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Anti-Hypertensive Drugs

Dr. Raymond V. Oliva


Department of Medicine
Philippine General Hospital

Basic Principles

Pharmacokinetic properties related to


absorption, distribution and elimination of
a drug
They are reflected in the approved dose
ranges and dose intervals

Pharmacodynamic properties
characteristics that describe its biologic
effects
Greater interest clinically

Efficacy and Peak:Trough Effects

Evaluated after single and multiple doses to


determine the time course of their effects

An antihypertensive drug is approved for


once a day use if its trough effects (24 hours
after last dose) is at least 50% of its peak
effects

Trough readings are derived from


ambulatory monitoring studies, and are
useful in determining whether BP is
effectively maintained.

Diuretics

Thiazide Diuretics

Initially used in the 1950s, were the first


truly effective, well-tolerated, once a day
antihypertensives

Step ladder approach:


1) diuretic
2) diuretic + beta blocker
3) diuretic + beta blocker + CCE

Taylor fit approach:


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

Used alone or in combination, thiazides


provide predictable and sustained
antihypertensive effects
i.e. hydrochlorothiazide

Thiazide Diuretics

Thiazide Diuretics

Mechanism of Action
Early renal (salt/water excretion) effects act
by inhibiting the Na/Cl reabsorption pump in
the DCT
wherever Na goes, water follows

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 is
increased excretion of K and Mg
There is decreased urinary calcium excretion
Occurs within the first to 2 weeks
after start of therapy

Thiazide Diuretics

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

Thiazide Diuretics

Loop Diuretics

Act on membrane ion transport


mechanism in the thick ascending limb of
the Loop of Henle

Prevent reabsorption of Cl and Na

Loop Diuretics

Loop diuretics are venodilators, and little


arterioloar dilator effect

Ineffective in reducing BP in vast majority


of individuals with hypertension
venous - capacitance
arterious - resistance
types of Unloaders:
Preloads - i.e.
diuretics
Afterload - degree of
peripheral resistance
present
Balance - dc preload
and afterload

Loop Diuretics

Loop Diuretics

Loop Diuretics

not used for maintenance

Mechanism of Action
Normal GFR
Variety of mechanisms blunts the ability to
persistently reduce ECF volume or BP
The initial diuresis is typically followed by longer
period of Na retention (neutral or positive balance)

Loop Diuretics

Mechanism of Action
Renal dysfunction
Loop diuretics effectively reduce ECF volume and
BP
The renal and antinatriuretic mechanisms are
blunted
AE: hypokalemia

Aldosterone Blockers

Prototype drug: spironolactone

used for Px with chronic liver disease


used with diuretics for CHF
not use for HTN

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

Aldosterone Blockers

Aldosterone Blockers

Aldosterone Blockers

Aldosterone Blockers

They provide effective antihypertensive


treatment, esp in low-renin and salt
sensitive forms of hypertension

Newer, more selective aldo blockers have


fewer of the progestational and antiandrogenic effects than spironolactone

Aldosterone Blockers

Aldo blockers provide additional benefit


in the treatment of HF when combined
with ACE-I, dig and loop diuretics

Other Diuretics

Carbonic Anhydrase inhibitors

most famous: Acetazolomide used for


glaucoma

Carbonic anhydrase predominantly found in


the luminal membrane of the PCT
Inhibitors block NaHCO3 reabsorption

Indicated in glaucoma, metabolic alkalosis


states, urine alkalinization, acute mountain
sickness

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

Beta Blockers

antihypertensives, antiangina, antiarrhythmics, toxic goiter/HYperthyroidism

Beta Blockers

reduce HR, vasodilation, reduce myocardial contractility

Beta blockers are appropriate for the treatment


of arterial HTN, esp in patients who have
concomitant ischemic heart disease, HF or
arrhythmias

They are highly heterogenous with respect to


various properties

They reduce mortality, nonfatal reinfarction rates


and improve clinical outcomes in patients with
stable ventricular dysfunction who are receiving
conventional HF treatment

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 in
Norepi release
Attenuation of pressor response to catecholamines
with exercise and stress

Beta Blockers

RAAS

Beta Blockers

present Beta receptor

Beta Blockers

Beta Blockers

Alpha blockers

vasodilation

Selective a1 adrenergic antagonists lower


BP by blocking postsynaptic
vasoconstrictor effects of Norepinephrine

Hemodynamically, selective a1 receptor


inhibitors cause balanced arterial and
venous dilation, with no increase in CO

Alpha blockers

Tend to cause greater BP lowering in the


upright compared to supine position

Non-selective alpha blockers given for


patients diagnosed with
pheochromocytoma
phenoxybenzamine

Alpha blockers

Alpha Blockers

Central and Peripheral


Sympatholytics
block sympatholytic effects

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

Central and Peripheral


Sympatholytics

Peripheral sympatholytics deplete nerve


terminal with norepi, decrease reflex
peripheral arterial and venous
constriction, and predispose to
orthostatic hypotension

Central and Peripheral


Sympatholytics

RAAS Blockers

ACE Inhibitors

All drugs reduce BP at appropriate doses

With the exception of lisinopril and


captopril, ACE-I are produgs, which improves
their absorption before hydrolysis to active
diacids in the liver or intestines

Distinguished by sulfyhdryl (captopril),


phosphinyl (fosinopril) or carboxyl side
groups

ACE Inhibitors

ACE is a pluripotent serine protease that


catalyzes the conversion of ang I to Ang II
while degrading bradykinins and other
vasodilator

ACE inhibition also increases BK


concentration leading to cough

Long term use may lead to angiotensin


escape

ACE Inhibitors

Result in the reduction of cardiac preload


(vasodilatory effects) and afterload
(through direct and indirect arterial
dilator effects)

Blunt stress-induced increases in


catecholamines and HR

There is modest reduction in SVR


without the reflex increase in CO

ACE Inhibitors

Angiotensin Receptor Blockers

ARBs work primarily by selective


blockade of AT1 receptors

Effective as monotherapy but when


combined with other antihypertensive
agents, are effective in virtually all
populations

Angiotensin Receptor Blockers

Angiotensin Receptor Blockers

Angiotensin Receptor Blockers

Angiotensin Receptor Blockers

ARBs act by binding selectively to the AT1


receptor; competitive (irbesartan,
valsartan) or insurmountable
(candesartan or losartan)

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

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

Calcium Channel Blockers

Calcium plays a critical role in cellular


communication, regulation and function
and any manipulation of transmembrane
Ca flux.

Calcium Channel Blockers

Calcium Channel Blockers

CCBS belong to a structurally and


pharmacologically diverse group of
compounds with 3 subclasses:
Phenylakylamines verapamil

Benzothiazepines Diltiazem
1,4 dihydropyridines rest
most common use for headaches

Calcium Channel Blockers

They decrease cellular Ca entry through


the L type Ca channel

CCB subtypes are quantitatively and


qualitatively distinct in that they have
differential sensitivity and selectivity for
binding the pharmacologic receptors
along with the Ca channel in various
tissues

Calcium Channel Blockers

Calcium Channel Blockers

Other Anti-HTN Meds


adverse effect: hirsutism

Direct arterial vasodilators minoxidil,


hydralazine
vasodilator given, IV, acute hypertensive emergencies

Direct Renin Inhibitors - aliskiren

Endothelin antagonists

Dopamine agonists - fenoldopam

Anti-Hypertensive Drugs

How Are We Going To Use


These Drugs???

NICE Guidelines 2011