrally acting drugs • Clonidine, methyldopa (α2 agonists) • Ganglio-blocking drugs • Hexamethonium, trimethapan • Postganglionic sympathetic terminal – blockers (peripheraly acting) • Reserpine, guanethidine • Adrenoreceptor blocking agents • Prazosin (α1 - selective); • Phentolamine, phenoxybenzamine (non-selective α ) • Propranolol ( β -blocker).

  11. CENTRALLY ACTING SYMPATHOPLEGIC DRUGS METHYLDOPA: • Is a prodrug; it is converted to methyl- norepinephrine in the brain. • Methyl norepinephrine is a FALSE MEDIATOR of the adrenergicreceptors. • Effects: peripheral resistance, blood pressure. • Side effects; sedation, drowsiness

  12. CENTRALLY ACTING SYMPATHOPLEGIC DRUGS

  13. CENTRALLY ACTING SYMPATHOPLEGIC DRUGS Clonidine • Was the drug used to identify the a2 receptor. • Action: Acts by reducing the sympathetic outflow in the CNS (centers controlling blood pressure). • Uses: mild to moderate hypertension. • Enters CNS given orally. • Side effects: • Sedation, drying of nasal mucosa. • Rebound hypertension, following abrupt withdrawal.

  14. GANGLION- BLOCKING DRUGS Hexamethonium, trimethapan • Nicotinic blockers are very efficacious, bet side effects are severe. • Side effects: • Parasympathetic blockade: blurred vision, constipation, urinary hesitancy. • Sympathetic blockade: sexual dysfunction, orthostatic hypotension.

  15. ADRENERGIC NEURON – BLOCKING AGENTS Reserpine • Blocks NA from entering to the vesicles, thus NA levels decrease due to exposure to MOA • Gradual decrease of BP • Gradual slowing of cardiac rate. • Side effects: depression. Guanethidine • Lowering of NA release from sympathetic nerve endings • At high doses can produce profound sympathoplegia • Rarely used in hypertension • Side effects: orthostatic hypotension; sexual dysfunction. Long duration of action (both): days to weeks.

  16. Adrenoreceptor blocking agents • Non-selective α (prevents vasocostriction) • Phentolamine, phenoxybenzamine • Long duration of action (24 h after single use) • Therapeutic use: Pheochromacytoma. • Are of value in chronic hypertension • postural hypothension, tachycardia. • α1 – selective (prevents vasocostriction) • Prazosin, terazosin • Are useful in chronic hypertension. • Free of severe side effects.

  17. Adrenoreceptor blocking agents • Propranolol ( non selective β -blocker) • Primary (early) antihypertensive effect: • Reduction of cardiac output. • Secondary (later) antihypertensive effect: • Decrease in vascular resistance • Reduced angiotensin level (reduces renin relese from kidney) • Side effects: • Bronchoconstriction • Arythmias (quick discontinuation) • Sexual impaiment • Disturbances of metabolism (fasting hypoglicaemia)

  18. VASODILATORS • OLDER ORAL • Minoxidil • Hydralazine • PARENTERAL • Nitroprusside • CA2+ CHANNNELSBLOCKERS • Verapamil • Diltiazem • Nifedipine

  19. OLDER ORAL VASODILATORSHydralazine • Mechanism of action: Release of nitric oxide from endothelial cells. • Effects: • direct vasodilatation (arterioles >veins) due to decreased systemic vascular resistance • increase of cardiac output • Antihypertensive effect is rapid. - Must be used in combination with beta blocker or loop diuretic. • Therapeutic uses:severe hypertension; HF. • Side effects: • lupus – like syndrome (21%) • Compensatory responces: • Tachycardia • Salt and water retention

  20. OLDER ORAL VASODILATORS Minoxidil • Mechanism of action: opens potassium channels - stabilizes membrane and makes contraction of the blood vessel less likely. • Effects: Dilates arterioles, not – veins - Extremely efficacious (greater potential than of hydralazine) • -Hypotensive effect may persist for 24 hours. • Must be used in combination with beta blocker or loop diuretic • Toxicity: • - Compensatory responses. • - Hirsutism.

  21. PARENTERAL VASODILATORSNitroprusside sodium Chemical composition Nitrofericianid (Fe2+, CN- , NO) Mechanism of action Release of NO Activation of guanylylcyclase Increase of cGMP concentration in smooth muscle Vasodilatation of arteries and veins.

  22. PARENTERAL VASODILATORSNitroprusside sodium • Therapeutic uses: • Hypertensive emergencies • Severe heart failure (in CHF patients – cardiac output increases) • Metabolized very rapidly and must be given by continuous drip • During the infusion of the drug BP must be constantly monitored because of hypotension. • Toxicity: - Excessive BP lowering, - Cyanide accumulation ( treated by sodium thiosulfate): metabolic acidosis, arrhythmias, death.

  23. ANGIOTENSIN ANTAGONISTS • Angiotensin -converting enzyme (AKF) inhibitors • Captopril • Enalaprilis • Ramipril • Angiotensin II competetive receptors blockers • Losartan • Valsartan

  24. ANGIOTENSIN ANTAGONISTSACE inhibitors Differences - Potency - Route of elimination - Duration of action - Being prodrugs or active drugs

  25. ANGIOTENSIN ANTAGONISTSACE inhibitors • Captopril (prototype) • Enalapril • Prodrug (deesterificated to active drug enalaprilat). • Lisinopril – lysine derivate of enalaprilate. • Fosinopril, ramipril – long-acting drugs • Prodrugs – hydrolysed to active in liver.

  26. ANGIOTENSIN ANTAGONISTSMechanism of action AngiotenzinogenKininogen Angiotenzin I Bradikinin Pg synthesis (inactiv peptid) (vazodilator) Angiotenzin II Inactive metabolit (vasoconstrictor) Vasoconstriction Aldosteron Vasodilation Peripheral resistance Na+ ir H2O retention Peripheral resistance BP BP Kalikrein Renin ACE ACE inhibitors AT blockers

  27. ANGIOTENSIN ANTAGONISTSACE inhibitors (Captopril) Effects • Decrease of peripheral resistance • Blood pressure • ↓afterload • Decreased Na+ ir water retention • ↓preload • Are not associated with such compensatory response as activation of sympathetic nervous system.

  28. ANGIOTENSIN ANTAGONISTSACE inhibitors (Captopril) Therapeutic uses • HF • Hypertension • State after myocardial infarction • Protect against sudden death and second myocardial infarction • Non-diabetic nephropathy. • Protect against progression nephropathy due to diminishing proteinuria.

  29. ANGIOTENSIN ANTAGONISTSACE inhibitors (Captopril) Pharmacokinetics • Rapid absorbtion. • BA about 70 % (decreases if taken concomitantly with food). • Captopril is distributed to most bodytissues (except - CNS). • Most – eliminated by kidneys – dose reduction in renal insufficiency.

  30. ADVERSE EFFECTS • Hypotension • Renal Insufficiency (if bilateral renal artery stenosis) • Hyperkalemia – special group of patients (Na restricted, on K-sparing diuretic, COX inhibitors, diabetic patients) • Cough – dry, persistent (20 %). • Bardykinin induced • Angioedema • Neutropenia, nephrotic syndrome, skin rash, taste disturbances. (captopril especially): • Contraindicated in pregnancy! Kinin-related SH group related

  31. ANGIOTENSIN ANTAGONISTSCompetetive inhibitors of angiotensin IILosratan • Effects – similar to ACE I (NOT AS EFFECTIVE AS ACEIs) • Blocks AT generated effects but not by ACE • No effect on bradykinin. • ADRs – similar to ACEI, but less cough and angioedema. • More complete AT inhibition. • At present recommended for use in ACEI intolerant patients. • Some suggestion that they may have benefit when added to ACEIs.

  32. AII Receptor Blocker ACE Inhibitor Blocks AT-1R AT-2R Free Blocks formation of AII incompletely Blocks Kininase II Preserve Anti- proliferative effect More complete Inhibition of AII effects ↑ Kinins ↓ AII effects & aldosterone PROTECTION

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