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Antihypertensive Drugs. Hypertension. Hypertension is not a disease It is an arbitrarily defined disorder to which both environmental and genetic factors contribute Major risk factor for: cerebrovascular disease myocardial infarction heart failure peripheral vascular disease

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Antihypertensive Drugs

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Antihypertensive drugs l.jpg

Antihypertensive Drugs


Hypertension l.jpg

Hypertension

  • Hypertension is not a disease

  • It is an arbitrarily defined disorder to which both environmental and genetic factors contribute

  • Major risk factor for:

    • cerebrovascular disease

    • myocardial infarction

    • heart failure

    • peripheral vascular disease

    • renal failure


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Definition

  • Elevation of arterial blood pressure above 140/90 mm Hg. Can be caused by:

    • an underlying disease process:In 5-10% a cause can be found

  • (secondary hypertension)

    • Renal artery stenosis

    • Hyperaldosteronism

    • pheochromocytoma

  • idiopathic process (primary or essential hypertension) In 95% of cases


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The left ventricle is markedly thickened in this patient with severe hypertension that was untreated for many years. The myocardial fibers have undergone hypertrophy.


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This left ventricle is very thickened (slightly over 2 cm in thickness), but the rest of the heart is not greatly enlarged. This is typical for hypertensive heart disease. The hypertension creates a greater pressure load on the heart to induce the hypertrophy.


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Major Risk Factors That Increase Mortality in Hypertension

  • Smoking

  • Dyslipidemias

  • Diabetes Mellitus

  • Age >60

  • Gender: men, postmenopausal women

  • Family history


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Prevalence

  • The hypertension prevalence in the big cities, small to medium cities and class 1 to class 4 rural areas in China was 20.4%, 18.8%, 21.0%, 19.0%, 20.2% and 12.6% respectively

  • Pakistan (NHSP):the prevalence of hypertension is 17.9%

  • 24% of the USA adult population representing 43,186,000 persons had hypertension.


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Diagnosis

  • Diagnosis is generally based on repeated, reproducible measurements of elevated blood pressure and not on patient symptoms. Patient compliance is a major obstacle to therapy


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Stage

Diastolic Range (mm Hg)

Systolic Range (mm Hg)

High Normal

85-89

130-139

Stage 1

90-99

140-159

Stage 2

100-109

160-179

Stage 3

> 109

>179

Stages of Hypertension


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Treatment Rationale

Long-term goal of antihypertensive therapy:

Reduce mortality due to hypertension-induced disease

  • Stroke

  • Congestive heart failure

  • Coronary artery disease

  • Nephropathy

  • Peripheral artery disease

  • Retinopathy


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Ways of Lowering Blood Pressure

  • Reduce cardiac output (ß-blockers, Ca2+ channel blockers)

  • Reduce plasma volume (diuretics)

  • Reduce peripheral vascular resistance (vasodilators)

MAP = CO X TPR


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"Individualized Care"

  • Risk factors considered

  • Monotherapy is instituted

  • Non pharmacological therapy tried first

  • Considerations for choice of initial monotherapy:

    • Renin status

    • Coexisting cardiovascular conditions

    • Other conditions


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Homeostasis of Blood Pressure


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Determinants of arterial pressure

Blood pressure is controlled by an integrated system

  • Prime contributors to blood pressure are:

    • Cardiac output

      • Stroke volume

      • Heart rate

    • Peripheral vascular resistance

      AP = CO x TPR

  • Each of these factors can be manipulated by drug therapy

    Treatment of hypertension seeks to lower CO and/or TPR.


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For Short-Term Neural Control

Baroreceptor reflex

Sit or stand up quickly, BP fallsneural responses reestablish normal BP or Sudden increase in stroke volume, BP rises, neural responses reestablish normal BP


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Figure 15-22


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Sympathetic nervous control


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Long-term Renal Control of BP: Direct

Pressure Diuresis

Blood volume too high, RenalSympathetic vasoconstriction reducedMore fluid enters kidney, more urine formed Lowers BP via lower blood volume

Blood pressure too low, Renal

Sympathetic vasoconstriction risesLess fluid enters kidney, less urine formedRaises BP by higher blood volume


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Figure 15-9


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Renal Control of BP: Indirect

If BP too low, increase BP by increasing __________

Kidney cells secrete _______Converts angiotensinogen to angiotensin I_______________________in lung converts angiotensin I to angiotensin II….


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Renin-angiotensin system


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Summary of Long Term Renal Control of BP

Regulates BP by Changing:

1.

Directly – by allowing more or less fluid

to enter kidney tubules

Indirectly – Reabsorbing more fluid that

was already destined to be urine

2.

Vasoconstriction / vasodilation


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MAJOR ANTIHYPERTENSIVE DRUGS

1) Diuretics

- Thiazides and congeners.

- Loop diuretics.

- Potassium-sparing diuretics.

2) Sympatholytic drugs

- Centrally acting antiadrenergic agents.

- Adrenergic neuron blocking agents.

- Alpha adrenergic blockers.

- Beta adrenergic blockers.

- Alpha-beta adrenergic blockers.

3) Vasodilators

- Nitric oxide releasers.

- Potassium channel openers.

- Calcium channel blockers.

4) Angiotensin inhibitors and antagonists.

- Angiotensin Converting Enzyme (ACE) inhibitors.

- Angiotensin receptor antagonists.


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Diuretics

  • First -line drug

  • Low dose diuretic therapy is safe and effective in preventing HTN complications

  • hydrochlorothiazide (Hydrodiuril), chlorthalidone (Hygroton

  • furosemide

  • spironolactone


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1.Thiazide diuretics

  • Thiazides are the most effective diuretics to reduce blood pressure in patients with normal renal function. The antihypertensives doses are lower that those required for diuretic effect.

  • MOA:The initial hypotensive effects of diuretics is associated with a reduction in blood volume and cardiac output. Peripheral vascular resistance is unaffected.


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After 6-8 weeks of continuous therapy intravascular volume and cardiac output return towards normal while peripheral vascular resistance decreases.

- Mechanisms of this decrease are probably related to

a depletion of body Na+ stores which leads to:

a) a decrease of interstitial fluid volume

b) a fall in smooth muscle Na+ concentration that in turn decreases intracellular Ca++ concentration

c) a change in response of cell surface receptors to vasoconstrictor hormones


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Thiazide diuretics: mechanism of action

Then

CO


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Effect of thiazides on BP: kinetic


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Thiazide diuretics: clinical use

  • Used for monotherapy of mild hypertension and for polydrug therapy of more severe cases.

  • Therapeutic expectation with monotherapy: 20/10 mmHg drop in 60% of patients.

  • Use low doses (ceiling effect) to minimize side-effects (K loss).

  • Low-dose thiazide/low dose beta-blocker combo

  • Can be used in conjunction with sympatholytics, ACEI, Ca-channel blockers


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Thiazide Diuretics: side-effects.

  • Major Side-effects: a) K loss(minimized by using low doses, diet, use of combos with K-sparing diuretics). b) hyperuricemia(bad for gout) c) hyperglycemia, glucose intolerance (bad for diabetes) d)increase LDL & VLDL (bad for atherosclerosis)

  • Beneficial effect: Ca-sparing (good for osteoporosis)


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Furosemide and high ceiling diuretics

  • Use in hypertension is limited . On their own they are not very effective at lowering BP

  • Main indications are:

  • a) severe hypertension when several drugs with Na-retaining properties are used (e.g. hydralazine, major sympatholytics). Usually a beta-blocker is also required . b) when GFR is < 30-40 ml/min

  • c) in CHF or cirrhosis.


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Beta-adrenergic antagonists

  • Propranolol

  • Nadolol"nonselective"

  • Pindolol - "nonselective";partial agonist (some intrinsic sympathomimetic activity); less bradycardia than other beta-blockers

  • Metoprolol - beta1 "selective"

  • Labetolol- ""beta / alpha";higher instance of side effects (orthostatic hypotension; sexual dysfunction);

  • useful in hypertension of pheochromocytomas


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Beta-adrenergic antagonists

  • Mechanism of action: beta-1 blockade a) in heart (they reduce cardiac contractility and CO). b) in kidney (they reduce renin release by sympathetic nerves). Drop in AII produces: - Na loss by kidney (leading to BV reduction) - vascular relaxation in some vascular beds. c) in the CNS (controversial)


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Beta-blockers: mechanism of action in hypertension


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Beta-adrenergic antagonists: side-effects/1

  • Bronchoconstriction (minimized by using beta-1 selective drug; bad for asthmatics)

  • Increase in LDL/HDL ratio (bad for atherosclerosis)

  • Depression, loss of energy (CNS effect)

  • Increase AV node refractoriness (good for SVTs but could be bad if abnormal SA or AV nodes)

  • Decreased cardiac contractility (good for angina, good or bad for CHF)


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Beta-adrenergic antagonists: side-effects/2

  • Block prodromal signs of hypoglycemia in insulin-dependant diabetics.

  • Withdrawal: Rebound hypertension and cardiac ischemia

  • Cold extremities. May precipitate or worsen Raynaud’s disease (vasospasm of extremities due to beta-blockade of AV shunts). Labetatol (alpha + beta blocker) or blocker with ISA may be prefered in this case.

  • Adverse effect in patients with occlusive peripheral vascular disease (Production or aggravation of intermittent claudication. IC is due to low calf blood flow)


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Beta-blockers: clinical use in hypertension

  • Can be used alone for monotherapy .

  • combined with low dose thiazide

  • Should not be combined with verapamil or diltiazem to avoid excessive cardiac depression

  • Non-selective, beta-1 selective and blockers with ISA work equally well.

  • Can be combined with ACEI, dihydropyridines (cautiously), other vasodilators.


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Renin-angiotensin system


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ACE inhibitors: mechanism of antihypertensive action

  • ACEIs  AII and  bradykinin (vasodilator).

  • In the context of hypertension ACEIs work: by  preload and  afterload via: a)  arteriolar dilation ( TPR).

    b) Na reabsorption by kidney (hemodynamic effect on kidney and drop in aldosterone secretion). This reduces blood volume and preload c)  release of NE (which lowers TPR and CO) d)  cardiac contractility


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ACEIs: mechanism of action


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ACEIs: side-effects/drug interactions

  • SAFE, effective and well-tolerated. Few side-effects but some potentially serious.

  • Common side-effects are due to bradykinin accumulation : cough, skin rashes, angioedema

  • Hyperkalemia (bad in presence of K-sparing diuretic, good in presence of thiazide)

  • First dose orthostatic hypotension (can be severe in hypovolemic patient e.g. using diuretics)

  • Risk of severe foetal pbs.

  • Acute Renal failure in patient with high grade renal artery stenosis.


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Use of ACEIs in hypertension

  • Excellent first line agent for monotherapy in absence of renal ischemia.

  • Can be combined with beta-blockers or thiazides diuretics (NOT with K-sparing diuretics) or alpha-1 blockers for enhanced effectiveness.

  • Notfor pregnant women.

  • Other major uses of ACEIs: diabetic nephropathy, CHF and post MI treatment.


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ACEIs differences between agents

  • Little difference except:

  • T1/2. a) short (2 hrs) e.g. captopril b) long (~ 10-12 hrs) e.g. enalapril, linosipril, fosinopril, several others.

  • Excretion: a) renal (most drugs). Doses should be reduced in patients with renal insufficiency. b) some liver metabolism (fosinopril)


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Angiotensin receptor antagonists

  • Prototype: Losartan.

  • Block AT1 not AT2 receptors, no effect on bradykinin.

  • Less efficacious than ACEIs (??)

  • Effect potentiated by thiazide.

  • Produces neither cough nor angiodema (bradykinin effects) but other side-effects are the same as those of ACEIs.


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Difference between ACEIs & AT1 blockers

AT1 R antagonists

ACEIs

AngII Bradykinin

AT1-RAT-2R

VasoconstrictionVasorelaxation

AngII Bradykinin

AT1-R AT2-R

VasoconstrictionVasorelaxation

Normal Reduced Increased


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DHPs:mechanism of action

SNA  is

minimal

with long-

lasting DHPs


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Dihydropyridine Ca channel blockers

  • Mechanism of antihypertensive action: arteriolar vasodilation, TPR drop.

  • DHPs are slightly more potent antihypertensives than verapamil or diltiazem

  • Side-effects:

  • a) orthostatic hypotension

  • b) reflex tachycardia may lead to cardiac ischemia and/or arrhythmias

  • (minimized by using slow-onset and long-lasting preps)

  • c) headache, flushing, dizziness d) pedal oedema.


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Non-selective Ca channel blockers: mechanism of action


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Non-selective Ca channel blockers: side-effects

  • Side-effects:

  • a) SA node inhibition: probably good as it prevents the baroreflex mediated tachycardia b) increase in AV node refractoriness. Good for SVTs but can produce AV block in patients with cardiac conduction problems.

  • c) decrease cardiac contractility


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Centrally Acting Drugs

  • Clonidine activates alpha2 and imidazoline receptors in the

    vasomotor center of the medulla which inhibits the sympathetic

    nervous system.

  • A reduced heart rate and cardiac output account for reduction

    in blood pressure.

  • Considered a second-line drug or for special cases

    (ie methyldopa in pregnant hypertensive patients).


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Alpha-2 adrenergic agonists

  • Clonidine, guanabenz, guanfacine, alpha-methyl dopa (the latter is a prodrug converted into alpha-methyl NE).

  • Mechanisms of action: sympatholytics; reduce CO & TPR a) Major site: CNS. Reduce activity of sympathetic nerves by action on vasomotor center b) peripheral site: reduce release of NE from sympathetic terminals


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Centrally Acting Drugs

  • Antihypertensive effect results from action in the CNS causing

    a reduced sympathetic nerve firing rate.

  • Prototype: clonidine


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Mechanism of action of clonidine

Central effect

Peripheraleffect


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Alpha-2 adrenergic agonists: side-effects

  • Sedation

  • Depression

  • Dry mouth, constipation.

  • Rebound hypertension (clonidine but not alphamethyl-dopa)

  • Impairment of sexual function

  • Na retention (improved by use of diuretics)


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Alpha-2 adrenergic agonists: therapeutic status

  • Second-line drugs in hypertension, not used for monotherapy.

  • Use of slow-release patch (clonidine) improves side-effects)

  • Methyl-dopa is safe in pregnancy.

  • Note: alpha-2 adrenergic agonists are used to treat glaucoma, pain, spasticity and opiate withdrawal.


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Ganglionic blockers

  • Historical interest only. These drugs produce intolerable side-effects (orthostasis, Na retention, GI and sexual dysfunction)

  • trimethaphan was withdrawn in 1996

  • mecamylamine still available but never used.


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Reserpine

  • Depletes NE from storage vesicles

  • Major action is in CNS. Reduces sympathetic outflow. Reasonably effective, especially with thiazide.

  • Side-effects: depression, sedation, GI hyperactivity.

  • Cheap, its only virtue.

  • Little used at present.


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Guanethidine

  • Peripheral sympatholytic drug.

  • Rides the NE transporter, dislodges NE from vesicles and prevents exocytosis.

  • Lots of side-effects: postural hypotension cerebral ischemia, GI hyperactivity, sexual dysfunction

  • Potentially very serious drug interactions (tricyclics, indirectly acting sympathomimetics e.g. cold medicines)

  • Use in hypertension restricted to severe cases. Must be combined with diuretic


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Vasodilators:

  • Hydralazine & Minoxidil

  • Oral vasodilators used are used for long-term outpatient treatment of severe hypertension in the context of a polydrug therapy.

  • Work by reducing afterload (TPR).

  • Cause marked Na retention and rapidly increase BV (pseudotolerance) i.e. must be used in conjunction with diuretics.

  • Cause marked reflex tachycardia and increased contractility (beta -mediated) ergo must be used with beta-blockers.

  • Minoxidil causes hypertrichosis(growth of body hair).


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Alpha-1 adrenergic antagonists

  • Mechanism of action:

  • a) antagonize effect of sympathetic tone in arteries and veins (reduce TPR and preload) b) reduce baroreflex via central action (thus produce very little reflex tachycardia).

  • Side-effects: few

  • a) first-dose hypotension (Pb with older patients)

  • b) retention of salt and water


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Alpha 1-blockers: mechanism of action


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Alpha-1 adrenergic antagonists: therapeutic use

  • Can be used for monotherapy of mild hypertension

  • May improve LDL/HDL ratio

  • Effects additive with thiazide diuretics and ACEI.

  • Should not be combined with vasodilators (e.g. dihydropyridines): tachycardia.

  • Good for patients with benign prostatic hyperplasia.


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Alpha-1 adrenergic antagonists: difference between agents

  • Prototype: prazosin

  • Newer agents (terazosin, doxazosin) have longer T1/2 .

  • Newer agents can be given once a day.


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Treatment of mild hypertension

  • Nonpharmacological (salt restriction , exercise, weight loss)

  • Pharmacological: alternatives for initial treatment include: a) monotherapy with thiazide, ACEI, beta-blocker or alpha-1 blocker or calcium-channel blocker. Drug is selected on the basis of efficacy,concurrent pathologies and individual sensitivity to side-effects. b) low thiazide/low beta-blocker combo c) thiazide/ K sparing combo.


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Principles of polydrug therapy

  • Monotherapy is sufficient in only 55% of cases.

  • In more severe cases 2 or 3 drugs have to be used.

  • Each drug must belong to a different class

  • The combination of 2 first-line drugs is tried first. One of the drugs is likely to be an ACEI.

  • Vasodilators if used must be given with a diuretic and a beta-blocker.


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Treatment of hypertensive emergencies

  • Goal: produce a rapid but well controlled fall in BP.

  • Context: hypertensive encephalopathy, eclampsia, pheo, hypertension with pulmonary oedema, aneurism, subarachnoid hemorrhage etc..

  • Labetalol iv (alpha & beta blocker)

  • I.v nitroprusside

  • I.v. nitroglycerine

  • hydralazine iv or im (eclampsia)

  • iv phentolamine or phenoxybenzamine po (pheo)


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