Antihypertensive Drugs (Part 2) PDF

Semester III Antihypertensive drugs (Part-2) Dr. Nada Mohammed Abd El -Latif Lecturer of Clinical Pharmacology  Nada Mohammed Abd El-latif Hamada MD,PhD ❑CONTACT: Email: [email protected] Tel: 0106943088...

Semester III Antihypertensive drugs (Part-2) Dr. Nada Mohammed Abd El -Latif Lecturer of Clinical Pharmacology  Nada Mohammed Abd El-latif Hamada MD,PhD ❑CONTACT: Email: [email protected] Tel: 01069430885  BLOILOsOD VESSELS 1. Describe mechanism of action of beta blockers as antihypertensive drug, common side effects and contraindications 2. List the other anti-HTN drugs. 3. Explain the mechanisms of action & the major side effects of each group. 4. Identify their uses in hypertension. Lecture Outline Beta blockers List of second choice groups Strategies & drug targets Management of hypertensive emergencies  IV.Beta Blockers Preparations ❖ Non selective (β1- & β2) ▪ e.g. propranolol ❖ Cardioselective β1-blocker ▪ e.g. atenolol ❖ β-blocker With α-blocking activity ▪ e.g. (β-blocker with VD effect) carvedilol, Labetalol  IV.Beta Blockers Mechanism of action ▪ Competitive inhibitors of catecholamine at β-adrenoceptor sites leading to: 1.Inhibit sympathetic stimulation of heart (β1) so decrease HR & contractility thus reducing COP 2.Decreased renin release from kidney (β1) 3.Some BB has VD action (e.g. Carvedilol) IV. Beta Blockers  Beta Blockers Uses in Hypertension ▪ β-blockers have beneficial effects in hypertensive persons with other cardiovascular diseases. ▪ Labetalol is used to treat chronic hypertension and hypertensive emergencies ▪ Esmolol is an intravenously administered, ultrashort-acting β1 - blocker used to treat hypertension in surgical patients and in persons with hypertensive emergencies. ❑N.B: The drug with the best safety record for preexisting hypertension in women who wish to become pregnant is labetalol, but nifedipine or, as a third-line drug, methyldopa can be considered. II- Beta Blockers  IV.Beta Blockers Side effects ❖ Beta-1 effects: ▪ Bradycardia, heart block, heart failure ❖ Beta-2 effects: ▪ bronchospasm, worsening PVD “peripheral vascular disease” ❖ Others : ▪ Fatigue, depression, nightmares, impotence  IV.Beta Blockers Cautions/contraindications 1) Variant angina (CI) 2) Asthma (CI) 3) Verapamil (CCB) and beta blockers are CI as both are myocardial depressants (inhibit conduction & contraction) 4) Avoid abrupt withdrawal. ❑ A 48-year-old hypertensive patient has been successfully treated with a thiazide diuretic for the last 5 years. Over the last 3 months, his diastolic pressure has steadily increased, and he was started on an additional antihypertensive agent. He complains of several instances of being unable to achieve an erection and not being able to complete three sets of tennis as he once did. Which is the likely second antihypertensive medication? a. Captopril. b. Losartan. c. Minoxidil. d. Nifedipine e. Metoprolol.  Other Classes ❑ Second choice groups (used in special cases): i. α1- blockers: prazosin. ii. Adrenergic neuron blockers: Reserpine. iii. Vasodilators: Hydralazine, Minoxidil, Diazoxide , , sodium nitroprusside. iv. Central α2 stimulant : Methyldopa-Clonidine. v. Endothelin-1 receptor antagonists vi. Dopamine agonists: Fenoldopam I- Alpha-1 adrenergic blockers  I- Alpha-1 adrenergic blockers Side effects: ▪ Postural (Orthostatic) hypotension more with first dose  II. Adrenergic neuron blockers ❖Reserpine ❑ Reserpine depletes adrenergic nerves of these biogenic amines, primarily by blocking the transport of norepinephrine, Dopamine and serotonin into storage vesicles. ❑Reserpine depletes adrenergic nerves of these biogenic amines; this explains the sedation, depression and parkinsonian side-effects that can accompany its use. ❑Reserpine is rarely used now because of numerous adverse effects.  III. Vasodilators ❑ Def. ▪ Drugs that dilate blood vessels by acting directly on smooth muscle cells through non-autonomic mechanisms ❑ Classification: 3) Mixed- 1) Arterio-dilators 2) Veno-dilators dilators Hydralazine Nitrates Na+ Nitroprusside ▪ They dilate mainly veins Minoxidil →↓ venous return (→ ↓ ACEI They dilate arteries and ↓↓ BP preload) ▪ ▪ They ↓ preload & afterload (→ ↓ afterload) ▪ used in acute pulmonary so they are used in CHF. ▪ used in severe systemic edema. hypertension. General feature of V. D: 1)Hydralazine Mechanism of Action ▪ Release of nitric oxide (NO) from endothelial cells so increase cGMP and relaxation of vascular smooth muscle and thus fall in blood pressure Uses: ▪ HTN during pregnancy Side effects: ▪ A SLE-like syndrome, which usually occurs after several months of treatment, is dose- related (and unusual at low doses of hydralazine) and more common in slow acetylators. ▪ NB: Significant baroreceptor homeostatic responses So, must be combined with diuretics and β-blockers. 2) Sodium niroprusside Mechanism of Action ▪ Nitroprusside is a nitrovasodilator; it reacts with oxyhemoglobin in erythrocytes to produce methemoglobin, cyanide and nitric oxide (NO) producing dilation of arterioles and veins. Uses: ▪ given by i.v. infusion in hypertensive emergencies and acute heart failure because it has rapid action ❑N.B ▪ can be converted to cyanide and thiocyanate. The accumulation of cyanide and risk of toxicity are minimized by concomitant administration of sodium thiosulfate or hydroxocobalamin (vitamin B12). ▪ Sodium nitroprusside in aqueous solution is sensitive to light and must be made up fresh before each administration and covered with opaque foil. 3) Minoxidil Mechanism of Action ▪ Minoxidil is a K+-channel opener that hyperpolarizes and relaxes vascular smooth muscle Uses: ▪ It is given orally for chronic hypertension(use as antihypertensive is declining). ▪ used topically to prevent hair loss in both males and females (stimulate hair growth (hypertrichosis) (by unclear mechanism). Side effects: ▪ Hirsutism (hypertrichosis) NB: Significant baroreceptor homeostatic responses So, must be combined with diuretics and β-blockers. 4) Diazoxide ▪ Structurally related to thiazides but it is not diuretic ▪ It is a direct arteriolodilator by opening K+ channels → hyperpolarization → relaxation of the vascular smooth ms. ▪ Given in hypertensive emergencies by intravenous bolus injection but its use is declining. ❑Significant relaxation of arteriolar and venular smooth muscles can be produced by which of the following drugs? a.Hydralazine b.Minoxidil c.Sodium nitroprusside d.Nifedipine e.Atenolol A 35-year-old man presents to the emergency department complaining of a cough and runny nose of 1-week duration. While being evaluated, it is discovered that his blood pressure is 230/120 mm Hg. An antihypertensive is immediately administered. Later, he develops lactic acidosis, headache, vertigo, and confusion. Which antihypertensive was given to him? (A) Enalapril (B) Labetalol (C) Losartan (D) Nifedipine (E) Nitroprusside  IV.Centrally Acting drugs 1)Alpha-Methyldopa Mechanism of Action ▪ Methyldopa is a prodrug that is metabolized in the nerve terminal as a ‘false substrate’ in the biosynthetic pathway for NA to produce α-methyl NA, a potent α 2 -adrenoceptor agonist Uses in Hypertension ▪ during pregnancy  IV.Centrally Acting drugs Side effects ▪ The most common side effect is sedation, nightmares, and mental depression due to central deficiency of norepinephrine. ▪ Mild hyperprolactinemia and extrapyramidal manifestations due to central deficiency of dopamine. ▪ Positive Coombs test and autoimmune hemolytic anemia. ▪ Autoimmune hepatitis is rare  IV.Centrally Acting drugs 2) Clonidine Mechanism of Action Clonidine is a central α2-receptor agonist Central sympathetic outflow and reduction in the total peripheral resistance. ▪ Reduction of BP is not associated with changes of the RBF or GFR. Uses in Hypertension ▪ Used in the management of hypertension complicated by renal disease. ▪ To reduce anxiety accompanying opiate withdrawal or surgical operations.  IV.Centrally Acting drugs Side effects ▪ Sedation and dry mouth (central effect). ▪ Sudden withdrawal of the drug can lead to rebound hypertension. ▪ Salt and water retention so it is usually combined with diuretics. V.Endothelin-1 receptor antagonists ▪ Endothelin-1 is a powerful vasoconstrictor secreted by the vascular endothelium. It is elevated in patients with pulmonary hypertension and coronary artery disease. ▪ It exerts its effects via two receptors, ETA and ETB. ETA receptors is the main subtype on vascular smooth ms cells and mediates VC and cell proliferation (vascular smooth ms hypertrophy) ▪ Bosentan is an antagonist at both ET A and ETB receptors, whereas ambrisentan is selective for ETA receptors. ▪ Both drugs are approved for treatment of primary pulmonary hypertension.  VI. Dopamine agonists: Fenoldopam Mechanism of action ▪ It is a selective dopamine D 1 receptor agonist and produces vasodilation in systemic vascular beds, including coronary, renal, and mesenteric vessels. In the kidney, fenoldopam dilates both afferent and efferent arterioles, thereby increasing renal blood flow. Uses in Hypertension ▪ Fenoldopam is a rapid-acting, intravenously administered vasodilator used to treat hypertensive emergencies.  Def: BP > than 180/120 mmHg with target organ damage Aim: lower BP within hours not minutes. A.Hospitalization B.Antihypertensive medications ▪ Drugs commonly used: sodium nitroprusside, labetalol, fenoldopam, all are given by slow i.v. infusion. ❑Which can precipitate a hypertensive crisis following abrupt cessation of therapy? a. Clonidine. b. Diltiazem. c. Enalapril. d. Losartan. e. Hydrochlorothiazide  References ▪ Brody's Human Pharmacology, Seventh Edition - ClinicalKey Student ▪ Rang & Dale's Pharmacology, Tenth Edition - ClinicalKey Student ▪ Medical Pharmacology and Therapeutics, Sixth Edition - ClinicalKey Student Thank You