Drugs for The Treatment of Hypertension pptx - D. Tahsin

Drugs for The Treatment of Hypertension (HT)

Hypertension: Definition & Overview

BP ≥ 140 mm Hg Systolic &/or 90 mm Hg diastolic
Very common, especially in older people
Incidence rising worldwide
Major cause of morbidity and mortality
Main complications are stroke, ischemic heart disease, renal failure and congestive heart failure
Effective treatment leads to significant reduction of complications, improve survival and quality of life
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HT: Physics, Physiology, & Pathophysiology

BP= Cardiac output (CO) x peripheral resistance (PR)
CO= Heart rate (HR) x stroke volume (SV)
SV α venous return (VR) & contractility
VR α blood volume & venous tone
PR α arteriolar tone
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HT: Physics, Physiology, & Pathophysiology

Regulation of BP:
Baro-receptors: acute settings
Renin-angiotensin-aldosterone system (RAAS): intermediate term settings
Renal regulation of BP: long term
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Baroreceptors

Involved in rapid control of BP
Mediated through stretch sensitive receptors in the carotid sinus and aortic arch
BP leads to reduced stretching of the receptors…
Fewer impulses to the vasomotor centers in the brainstem
Reduced parasympathetic drive and increased sympathetic drive
Peripheral vasoconstriction, tachycardia, increased LV contractility
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Renin-Angiotensin-Aldosterone system (RAAS)

Renin is released from the JG apparatus
β1 sympathetic stimulation
Reduced afferent arteriolar stretching (in hypotension)
Reduced tubular Na+ and water load (macula densa)
Activates angiotensinogen (AT) into AT I, which is activated to AT II by angiotensin-converting enz. (ACE)
AT II has many actions that raise BP

Actions of AT II to Raise BP

Central activation of the sympathetic NS
Stimulates catecholamine release from the adrenal medulla
Stimulates the degranulation of sympathetic nerve endings
Direct vasoconstrictor action: arteriolar ( PR) & venous
( venous return)
Stimulates the release of aldosterone from the adrenal cortex: enhance sodium reabsorption from DCT
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Actions of AT II to Raise BP

Direct constrictor effect on the efferent arteriole in the glomeruli:
Increase filtration pressure and filtration fraction
Reduce hydrostatic pressure and increase oncotic pressure in the medullary arterioles
Net increase of volume reabsorption, increased blood volume and BP

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BP Manipulation
Targeting the various components of the regulatory process of BP, i.e:

Reducing plasma volume, venous return, CO, HR, LV contractility, PR

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Pharmacological BP Manipulation

Drugs modifying the
sympathetic nervous system
RAAS
HR, contractility
Peripheral resistance
Venous tone and venous return
Blood volume

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Classes of Anti-HT Medications

Diuretics
β- adrenergic blockers
Angiotensin converting enzyme inhibitors (ACE I)
Angiotensin receptor blockers (ARBs)
Calcium channel blockers
α- receptor blockers
Combined α- and β- blockers
Centrally acting drugs
Emergency treatment
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Diuretics

Thiazide diuretics

Loop diuretics

K+ sparing diuretics
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Thiazide Diuretics

Chlorthiazide, hydrochlorthiazide, chlorthalidone, metolazone
Initial action:
Diuresis: increase Na+ and water excretion in distal convoluted tubules
Reduction of plasma volume
Reduction of venous return
Reduce cardiac output
Reduction of renal blood flow
Later on: restoration of plasma volume, but a hypotensive effect persists due to reduction of vasomotor tone & periph. resistance
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Thiazide Diuretics: Side Effects (SE)
Hypokalemia
Hyperglycemia
Hyperuricemia
Fatigue
Agranulocytosis
NOT useful in renal failure (GFR ≤30 ml/min) except metolazone
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Loop Diuretics

Furosemide, bumetanide, ethacrynic acid, torsemide
Most potent diuretic action: Block Na+ and water reabsorption in ascending limb of loop of Henle
Increase renal blood flow (≠ thiazides)
Usually used in combination with other drugs
SE: K+, Ca++, Mg++; urine Ca++(≠ thiazides)

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K+ Sparing Diuretics

Aldosterone antagonists: Spironolactone, eplerinone
DCT inhibitors: amiloride, triamterene
Potentiate the effect of other classes of diuretics
May cause hyperkalemia if used in combination with ACE I or ARBs
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Classes of Anti-HT Medications
Diuretics
β- adrenergic blockers
Angiotensin converting enzyme inhibitors (ACE I)
Angiotensin receptor blockers (ARBs)
Calcium channel blockers
α- receptor blockers
Combined α- and β- blockers
Centrally acting drugs
Emergency treatment
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β- Adrenergic Blockers

Non cardioselective: block β1 (heart, kidney) and β2 receptors (arteries, bronchi), e.g. propranolol, nadolol

Cardioselective: only block β1 receptors: e.g. atenolol, metoprolol, bisoprolol: have little effect on bronchial and peripheral arterial tone

Reduce BP by reducing C.O. and PR

β-Blockers: Pharmacokinetics

Orally active: propranolol has individual variation of first pass liver metabolism, so effective dose can vary from patient to patient
Intravenous preparations: propranolol, metoprolol, atenolol, and esmolol
Most are metabolized in the liver
Hydrophilic preparations (e.g. atenolol) are metabolized in the kidneys. They don’t cross the blood-brain barrier (no CNS S.E)

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β-Blockers: Side Effects

Brady cardia: avoided in patients with heart block
Impaired LV contractility: avoided in patients with decompensated heart failure. However, some are the agents of choice in chronic heart failure
Peripheral vasoconstriction: more with the non-selective agents. Should be avoided in critical limb ischemia
Worsening of asthma: especially for non selective β blockers. Selective ones may be used cautiously in asthmatic patients

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β-Blockers: Side Effects

Other non cardiovascular SEs:
insomnia with lipid soluble agents,
nightmares,
erectile dysfunction and reduced libido

Disturbance of lipid metabolism: non cardioselective agents:
HDL

triglycerides

β-Blockers: Side Effects

Abrupt withdrawal in patients with IHD may cause worsening of angina, precipitate acute MI, or even sudden death

Therefore, should be withdrawn gradually (tapered) over a period of several weeks in patients with HT & IHD
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Classes of Anti-HT Medications

Angiotensin Converting Enzyme Inhibitors (ACE Is)
Captopril, enalapril, lisinopril, ramipril, fosinopril
Reduce BP by inhibiting the activation of AT II
Impair degradation of bradykinin, causing its level, NO and prostacyclin, which are vasodilators
Lower aldosterone level, salt and water reabsorption from DCT
Prevent efferent arteriolar constriction: intra-glomerular pressure
Reduce vasomotor tone, afterload without CO

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ACEI: Pharmacokinetics

All ACEIs are orally bioavailable
Captopril and lisinopril are active drugs.
All other ACEIs are prodrugs, i.e. converted by the liver to an active metabolite
Fosinopril is the only drug that is not excreted by the kidneys, so doesn’t need dose modification in CKD
Enalaprilat is an intravenous preparation
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ACEIs: Clinical Use

HT, HT due to unilateral renal artery stenosis
Drugs of choice in HT patients with renal impairment
Reversal of LV hypertrophy (LVH)
Control of proteinuria in diabetic nephropathy

ACEIs: Clinical Use

Treatment of acute and chronic ischemic heart disease, & atherosclerosis
Reversal of LV remodeling after acute myocardial infarction
Standard therapy in all causes of systolic heart failure
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ACEIs: SE

Dry cough: bradykinin in the lung
Skin rash
Fever
Altered taste
Hyperkalemia: caution should be exercised when combining with K+ sparing diuretics or K+ supplements
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ACEIs: SE

Renal impairment: monitor S.K+
Contra-indicated in bilateral renal artery stenosis (why?)
Angioedema: rare but serious: also due to high bradykinin levels
Teratogenic effects: should be avoided in pregnancy!

Classes of Anti-HT Medications

Angiotensin Receptor Blockers (ARBs)

Losartan, valsartan, telmisartan, irbisartan, candisartan
Block the AT receptor type 1
Same action as ACEIs:
reduce sympathetic tone: vasodilatation
reduce peripheral resistance
Inhibit aldosterone release
Renal efferent arteriolar dilatation

≠ ACEIs: they don’t inhibit bradykinin metabolism
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Angiotensin Receptor Blockers (ARBs)

SE: similar to ACEIs, except that cough is much less frequent (why?)

Should not be combined with ACEIs: ineffective combination and more incidence of hyperkalemia

Teratogenic effect: avoid in pregnancy!

Renin Antagonist

Aliskerin
Not widely used
Equivalent anti-HT effect to ACEIs & ARBs
May cause dry cough and angioedema (= ACEI)
Other S.E: diarrhea
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Classes of Anti-HT Medications

Calcium Channel Blockers (CCBs)
Dihydropyridines: nifedipine, amlodipine, felodipine, nicardipine, isradipine
Diphenylalkylamine group: verapamil
Benzothiazipine group: diltiazem
Generally divided into dihydropyridines and non-dihydropyridines
Have different tissue affinity, different actions, and different SE profile
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CCBs: Mechanism of Action

Voltage sensitive Ca++ channels in excitable tissue (cardiac muscle and vascular smooth muscles)
When stimulated, Ca++ influx into the cell causes augmented release of Ca++ from sarcoplasmic reticulum and mitochondria
Ca++ release causes contraction of cardiac muscle ( contra-ctility) and vasoconstriction ( PR), i.e. increased BP
CCBs inhibit this Ca++ mediated effect & lower BP
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Not All CCBs Are Created Equal!

Dihydropyridines (DHPs) act mainly on vascular SM cells:
Relaxation and reduced vasomotor tone.
Little effect on heart rate

Non dihydropyridines act mainly on cardiac conductive system and myocardial cells:

Bradycardia
Negative inotropic state ( contractility)

Group difference in SE profile
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Pharmacokinetics of CCBs

All have short plasma half life except amlodipine

Therefore, sustained release preparations are used

SE of CCBs: Dihydropyridines

Headache
Flushing
Edema
Dizziness
Gingival hypertrophy
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SE of CCBs: Non-dihydropyridines

Bradycardia
Atrio-ventricular block
Worsening of heart failure (contraindicated in any condition with impaired LV function, ≠ β-blockers)
constipation
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α- Adrenergic Blockers

Prazocin, terazocin, doxazocin
Block the α-1 receptors in arterial and venous smooth muscles
Vasodilatation without alteration of CO or renal blood flow
Initial effect: tachycardia and postural hypotension
Later: SE disappear
Low efficacy: so no longer used as standard therapy for HT,
May be used for refractory cases with conjunction with other anti-HT drugs
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Combined α- & β-Adrenergic Blockers

Carvedilol, labetalol
α, β1, and β2 receptor blockers
Carvedilol: main use is in systolic HF, where it has been shown to improve outcome, preserve LV function and reduce mortality (other β blockers in this respect include bisoprolol and metoprolol)
Labetalolo: main use is in gestational HT and hypertensive emergencies
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Classes of Anti-HT Medications

Centrally Acting Antihypertensive Drugs
Clonidine and α-methyl dopa
Clonidine: acts by stimulating central α2 sympathetic receptors in the vasomotor centers in the CNS
This stimulation results in inhibition of the peripheral sympathetic tone
Reduction in PR without any effect on the kidneys
Low efficacy drug: used as a adjunctive therapy if other drugs fail to control BP

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Centrally Acting Antihypertensive Drugs: Clonidine

Available in oral and transdermal forms
Well absorbed via the oral route
SE: sedation, constipation, and dry mouth
Abrupt cessation leads to rebound increase of BP (sudden increase to more than pre-treatment levels)
Rarely used clinically

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Centrally Acting Antihypertensive Drugs: α-methyl dopa

Central stimulation of sympathetic α-2 receptors
Converted in the CNS into methylnorepinephrine
Reduce central sympathetic flow
Safe in pregnancy
S.E: drowsiness, depression, SLE like syndrome
Requires frequent dosing (2-3 times/day)
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Peripheral Vasodilators
Hydralazine, Minoxidil
Direct arterial and arteriolar smooth muscle relaxation
Reduce peripheral resistance
Over-compensated by reflex tachycardia and enhanced LV contractility
Increase myocardial oxygen consumption
May precipitate angina, MI, and heart failure
Also: increase plasma renin concentration (≠ DHPs): Na+ retention & edema

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Peripheral Vasodilators: Hydralazine

Used mainly in pregnancy-induced HT
Injectable form used in HT emergencies
Otherwise, used in combination therapy:
Reflex tachycardia offset by a β-blocker
Fluid retention counterbalanced by a diuretic
S.E: headache, tachycardia, angina, nausea, sweating, arrhythmia,
Also: SLE-like syndrome

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Peripheral Vasodilators: Minoxidil
No longer used due to low efficacy and cardiac S.E
(Useful) SE: hirsutism
Major current use: to stimulate hair growth in androgenic alopecia as a topical preparation(!)
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Emergency Treatment of Hypertension

Rarely effective or necessary
Rapid lowering of BP may cause CNS catastrophes (stroke):
The phenomenon of autoregulation
Situations requiring rapid control of pressure, e.g. aortic dissection, unstable angina, STEMI, HT encephalopathy, toxemia of pregnancy

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Emergency Treatment of Hypertension

Intravenous forms
Sodium nitroprusside:
instantaneous titration of the drug according to BP
SE: methemoglobinemia
Glyceryl trinitrate:
arterial and venous dilator
Main use: Acute coronary syndrome (ACS)
Isosorbide mononitrate:
Arterial dilator

Emergency Treatment of Hypertension

Labetalol:
Combined α- & β- blocker
Intravenous Ca++ blockers: nicardipine
Hydralazine: i.v or i.m
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