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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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Aldosterone Blockers
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Aldosterone Blockers
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Aldosterone Blockers
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Aldosterone Blockers
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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Aldosterone Blockers
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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Central and Peripheral
Sympatholytics
Peripheral sympatholytics deplete nerve
terminal with norepi, decrease reflex
peripheral arterial and venousconstriction, and predispose to
orthostatic hypotension
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Central and Peripheral
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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Angiotensin Receptor Blockers
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Angiotensin Receptor Blockers
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Angiotensin Receptor Blockers
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Angiotensin Receptor Blockers
ARBs act by binding selectively to the AT1
receptor; competitive (irbesartan,
valsartan) or insurmountable(candesartan or losartan)
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Angiotensin Receptor Blockers
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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Angiotensin Receptor Blockers
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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Calcium Channel Blockers
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Calcium Channel Blockers
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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Calcium Channel Blockers
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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Calcium Channel Blockers
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Calcium Channel Blockers
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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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