Antihypertensive Drugs

Munir Gharaibeh, MD, PhD, MHPESchool of Medicine,

The University of JordanOctober, 2017

Antihypertensive Drugs

What is Hypertension?A common, incurable, persistent, but usually asymptomatic disease whose treatment provides no obvious benefit.

Why do we treat hypertension?

Introduction30% patients don’t know they have it.11% are not on therapy.25% are on inadequate therapy.34% are on adequate therapy.

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Average 14 readings: two per session, taken morning and evening for 7 days.Nov-17 4Munir Gharaibeh MD, PhD, MHPE

BP variationsIncreased BP variability is associated with

increased organ damage and cardiovascular morbidity.

“White Coat” or isolated office hypertension.Masked hypertension.Morning surge of BP.During Sleep: “Non dipping’ and “extreme dipping”.

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Benefits of Lowering BPAntihypertensive therapy has been

associated with:35% to 40% mean reduction in stroke incidence.20% to 25% reduction in myocardial infarction. More than 50% reduction in HF.

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Non-pharmacologic TreatmentLifestyle Modifications:ØWeight reduction ØDiet rich in potassium and calcium and

sodium reduction. ØDietary Approaches to Stop Hypertension

(DASH) eating plan( 1600-mg sodium) has effects similar to single drug therapy.

ØPhysical activity.

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Goals of TherapyMaximal protection against cardiovascular consequences with minimal bother to the patient.Stroke, coronary, and renal complications increase when BP is vigorously lowered (Why?)

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Determinants of Blood Pressure

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Sites of action of antihypertensive drugs.

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Sites of action of antihypertensive drugs.

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Hemodynamic Effects of Antihypertensive Drugs

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Diuretics (Saluretics)Widely recommended as first-line therapy, especially in the elderly, the obese, and black patients.Better at reducing coronary heart disease, HF, stroke, and mortality.Inexpensive.Combine well with others.Lower doses, with sodium restriction, cause fewer metabolic side effects, but retain antihypertensive activity.All have same efficacy in lowering BP, although not same diuretic activity.

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Diuretics (Saluretics)Early Effects (3-4 days): – Diuresis lowers blood volume and cardiac

output.– Mainly affects the systolic BP.

Late Effects (3-4 weeks):– Decreased Na+ & Cl-, lowers blood vessel

contractility. Appear even with low doses.Increase Plasma ReninSide Effects: metabolic side effects, ++++

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Diuretics (Saluretics)Thiazide diuretics:Effective in mild and moderate Ht with normal renal and heart function.– Hydrochlorthiazide.– Chlorthalidone: long acting.– Bendrofluazide.– Indapamide: vasodilating and lipid neutral. Also

induces regression of LVH

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Diuretics (Saluretics)Loop Diuretics:Needed in severe Ht, in renal insufficiency, and in heart failure or cirrhosis.– Furosemide: not ideal , short acting.– Torsemide: free of metabolic side effects.

Potassium- sparing diuretics:Useful in heart failure.– Spironolactone:– Eplerenone.– Ameloride.– TriamtereneNov-17 22Munir Gharaibeh MD, PhD, MHPE

VASODILATORSWork directly on arterial blood vessels, or veins.Actions not antagonized by known blockers.Reduce peripheral resistance, which will elicit compensatory mechanisms leading to tolerance, resistance or pseudoresistance.Usually other drugs are combined with vasodilators to avoid this problem.

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Compensatory responses to vasodilators

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VASODILATORSHydralazine:

Oldest vasodilator(1950s), was withdrawn and then came back.Arteriolar dilator, works by release of NO.Tachyphylaxis (Tolerance or Peusdoresistance).

Activates baroreceptor reflex.Metabolized by acetylation.Drug-induced lupus syndrome.Other side effects.Replaced by CCBs.Used in heart failure, combined with isosorbidedinitrateNov-17 26Munir Gharaibeh MD, PhD, MHPE

VASODILATORSDiazoxide:

Thiazide derivative, but not a diuretic.Potent arterial dilator, works by opening potassium channels.Causes excessive hypotension.Used in emergencies by rapid I.V. bolus injection.Rapidly bound to albumin.Onset 10-30 seconds.Duration 2-4 hours.Does not require constant monitoring.

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VASODILATORSSodium Nitroprusside:

Cyanide-containing molecule.Useful in emergencies, surgery and heart failure.Relaxes both arterial and venous smooth muscle, works by release of NO.No excessive reflex increase in cardiac output.Might increase C.O. if there is failure.

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VASODILATORSSodium Nitroprusside:

Short half life.Action is immediate, requires constant monitoring in ICU. Drug is light sensitive.Thiocyanate levels and acid-base balance: weakness, nausea, tinnitus, flushing, lactic acidosis and anoxia.

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VASODILATORSMinoxidil:

K+ channel-opener: increases efflux leading to hyperpolarization.Prolonged arterial relaxation.Superior to hydralazine.For severe intractable hypertension, or renal insufficiency, usually in combination with a diuretic and β blocker.Hypertrichosis, so useful for baldness.Pericarditis.

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VASODILATORSFenoldopam:

Dopamine D1 agonist, which results in vasodilation, renal vessel dilation, and natriuresis.Rapidly metabolized, short acting.Used by continuous infusion in emergencies or postoperatively.

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Calcium Channel BlockersMore effective than others in protection

against stroke.Primarily act to reduce PVR, aided by at least

an initial diuretic effect, especially with the short-acting DHPs.

Effective in the elderly.Equally effective in blacks and nonblacks.Cause no metabolic disturbances

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Calcium Channel BlockersPVR HR CO

Nifedipine - - - +++ ++(Reflexly)

Diltiazem - - - -

Verapamil - - - - --

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Angiotensin - Converting Enzyme Inhibitors(ACEI)

Angiotensin II:Potent vasoconstrictor by itself.Facilitates release of NE.Central actions to increase BP.Promotes release of aldosterone.Regulates tubular function.Regulates intra-renal blood flow.

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Angiotensin - Converting Enzyme Inhibitors(ACEI)

Inhibit ACE in the lungs.Also inhibit kinin metabolism.

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Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system.

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Angiotensin - Converting Enzyme Inhibitors(ACEI)

Captopril --------------Prototype.EnalaprilQuinaprilLisinopril.BenazeprilFosonopril

All are similarly effective Might differ in toxicityNov-17 39Munir Gharaibeh MD, PhD, MHPE

Angiotensin - Converting Enzyme Inhibitors(ACEI)

Therapeutic Benefits:Effective in high-rennin hypertension (20%), HF and

Ischemic Heart Disease.Do not increase HR.Useful in diabetic nephropathy by dilating efferent arterioles thus reducing intraglomerular pressure and consequently protects against progressive glomerulosclerosis.No need for a diuretic but a diuretic can be added.Can be combined with CCBs.Should not be combined with Beta blockers. No metabolic effects.

* Contraindicated in pregnancy and bilateral renal artery stenosis.Nov-17 40Munir Gharaibeh MD, PhD, MHPE

Angiotensin - Converting Enzyme Inhibitors(ACEI)

Side Effects:Captopril is SH containing drug, so very toxic(

bone marrow suppression, disguesia, proteinuria, allergic skin rash, fever) Hypotension( First Dose Phenomena) especially with renovascular hypertension.K+ retention, especially in the presence of renal dysfunction or when combined with K+ sparing diuretics or ARBs. Cough(10% of patients).Angioedema.

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Angiotensin II Receptor Blockers (AT-1)Result in more complete inhibition of angiotensin actions (Chymase ?) with no effects on bradykinins.May be only indicated when ACEI are intolerable.Most expensive, but fastest growing class of antihypertensive drugs.Free of side effects, especially cough.May be better than ACEI in protection against stroke (activation of AT-2 receptor facilitates collateral vessels and neuronal resistance).

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Angiotensin II Receptor Blockers (AT-1)

Losartan.Valsartan.Candesartan.Irbesartan.Telmisartan ( additional peroxisome proliferator- activated receptor-g agonist activity).Eprosartan.

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ChymaseLong-term treatment with ACE inhibitors is often associated with so-called “angiotensin escape,” characterized by the return of plasma angiotensin II concentration to pretreatment levels (although the beneficial effects on blood pressure usually persist).This rebound generation of angiotensin II occurs through the action of the serine proteases such as chymase and cathepsinG.

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ChymaseVascular chymase has been implicated in the ACE-independent mechanism for local angiotensin II formation in human arteries.ACE-independent generation of angiotensin II plays a central role in the regulation of renal hemodynamics during the progression of diabetic nephropathy.

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ChymaseThe physiologic importance of

chymase is uncertain, because of the presence of natural protease inhibitors in the interstitial fluid which inhibit chymase-induced angiotensin II production.

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Renin Enzyme Inhibitors

Aliskiren:– The first in the group. – Other better studied medications

are typically recommended due to concerns of higher side effects and less evidence of benefit.

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Sympatholytics or Adrenergic Blockers

Alpha Adrenergic Antagonists– Non selective Antagonists– a1 -Selective Antagonists.

Beta Adrenergic BlockersAdrenergic Neurone Blockers.Ganglionic Blockers

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Non selective Alpha Adrenergic Antagonist

Phentolamine Phenoxybenzamine– Block both a1 and a2 receptors, so cause reflex

tachycardia and increased contractility. – Blockade of α 2-presynaptic receptors leads to

augmented release of NE leading to tachycardia and increased contractility of the heart.

– Used only for pheochromocytoma.

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a1 -selective Alpha Adrenergic AntagonistsPrazosinTerazocinDoxazosin

Selective (α 1 > α 2) blockers will lower the BP but will not cause tachycardia.First - Dose Phenomenon.All are free of metabolic effects, but can cause drowsiness, diarrhea, postural hypotension, tachycardia, and tolerance due to fluid retention.Effective in moderate hypertension as well as benign prostatic hypertrophy. 51Munir Gharaibeh MD, PhD, MHPE

Beta Adrenergic BlockersAntihypertensive Mechanisms:

1. Decrease HR, SV, and consequently C.O.2. Decrease Rennin Release3. Central Action in the vasomotor center.4. Inhibit NE release

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Beta Adrenergic BlockersPreparations: 30

Propranolol: Prototype,1957 Timolol LipophilicNadolol Long actingPindolol ISAAcebutelol ISAEsmolol Short half lifeMetoprolol β1 selectiveAtenolol β1 selective.Betaxolol β1 selective.Bisoprolol β1 selective.Nov-17 53Munir Gharaibeh MD, PhD, MHPE

Beta Adrenergic BlockersTherapeutic Effectiveness:

Effect not immediate.Useful in high - rennin hypertensionCombination or monotherapyHyperkinetic heartsUsed in other cardiovascular conditionsIneffective in blacksNo postural hypotension

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Beta Adrenergic BlockersSide Effects:

Bronchospasm , especially with the non selectiveHeart Failure?CNS: fatigue, depression, impotence ..etcImpair lipid and glucose metabolism Mask hypoglycemia !!!Claudication, due to α receptor overactivity.Withdrawal Syndrome

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Vasodilating Beta Adrenergic BlockersLabetalol: – b, a1 (20% of b) antagonist & b2 partial agonist.– Useful for pheochromocytoma and

emergencies.

Carvedilol:– b, a1 (10% of b) antagonist.

Esmolol:– b1 selective, rapidly metabolized.– Used by continuous IV infusion.

Nebivolol– b1 selective and nitric oxide-potentiating vasodilatory

effect.Nov-17 56Munir Gharaibeh MD, PhD, MHPE

Adrenergic Neurone BlockersGuanethidineBethanedineDebrisoquinGuanadrel

Hydrophilic.Uptake 1.Block NE release. Displace NE from vesicles ------- MAO.Cause depletion of NE.

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Life Cycle of Norepinephrine

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Adrenergic Neurone BlockersReserpine (Rauwolfia Alkaloids):

LipophilicBinds to the sympathetic vesicles.Prevents DA uptake into vesicles.Amines are metabolized by MAO.Depletes: NE, 5HT, ACTH, DA.Old fashioned, slow onset and offset, very cheap.

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Ganglionic Blockers

TrimethaphanPentoliniumMecamylamineBlock transmission in both symp & parasypathetic systems.Act immediately and are very efficacious.Effect rapidly reversed, so used for short term control of BP, e.g. intraoperatively or emergency.Many side effects.Nov-17 60Munir Gharaibeh MD, PhD, MHPE

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Centrally Acting Antihypertensive DrugsVasomotor Center:

a Receptor activation decreases BPb Receptor activation increases BP

Nucleus Tractus SolitariusNucleus AmbiguusRostral Ventral Medulla

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Autonomic and hormonal control of cardiovascular function

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Centrally Acting Antihypertensive DrugsCommon Properties:

Cross BBB.Reduce preganglionic sympathetic activity. Orthostasis is unusual, due to preservation of peripheral sympathetic activity.CNS side effects.

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Centrally Acting Antihypertensive Drugs1. Propranolol2. Reserpine.3. a- Methyl Dopa:

Old drug, thought to work by forming a pseudo transmitter which works peripherally.

Central a agonist.a MD-------- a MDA -------- a MNE.Lowers BP but not CO or renal blood flow.Can cause lactation and positive Coomb’s test.Safe in pregnancy.

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Centrally Acting Antihypertensive Drugs4. Clonidine:

Imidazoline derivative, tried initially as a nasal decongestant.Central a agonist.I.V: Biphasic Effect: peripheral then central actions. Oral. Transdermal Patch(7 days).

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Causes of Resistant HypertensionImproper BP measurement.“White Coat Hypertension”.Noncompliance.Psychological stresses, secondary hypertension, sleep disordersVolume overload and pseudotolerance. Excess sodium intake Volume retention from kidney disease.Inadequate diuretic therapy.

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Causes of Resistant Hypertension

Inadequate doses. Inappropriate combinations .NSAID; cyclooxygenase 2 inhibitors. Cocaine, amphetamines, other illicit drugs. Sympathomimetics, e.g. decongestants, anorectics

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Causes of Resistant Hypertension

Oral contraceptives Corticosteroids Cyclosporine Erythropoietin Licorice (including some chewing tobacco). Excess alcohol intake.

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