Transcript and β- blockers

Drugs for The Treatment of
Hypertension (HT)
1
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
2
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
7
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
8
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
9
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
14
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
17
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
18
Thiazide Diuretics: Side Effects (SE)
• Hypokalemia
• Hyperglycemia
• Hyperuricemia
• Fatigue
• Agranulocytosis
• NOT useful in renal failure (GFR ≤30 ml/min)
except metolazone
19
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)
20
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
21
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
22
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
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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)
25
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
26
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
27
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
28
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
29
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
32
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
33
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
34
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
35
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!
36
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
37
Angiotensin Receptor Blockers (ARBs)
38
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
39
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!
40
Renin Antagonist
• Aliskerin
• Not widely used
• Equivalent anti-HT effect to ACEIs & ARBs
• May cause dry cough and angioedema (= ACEI)
• Other S.E: diarrhea
41
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
42
Calcium Channel Blockers (CCBs)
• Dihydropyridines: nifedipine, amlodipine, felodipine,
nicardipine, isradipine
• Diphenylalkylamine group: verapamil
• Benzothiazipine group: diltiazem
• Generally divided into dihydropyridines and nondihydropyridines
• Have different tissue affinity, different actions, and different
SE profile
43
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 ( contractility) and vasoconstriction ( PR), i.e. increased BP
• CCBs inhibit this Ca++ mediated effect & lower BP
44
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
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SE of CCBs: Dihydropyridines
• Headache
• Flushing
• Edema
• Dizziness
• Gingival hypertrophy
48
SE of CCBs: Non-dihydropyridines
• Bradycardia
• Atrio-ventricular block
• Worsening of heart failure (contraindicated in
any condition with impaired LV function, ≠ βblockers)
• constipation
49
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
50
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 antiHT drugs
51
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
52
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
53
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
54
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
55
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
56
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)
57
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
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Emergency Treatment of Hypertension
• Labetalol:
• Combined α- & β- blocker
• Intravenous Ca++ blockers: nicardipine
• Hydralazine: i.v or i.m
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