Pharmacology 3.1 - Anti-hypertensive Drugs OLD

7/23/2019 Pharmacology 3.1 - Anti-hypertensive Drugs OLD

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Anti-Hypertensive Drugs

Dr. Raymond V. Oliva

Department of Medicine

Philippine General Hospital


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Basic Principles

Pharmacokinetic propertiesrelated toabsorption, distribution and elimination ofa drug

They are reflected in the approved doseranges and dose intervals

Pharmacodynamic properties

characteristics that describe its biologiceffects

Greater interest clinically


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Efficacy and Peak:Trough Effects

Evaluated after single and multiple doses todetermine the time course of their effects

An antihypertensive drug is approved for

once a day use if its trough effects (24 hoursafter last dose) is at least 50% of its peakeffects

Trough readings are derived from

ambulatory monitoring studies, and areuseful in determining whether BP iseffectively maintained.


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Diuretics


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Thiazide Diuretics

Initially used in the 1950s, were the first

truly effective, well-tolerated, once a day

antihypertensives

Used alone or in combination, thiazides

provide predictable and sustained

antihypertensive effects

Step ladder approach:

1) diuretic2) diuretic + beta blocker3) diuretic + beta blocker + CCE

Taylor fit approach:

dont start on any HTN drugpx will decide and check for underlying factors

i.e. hydrochlorothiazide


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Thiazide Diuretics


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Thiazide Diuretics

Mechanism of Action

Early renal (salt/water excretion) effectsact

by inhibiting the Na/Cl reabsorption pump in

the DCT There is dose dependent degree of ECF

contraction but plasma volume returns to normal

within several days

By increasing Na availability at the DCT, there isincreased excretion of K and Mg

There is decreased urinary calcium excretion

Occurs within the first to 2 weeks

wherever Na goes, water follows

after start of therapy


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Thiazide Diuretics


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Thiazide Diuretics

Mechanism of Action

Chronic vascular effects (several months)

Chronically, ECF and CO return toward baseline,

while systemic vascular resistance decreases In the subacute phase, CO and SVR coexist but in

a transition state

The cellular mechanism is still unknown


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Thiazide Diuretics


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Loop Diuretics

Act on membrane ion transportmechanism in the thick ascending limb of

the Loop of Henle

Prevent reabsorption of Cl and Na


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Loop Diuretics

Loop diuretics are venodilators, and littlearterioloar dilator effect

Ineffective in reducing BP in vast majority

of individuals with hypertensionvenous - capacitancearterious - resistancetypes of Unloaders:Preloads - i.e.diuretics

Afterload - degree ofperipheral resistancepresentBalance - dc preloadand afterload


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Loop Diuretics


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Loop Diuretics


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Loop Diuretics

Mechanism of Action

Normal GFR

Variety of mechanisms blunts the ability topersistently reduce ECF volume or BP

The initial diuresis is typically followed by longer

period of Na retention (neutral or positive balance)

not used for maintenance


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Loop Diuretics

Mechanism of Action

Renal dysfunction

Loop diuretics effectively reduce ECF volume andBP

The renal and antinatriuretic mechanisms are

blunted

AE: hypokalemia


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Aldosterone Blockers

Pathophysiologic actions of aldosterone

Sodium retention/volume expansion

Reduction in vascular compliance

Promotion of endothelial dysfunction

Upregulation of angio II receptors

Potentiation of the pressor responses of angio II

Increases in sodium influx in vascular smooth

muscle cells

Fibrosis in the heart, kidneys and vasculature

Prototype drug: spironolactone

used for Px with chronic liver diseaseused with diuretics for CHFnot use for HTN


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They provide effective antihypertensivetreatment, esp in low-renin and salt

sensitive forms of hypertension

Newer, more selective aldo blockers have

fewer of the progestational and anti-

androgenic effects than spironolactone


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Aldo blockers provide additional benefitin the treatment of HF when combined

with ACE-I, dig and loop diuretics


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Other Diuretics

Carbonic Anhydrase inhibitors

Carbonic anhydrase predominantly found in

the luminal membrane of the PCT

Inhibitors block NaHCO3reabsorption

Indicated in glaucoma, metabolic alkalosis

states, urine alkalinization, acute mountain

sickness

most famous: Acetazolomide used forglaucoma


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Other Diuretics

Osmotic Diuretics Prototype is mannitol (nonreabsorbable

solute)

Major effect is in the proximal tubule and

descending limb of Loop of Henle

Prevents normal absorption of water by

interposing a countervailing osmotic force


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Beta Blockers antihypertensives, antiangina, antiarrhythmics, toxic goiter/HYperthyroidism


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Beta Blockers

Beta blockers are appropriate for the treatmentof arterial HTN, esp in patients who haveconcomitant ischemic heart disease, HF orarrhythmias

They are highly heterogenous with respect tovarious properties

They reduce mortality, nonfatal reinfarction rates

and improve clinical outcomes in patients withstable ventricular dysfunction who are receivingconventional HF treatment

reduce HR, vasodilation, reduce myocardial contractility


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Mechanism of Action

Reduction of HR and CO CNS effect

Inhibition of renin release

Reduction in venous return and plasma volume

Reduction in peripheral vascular resistance Reduction in vasomotor tone

Improvement in vascular compliance

Resetting of baroreceptor levels

Effects on prejunctional B receptors, reduction inNorepi release

Attenuation of pressor response to catecholamineswith exercise and stress


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Beta Blockers

RAAS


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Beta Blockers

present Beta receptor


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Beta Blockers


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Beta Blockers


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Alpha blockers

Selective a1 adrenergic antagonists lowerBP by blocking postsynaptic

vasoconstrictor effects of Norepinephrine

Hemodynamically, selective a1 receptor

inhibitors cause balanced arterial and

venous dilation, with no increase in CO

vasodilation


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Alpha blockers

Tend to cause greater BP lowering in theupright compared to supine position

Non-selective alpha blockers given forpatients diagnosed with

pheochromocytoma phenoxybenzamine


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Alpha blockers


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Alpha Blockers


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Central and Peripheral

Sympatholytics

Central a2 sympathetic agonists reduce

BP by decreasing SNS outflow, systemic

vascular resistance and HR

Clonidine is an agonist for both central a2

and I1-imidazoline receptors

block sympatholytic effects


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Sympatholytics

Peripheral sympatholytics deplete nerve

terminal with norepi, decrease reflex

peripheral arterial and venousconstriction, and predispose to

orthostatic hypotension


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Sympatholytics


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RAAS Blockers


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ACE Inhibitors

All drugs reduce BP at appropriate doses

With the exception of lisinopril andcaptopril, ACE-I are produgs, which improves

their absorption before hydrolysis to activediacids in the liver or intestines

Distinguished by sulfyhdryl (captopril),

phosphinyl (fosinopril) or carboxyl sidegroups


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ACE Inhibitors

ACE is a pluripotent serine protease thatcatalyzes the conversion of ang I to Ang IIwhile degrading bradykinins and othervasodilator

ACE inhibition also increases BKconcentrationleading to cough

Long term use may lead to angiotensinescape


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ACE Inhibitors

Result in the reduction of cardiac preload(vasodilatory effects) and afterload(through direct and indirect arterialdilator effects)

Blunt stress-induced increases incatecholamines and HR

There is modest reduction in SVRwithout the reflex increase in CO


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ACE Inhibitors


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Angiotensin Receptor Blockers

ARBs work primarily by selectiveblockade of AT1 receptors

Effective as monotherapy but whencombined with other antihypertensive

agents, are effective in virtually all

populations


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ARBs act by binding selectively to the AT1

receptor; competitive (irbesartan,

valsartan) or insurmountable(candesartan or losartan)


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ARBs are generally administered once

daily, minor pharmacokinetic differences

exist

Adequate doses of any of them produce

reasonable 24 hour BP control


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Positive outcome benefits have been

demonstrated in diabetic kidney disease,

HF, IHD, and stroke

Reduce the incidence of AF and new

onset DM and regression of LVH


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Calcium Channel Blockers

Calcium plays a critical role in cellularcommunication, regulation and function

and any manipulation of transmembraneCa flux.


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CCBS belong to a structurally andpharmacologically diverse group ofcompounds with 3 subclasses:

Phenylakylaminesverapamil

BenzothiazepinesDiltiazem

1,4 dihydropyridinesrestmost common use for headaches


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They decrease cellular Ca entry throughthe L type Ca channel

CCB subtypes are quantitatively andqualitatively distinct in that they have

differential sensitivity and selectivity for

binding the pharmacologic receptorsalong with the Ca channel in various

tissues


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Other Anti-HTN Meds

Direct arterial vasodilatorsminoxidil,hydralazine

Direct Renin Inhibitors - aliskiren

Endothelin antagonists

Dopamine agonists - fenoldopam

adverse effect: hirsutism

vasodilator given, IV, acute hypertensive emergencies


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Anti-Hypertensive Drugs


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How Are We Going To Use

These Drugs???


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NICE Guidelines 2011


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Documents

Pharmacology 3.1 - Anti-hypertensive Drugs OLD