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  • 1. Clinical Pharmacology of Antihypertensives The department of internal medicine, clinical pharmacology and occupational diseases, BSMU, Chernivtsi Eugene I. Shorikov, associate prof., PhD
  • 2.
    • Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle.
    • As a consequence, hypertension is the principal cause of stroke, is a major risk factor for coronary artery disease and its attendant complications : myocardial infarction and sudden cardiac death, and is a major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of the aorta.
  • 3. Base of therapy
    • The decision to start antihypertensive treatment shuold be based on criteria:
    • the level of systolic and diastolic blood pressure
    • the level of total cardiovascular risk
  • 4.  
  • 5.  
  • 6.  
  • 7.  
  • 8.  
  • 9. Very High Risk Of Hypertension
  • 10. Principles of Treatment
  • 11. Goals of Treatment
  • 12. Classification of Antihypertensive Drugs by Their Primary Site or Mechanism of Action
    • Diuretics
    • Thiazides and related agents (hydrochlorothiazide, chlorthalidone, etc .)
    • Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid)
    • K+-sparing diuretics (amiloride, triamterene, spironolactone)
    • Sympatholytic drugs
    • b eta Adrenergic antagonists (metoprolol, atenolol, etc .)
    • a lpha Adrenergic antagonists (prazosin, terazosin, doxazosin, phenoxybenzamine, phentolamine)
    • Mixed adrenergic antagonists (labetalol, carvedilol)
    • Centrally acting agents (methyldopa, clonidine, guanabenz, guanfacine)
    • Adrenergic neuron blocking agents (guanadrel, reserpine)
  • 13. Classification of Antihypertensive Drugs by Their Primary Site or Mechanism of Action
    • Ca2+ channel blockers (verapamil, diltiazem, nimodipine, felodipine, nicardipine, isradipine, amlodipine)
    • Angiotensin converting enzyme inhibitors ( ACEI ) , (captopril, enalapril, lisinopril, quinapril, ramipril, benazepril, fosinopril, moexipril, perindopril, trandolapril)
    • Angiotensin II-receptor antagonists (losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan)
    • Vasodilators
    • Arterial (hydralazine, minoxidil, diazoxide, fenoldopam)
    • Arterial and venous (nitroprusside)
  • 14. Classification of Diuretics by Their Primary Site or Mechanism of Action
    • Inhibitors of carbonic anhydrase (primary site of action is proximal tubule)
    • Osmotic diuretics (primary site of action is loop of Henle)
    • Inhibitors of Na+-K+-2Cl- symport (primary site of action is thick ascending limb)
    • Inhibitors of Na+-Cl- symport (primary site of action is distal convoluted tubule)
    • Inhibitors of renal epithelial sodium channels (primary site of action is late distal tubule and collecting duct)
    • Antagonists of mineralocorticoid receptors (primary site of action is late distal tubule and collecting duct)
  • 15. Primary Site and Mechanism of Action of Diuretics
  • 16. Main Effects of Diuretics
  • 17.
    • These drugs decrease extracellular volume by interacting with a thiazide-sensitive Na-Cl cotransporter in the kidney, leading to a fall in cardiac output. However, the hypotensive effect is maintained during long-term therapy because of reduced vascular resistance; cardiac output returns to pretreatment values and extracellular volume returns almost to normal due to compensatory responses such as activation of the renin-angiotensin system.
    • Antihypertensive effects can be achieved in many patients with as little as 12.5 mg of chlorthalidone (HYGROTON) or hydrochlorothiazide (HYDRODIURIL) daily. Furthermore, when used as monotherapy, the maximal daily dose of thiazide-class diuretics usually should not exceed 25 mg of hydrochlorothiazide or chlorthalidone (or equivalent).
  • 18.
    • Most patients will respond to thiazide diuretics with a reduction in blood pressure within about 4 weeks, although a minority will not achieve maximum reduction in arterial pressure for up to 12 weeks on a given dose.
    • Therefore, doses should not be increased more often than every 4 to 6 weeks. There is no way to predict the antihypertensive response from the duration or severity of the hypertension in a given patient, although diuretics are unlikely to be effective as sole therapy in patients with stage 2 hypertension. Since the effect of thiazide diuretics is additive with that of other antihypertensive drugs, combination regimens that include these diuretics are common and rational. Diuretics also have the advantage of minimizing the retention of salt and water that is commonly caused by vasodilators and some sympatholytic drugs.
  • 19.  
  • 20. Beta blockers ( β Receptor Antagonists )
    • Antagonism of b adrenergic receptors affects the regulation of the circulation through a number of mechanisms, including a reduction in myocardial contractility, heart rate, and cardiac output.
    • An important consequence of using b adrenergic receptors is blockade of the b receptors of the juxtaglomerular complex, reducing renin secretion and thereby diminishing production of circulating angiotensin II. This action likely contributes to the antihypertensive action of this class of drugs, in concert with the cardiac effects. b
    • Adrenergic receptor antagonists may lower blood pressure by other mechanisms, including alteration of the control of the sympathetic nervous system at the level of the CNS, altered baroreceptor sensitivity, altered peripheral adrenergic neuron function, and increased prostacyclin biosynthesis.
  • 21. Pharmacological/Pharmacokinetic Properties of β Receptor Blocking Agents DRUG MEMBRANE STABILIZING ACTIVITY INTRINSIC AGONIST ACTIVITY LIPID SOLUBILITY EXTENT OF ABSORPTION (%) ORAL BIOAVAILABILITY (%) PLASMA t 1/2 (hours) PROTEIN BINDING (%) Classical non-selective β blockers: First generation Nadolol 0 0 Low 30 30-50 20-24 30 Penbutolol 0 + High ≈ 100 ~100 ~5 80-98 Pindolol + +++ Low >95 ~100 3-4 40 Propranolol ++ 0 High <90 30 3-5 90 Timolol 0 0 Low to Moderate 90 75 4 <10 β 1 -Selective β blockers: Second generation Acebutolol + + Low 90 20-60 3-4 26 Atenolol 0 0 Low 90 50-60 6-7 6-16 Bisoprolol 0 0 Low ≤ 90 80 9-12 ~30 Esmolol 0 0 Low NA NA 0.15 55 Metoprolol + * 0 Moderate ~100 40-50 3-7 12 Non-selective β blockers with additional actions: Third generation Carteolol 0 ++ Low 85 85 6 23-30 Carvedilol ++ 0 Moderate >90 ~30 7-10 98 Labetalol + + Low >90 ~33 3-4 ~50 β 1 -selective β blockers with additional actions: Third generation Betaxolol + 0 Moderate >90 ~80 15 50 Celiprolol 0 + Low ~74 30-70 5 4-5 * Detectable only at doses much greater than required for β blockade.
  • 22. Third-Generation β Receptor Antagonists with Additional Cardiovascular Actions: Proposed Mechanisms Contributing to Vasodilation Nitric Oxyde produc-tion β2 receptor agonism α1 receptor anta - gonism C a2+ entry blockade K + channel opening Antioxi - dant activity Nebivolol Celiprolol Carvedilol Carvedilol Tilisolol Carvedilol Celiprolol Carteolol Labetalol Betaxolol Bopindolol Bopindolol Nipradilol Bevantolol Nipradilol Bucindolol
  • 23. Adverse effects of beta blockers
    • D rugs should be avoided in patients with reactive airway disease (asthma) or with sinoatrial or atrioventricular (AV) nodal dysfunction or in combination with other drugs that inhibit AV conduction, such as verapamil . Patients with insulin-dependent diabetes also are better treated with other drugs. b Receptor antagonists without intrinsic sympathomimetic activity increase concentrations of triglycerides in plasma and lower those of HDL cholesterol without changing total cholesterol concentrations. b Adrenergic blocking agents with intrinsic sympathomimetic activity have little or no effect on blood lipids or increase HDL cholesterol. The long-term consequences of these effects are unknown. Sudden discontinuation of some b adrenergic blockers can produce a withdrawal syndrome that is likely due to up-regulation of b receptors during blockade, causing enhanced tissue sensitivity to endogenous catecholamines; this can exacerbate the symptoms of coronary artery disease. The result, especially in active patients, can be rebound hypertension. Thus, b adrenergic blockers should not be discontinued abruptly except under close observation; dosage should be tapered over 10 to 14 days prior to discontinuation. Nonsteroidal antiinflammatory drugs such as indomethacin can blunt the antihypertensive effect of propranolol and probably other b receptor antagonists. This effect may be related to inhibition of vascular synthesis of prostacyclin, as well as to retention of Na+
  • 24. Therapeutic uses
    • The b receptor antagonists provide effective therapy for all grades of hypertension. Despite marked differences in their pharmacokinetic properties, the antihypertensive effect of all the b blockers is of sufficient duration to permit once or twice daily administration. Populations that tend to have a lesser antihypertensive response to b-blocking agents include the elderly and African-Americans. However, intraindividual differences in antihypertensive efficacy are generally much larger than statistical evidence of differences between racial or age-related groups. Consequently, these observations should not discourage the use of these drugs in individual patients in groups reported to be less responsive. The b receptor antagonists do not usually cause retention of salt and water, and administration of a diuretic is not necessary to avoid edema or the development of tolerance. However, diuretics do have additive antihypertensive effects when combined with b blockers. The combination of a b receptor antagonist, a diuretic, and a vasodilator is effective for patients who require a third drug. b Adrenergic receptor antagonists are highly preferred drugs for hypertensive patients with conditions such as myocardial infarction, ischemic heart disease, or congestive heart failure.
  • 25. Ca 2+ entry blockers
    • Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes and sinoatrial (SA) and atrioventricular (AV) nodal cells in response to electrical depolarization. In both smooth muscle and cardiac myocytes, Ca2+ is a trigger for contraction, albeit by different mechanisms. Ca2+ channel antagonists, also called Ca 2+ entry blockers, inhibit Ca2+ channel function. In vascular smooth muscle, this leads to relaxation, especially in arterial beds. These drugs also may produce negative inotropic and chronotropic effects in the heart.
  • 26. Ca 2+ entry blockers
    • The basis for their use in hypertension comes from the understanding that hypertension is generally the result of increased peripheral vascular resistance. Since contraction of vascular smooth muscle is dependent on the free intracellular concentration of Ca2+, inhibition of transmembrane movement of Ca2+ through voltage-sensitive Ca2+ channels can decrease the total amount of Ca2+ that reaches intracellular sites. Ca2+-calmodulin-dependent activation of myosin light chain kinase, resulting in phosphorylation of myosin light chains, causes an increase in actin-myosin ATPase activity and contraction
  • 27. Ca 2+ entry blockers
    • Verapamil was the first clinically available calcium-channel blocker; it is a congener of papaverine . Many other calcium entry blockers with a wide range of structures are now available. The largest group, including amlodipine , felodipine , isradipine , and nifedipine , are termed dihydropyridines. Diltiazem is, with verapamil, the other non-dihydropyridine available clinically. Interestingly, these different structures lead to differences in their sites and modes of action on calcium entry for reasons that are not well understood.
  • 28.  
  • 29.  
  • 30. Classification of Ca 2+ blockers
    • I generation – verapamile, diltiazem, nifidipine
    • IIa generation – long-term forms of these drugs (slow release tabs, GITS, retard)
    • IIb generation – galopamile, clentiazem, isradipine, felodipine
    • III generation – amlodipine, lacidipine, lerkanydipine
  • 31. Ca 2+ entry blockers
    • Indeed, all of the Ca2+ channel blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing peripheral vascular resistance. As a consequence of a decrease in peripheral vascular resistance, the Ca2+ channel blockers evoke a baroreceptor-mediated sympathetic discharge. In the case of the dihydropyridines, tachycardia may occur from the adrenergic stimulation of the sinoatrial node; this response is generally quite modest except when the drug is administered rapidly. Tachycardia is typically minimal to absent with verapamil and diltiazem because of the direct negative chronotropic effect of these two drugs.
  • 32. Ca 2+ entry blockers
    • The profile of adverse reactions to the Ca2+ channel blockers varies among the drugs in this class. Patients receiving immediate-release capsules of nifedipine develop headache, flushing, dizziness, and peripheral edema. However, short-acting formulations of nifedipine are not appropriate in the long-term treatment of hypertension. Dizziness and flushing are much less of a problem with the sustained-release formulations and with the dihydropyridines having a long half-life and relatively constant concentrations of drug in plasma. The peripheral edema is not the result of generalized fluid retention; it most likely results from increased hydrostatic pressure in the lower extremities owing to precapillary dilation and reflex postcapillary constriction. Some other adverse effects of these drugs are due to actions in nonvascular smooth muscle. Contraction of the lower esophageal sphincter is inhibited by the Ca2+ channel blockers. For example, Ca2+ channel blockers can cause or aggravate gastroesophageal reflux. Constipation is a common side effect of verapamil, but it occurs less frequently with other Ca2+ channel blockers. Urinary retention is a rare adverse effect. Inhibition of sinoatrial node function by diltiazem and verapamil can lead to bradycardia and even sinoatrial node arrest, particularly in patients with sinoatrial node dysfunction.
  • 33. ACE-inhibitors
    • There is the pharmacokinetic classification of ACEI , which includes some classes (by Opie, 1997) :
    • Class I – lipophillic drugs : Captopril
    • Class II - ipophillic prodrugs :
    • group IIА – medications with kidney path of elimination (> 60%): Perindopril , Quinapril , Benazepril , Enalapril
    • group IIВ – medications with 2 ways of eliminatin : Moexipril , Ramipril , Fosinopril ;
    • group IIС – medications with hepatic path of elimination (> 60%): Trandolapril .
    • Class III – hydrophillic drugs : Lisinopril , Enalaprilat
  • 34.  
  • 35. Adverse Effects of ACE Inhibitors
    • Hypotension
    • Cough
    • Hyperkalemia
    • Acute Renal Failure
    • Fetopathic Potential
    • Skin Rash
    • Proteinuria
    • Angioedema
    • Neutropenia
    • Hepatotoxicity
  • 36.  
  • 37.  
  • 38.  
  • 39.  
  • 40.  
  • 41.  
  • 42. Antihypertensive drugs of different classes can be combined if:
    • they have different and complementary mechanisms of action.
    • there is evidence that the antihypertensive effect of the combination is greater than at of either combination component.
    • the combination may have a favourable tolerance profile, the complementary mechanisms of action of the components minimizing their individual side effects.
    • The following two-drug combinations have been found to be effective and well tolerated, and have been favourably used in randomized efficacy trials.
  • 43.  
  • 44. Thank You

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