1. THE THERAPY OF HYPERTENSION
(Anti-hypertensive drugs)
Dr. Fayhaa
Assistant professor of pharmacology

2. Definition Hypertension: is a multifactorial disease,
Characterized by elevated systolic &/ or diastolic arterial blood pressure above normal on repeated, reproducible measurements.

3. CLASSIFICATION OF BLOOD PRESSURE IN ADULTS
SBP (mmHg) DBP (mmHg) Normal < 120 < 80 Prehypertension Stage Stage 2 ≥ 160 ≥ 100

4. Classification
Essential hypertension: sustained, elevated blood pressure for which no cause is apparent.
Secondary hypertension: results from known disorder, such as renal and vascular disease.

5. MAP = CO × TPR

6. REGULATION OF Blood Pressure
Physiologically,in both normal and hypertensive individuals,blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance.

7. REGULATION OF Blood Pressure
Regulatory mechanisms:
Short-term control afforded by the sympathetic nervous system (Baroreflexes)
Long-term control, which is the function of the renal system (kidney)

8. Baroreflex
The baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms for maintaining blood pressure. It provides a negative feedback loop in which an elevated blood pressure reflexively causes heart rate to decrease and also causing blood pressure to decrease; likewise, decreased blood pressure activates the baroreflex, causing heart rate to increase, and also causing an increase in blood pressure.

9. Baroreflex

10. THE MANAGEMENT OF Hypertension
There are over 100 drug products that are available for the treatment of hypertension.
In addition to pharmacologic means to lower blood pressure, life-style modifications can also decrease blood pressure.

11. General Aims of Anti-hypertensive drug Therapy
The goal of therapy is not the reduction in blood pressure . Rather, it is to decrease the end organ damage and subsequent pathophysiology that occurs with sustained, untreated elevated blood pressure.

12. General Aims of Anti-hypertensive drug Therapy
Another goal of therapy is minimize the number of drugs prescribed as well as the times that drugs have to be taken.

13. Hypertension is a unique clinical problem because it is an asymptomatic disease. Therefore, therapy with antihypertensive drugs can cause a variety of unpleasant side effects which can reduce patient compliance.

14. The categories include the following
1. Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood volume.

15. 2. Sympathoplegic agents, which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels.

16. 3. Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well.

17. 4. Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance and blood volume.

18. Classification of Antihypertensive Drugs
Diuretics
—Thiazides
—Loop diuretics
—Potassium-sparing diuretics
Beta blockers
Alpha-beta blockers
Alpha1 receptor blockers.
ACE inhibitors
Calcium antagonists
Direct vasodilators

19. how drugs act:
Dilatation of arteriolar resistance vessels; the heart pumps against lower resistance (after load), with more rapid run-off of pressure.
Dilatation of venous capacitance vessels; reduced venous return to the heart (preload) leads to reduced cardiac output, especially in the upright position

20. how drugs act:
Reduction of cardiac contractility and rate leads to reduced output at lower pressure, especially in response to stress, e.g. upright posture, exercise
Depletion of body sodium reduces plasma volume (transiently), and reduces arteriolar response to norepinephrine.

21. how drugs act:
Inhibition of angiotensin II formation or action leads to vasodilatation.

23. Diuretics
The major diuretic class used in the long term treatment of hypertension are the thiazides. K+ sparing and loop diuretics can also be used.
Numerous clinical studies have shown these agents to decrease the risks of other cardiovascular diseases.
Diuretics lower blood pressure primarily by depleting body sodium
stores.

24. Mechanism of action
The diuretics reduce plasma volume by increasing Na+ and water excretion.
This effect lowers blood pressure by decreasing CO initially.

25. Mechanism of Action
The hypotensive effect persist because of a reduction in the peripheral resistance (electrolyte changes in vascular smooth muscle account for vasodilation).

27. Clinical Uses
Diuretics can be used as monotherapy for mild hypertension as well as in combination with other antihypertensives.

28. Side Effects Hyponatremia. Hypokalemia.
These agents increase uric acid levels,
and should be used carefully in individuals with gout.

29. increases in lipid and cholesterol levels.
Glucose intolerance and a reduction in the efficacy of oral hypoglycemic agents.
increases in lipid and cholesterol levels.

31. Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin (AT1)-Receptor Antagonists.
ACE inhibitors( Captopril, & Enalapril) and AT1- receptor antagonists (Losartan ) are first line agents for the treatment of hypertension.

32. Mechanism of action
The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexly increasing cardiac output, rate, or contractility.
These drugs block the ACE that cleaves angiotensin I to form the potent vasoconstrictor, angiotensin II .

33. These inhibitors also diminish the rate of bradykinin inactivation.
Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin.

35. Side Effects dry cough. Rashes. Fever. Altered taste or loss of taste.
Hypotension (in hypovolemic states) .
Hyperkalemia.

36. Angio­edema is a rare but potentially life-threatening reaction.
Non-inflammatory edema involving skin, subcutaneous tissue, underlying muscle & mucous membranes.
Occurs in response to allergen
Most critical in the larynx

38. ANGIOTENSIN II ANTAGONISTS (ARBs)
losartan , a highly selective, orally active, angiotensin II receptor blocker, has recently been approved for antihypertensive therapy.

39. Mechanism of Action They are selective inhibitors of the AT1 receptor.
Bind to the receptor and competitively inhibit the action of angiotensin II and IIІ.

40. Pharmacologic Effects
Its pharmacologic effects are similar to ACE inhibitors in that it produces vasodilation and blocks aldosterone secretion.

42. Calcium Channel Blockers
Calcium channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective.

43. Mechanism of Action
Calcium channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature.
This causes vascular smooth muscle to relax, dilating mainly arterioles.

44. Classes of calcium channel blockers
The calcium channel blockers are divided into :three chemical classes, each with different pharmacokinetic properties and clinical indications.
Benzothiazepines: Diltiazem
Diphenylalkylamines: Verapamil
Dihydropyridines: nifedipine , amlodipine, isradipine, nicardipine.

45. Pharmacologic Effects
Verapamil is the least selective of any calcium channel blocker, and has significant effects on both cardiac and vascular smooth-muscle cells.
It is used to treat angina, supraventricular tachyarrhythmia's, and migraine headache

46. Like verapamil, diltiazem affects both cardiac and vascular smooth-muscle cells.

47. All the dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart.
They are therefore particularly attractive in treating hypertension.

48. Clinical Uses
These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

49. Side Effects Headache. Flushing. Dizziness. Palpitations.
Hypotension may occur during the first few hours after dosing, as the plasma concentration is increasing, particularly if the initial dose is too high or increased too rapidly.

50. Ankle edema also develop
Ankle edema also develop. This is due to a rise in intracapillary pressure as a result of the selective vasodilatation by calcium blockers.
The edema is not a sign of Na+ retention. It is not therefore relieved by diuretics but disappears after lying flat (e.g. overnight).

51. Bradycardia and dysrhythmia may occur.
Gastrointestinal effects include constipation, nausea and vomiting; palpitation and lethargy may be felt.

54. Beta Blockers
Beta blockers are first line agents in the treatment of hypertension. These drugs have diverse effects on cardiovascular function and have a variety of cardiovascular and noncardiovascular uses.

55. Mechanism of Action
The β-blockers reduce blood pressure primarily by decreasing cardiac output .
They also block the release of renin (mediated by β1-receptors).

57. Classes of Beta Blockers
There are selective and nonselective beta blockers
The prototype β-blocker is propranolol, which acts at both β1- and β2 receptors.
Newer agents, such as atenolol and metoprolol, are selective for β1 receptors.

60. Therapeutic uses
Subsets of the hypertensive population: The β-blockers are more effective for treating hypertension in white than in black patients, and in young patients compared to the elderly.

61. Therapeutic uses
Hypertensive patients with concomitant diseases: The β-block­ers are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, glaucoma (applied topically), and migraine headache.

62. Side Effects
Common effects: The β -blockers may cause CNS side effects such as fatigue, lethargy, insomnia, and hallucinations; these drugs can also cause hypotension.
Alterations in serum lipid patterns: The β-blockers may disturb lipid metabolism, decreasing high-density lipoproteins (HDL) and increasing plasma triacylglycerol.

63. Side Effects
Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β-receptors.
Patients should be tapered off of β1-blocker therapy in order to avoid precipitation of arrhythmias.

64. Side Effects
The β-blockers should be avoided in treating patients with asthma, congestive heart failure, and peripheral vascular disease.

67. α -ADRENERGIC BLOCKING AGENTS
Prazosin, oxazosin and terazosin produce a competitive block of α1 adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle.

68. α -ADRENERGIC BLOCKING AGENTS
These drugs cause only minimal change in cardiac output, renal blood flow, and glomerular filtration rate.
Postural hypotension is the most common side effect.

70. Prazosin
Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects.
Reflex tachycardia and first dose syncope are almost universal adverse effects.

71. CENTRALLY-ACTING ADRENERGIC DRUGS
A. Clonidine:
This α 2-agonist diminishes central adrenergic outflow.

72. Clonidine is used primarily for the treatment of mild to moderate hypertension that has not responded adequately to treatment with diuretics alone.
Clonidine does not decrease renal blood flow or glomerular filtration and therefore is useful in the treatment of hypertension complicated by renal disease.

73. Side Effects
Adverse effects are generally mild, but the drug can produce sedation and drying of nasal mucosa.
Rebound hypertension occurs following abrupt with­drawal of clonidine.
The drug should therefore be withdrawn slowly if the clinician wishes to change agents.

74. B. α-Methyldopa
This α2-adrenergic agonist diminishes the adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure.
Cardiac output is not decreased and blood flow to vital organs is not diminished ( it is especially valuable in treating hypertensive patients with renal insufficiency ).

75. Side Effects
The most common side effects of α -methyldopa are sedation and drowsiness

76. VASODILATORS

77. . VASODILATORS
The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, have traditionally not been used as primary drugs to treat hypertension.

78. . VASODILATORS
Vasodilators act by producing relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure.
These agents produce reflex stimulation of the heart, resulting in the competing symptoms of increased myocardial contractil­ity, heart rate, and oxygen consumption.

79. A. Hydralazine
This drug causes direct vasodilatation, acting primarily on arteries and arterioles.
This results in a decreased peripheral resistance, which in turn prompts a reflex elevation in heart rate and cardiac output.

80. Clinical Uses
Hydralazine is used to treat moderately severe hypertension.

81. Clinical Uses
It is almost always administered in combination with a β-blocker such as propranolol (to balance the reflex tachycardia) and a diuretic (to decrease NA+ retention).
Together, the three drugs decrease cardiac output, plasma volume, and peripheral vas­cular resistance.

82. Side Effects
Adverse effects of hydralazine therapy include headache, nausea, sweating, arrhythmia, and precipitation of angina.
A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug.

83. B. Minoxidil
This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules).

84. B. Minoxidil
Minoxidil is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs.
Reflex tachycardia may be severe and may require the concomitant use of a diuretic and a β-blocker.

85. Side Effect
Minoxidil causes serious NA+ and water retention, leading to volume overload, edema, and congestive heart failure.
[Note: Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used topically to treat male pattern baldness.]

86. TREATMENT OF HYPERTENSIVE CRISIS
Hypertensive crisis is an elevation in blood pressure in which diastolic pressure exceeds 120 mmHg. In the presence of ongoing end-organ damage this is referred to as a hypertensive emergency. Without such complications, it is referred to as a hypertensive urgency.

87. TREATMENT OF HYPERTENSIVE CRISIS
Hypertensive emergencies require blood pressure to be reduced within a few hours.
The blood pressure in hypertensive urgencies can be lowered over a period of 1-2 days.
Intravenous medications are often used to treat these conditions.
Some agents are used

88. A. Sodium nitroprusside
Nitroprusside is administered intravenously, and causes prompt vasodilatation, with reflex tachycardia.
It is capable of reducing blood pressure in all patients, regardless of the cause of hypertension.

89. Notes
Nitroprusside is metabolized rapidly (t1/2 12 of minutes) and requires continuous infusion to maintain its hypotensive action.

90. Mechanism of Action
The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle.
[Note: Because nitroprusside also acts on the veins, it can reduce cardiac preload.]

91. Side Effect
Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose.

92. Side Effect
Nitroprusside metabolism results in cyanide ion production, although cyanide toxicity is rare and can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys .
[Note: Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.)

93. B. Diazoxide
Diazoxide is a direct-acting arteriolar vasodilator. It has vascular effects like those of hydralazine.
For patients with coronary insufficiency, diazoxide is administered intravenously with a β-blocker, which diminishes reflex activation of the heart.

94. Therapeutic Uses Diazoxide is useful in the treatment of:
hypertensive emergencies.
hypertensive encephalopathy.
eclampsia.

95. Side Effect
Excessive hypotension is the most serious toxicity.

96. C. Labetalol
Labetalol is both an α1- and β-blocker that has been successfully used in hypertensive emergencies.

97. C. Labetalol
Labetalol does not cause the reflex tachycardia that may be associated with diazoxide.
Labetalol carries the contraindications of a nonselective β-blocker.

99. Implications for Dentistry

100. Antihypertensive drugs are able to induce a series of adverse effects with the oral cavity:
patients can present oral manifestations in the form of xerostomia, lichenoid reactions,burning mouth sensation, loss of taste sensation or gingival hyperplasia, as well as extraoral manifestations such as sialadenosis.

101. Drug Interactions:
Certain nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, indomethacin or the naproxen, can interact with antihypertensive drugs (beta-blockers, diuretics,(ACEIs),thereby lowering their antihypertensiveaction. Normally more than five days of treatment with both types of drugs are required for interactions to manifest; as a result, NSAIDs should not be prescribed for longer than this five-day period.

102. Drug Interactions:
Aspirin & other NSAIDs antagonize the antihypertensive effect of ACE & diuretics, due to inhibition of prostaglandin synthesis.
Vasoconstrictor in local anesthesia )amount & type ) should be considered, especially in patient receiving propranolol

103. Notes:
the use of the aspiration technique to avoid intravascular injection can reduce the chance of vasoconstrictor adverse reactions.

104. Adverse Effects Xerostomia ( reserpine & the centrally Acting drug(.
Dysgeusia ( ACE ).
Gingival hyperplasia ( ca channel blocker).
Postural hypotension.

105. Thank you for your attention