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ANTI-HYPERTENSIVE
AGENTS
Dr.V.V.Gouripur, B.Sc, MBBS, MD
Hypertension
• Elevation of arterial blood pressure above
140/90 mm Hg. Can be caused by:
– an underlying disease process
hypertension)
(secondary
• Renal artery stenosis
• Hyperaldosteronism
• pheochromocytoma
– idiopathic process (primary or essential
hypertension)
HypertensionPersistent high blood pressure
• What is Blood Pressure?
– Pressure created by the heart as it pumps blood
through the arteries and the circulatory system
• What do Blood Pressure Numbers
Mean?
– Top number (Systolic)= Pressure while heart is
beating
– Bottom number (Diastolic)= Pressure while heart
is resting between beats
Hypertension
• What Causes High Blood
Pressure?
– Cause unknown in 90 to 95% of cases =
Primary Hypertension
– Secondary Hypertension = 5 to 10%
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Kidney Abnormalities
Narrowing of certain arteries
Rare tumors
Adrenal gland abnormalities
Pregnancy
Regulation of blood pressure
• Arterial blood pressure (BP) is equal
to the product of the rate of blood
flow (cardiac output [CO]) and the
resistance to passage of blood
through precapillary arterioles
(peripheral vascular resistance
[PR]).
• BP = CO x PR.
: Autonomic and Renal
Regulation of Blood Pressure
• Postural Baroreflex (Autonomic Feedback Loop)
– Baroreceptors (e.g., carotid sinus) sense
reduction in BP caused by pooling of blood
below the heart.
– Vasomotor and cardio regulatory centers in
the brain stem are activated resulting in
increased sympathetic output.
» Increase in peripheral vascular resistance
(PR; constriction of arterioles).
» Increased cardiac output (direct stimulation
of the heart).
» Increased venous return to the heart
(constriction of postcapillary venules or
capacitance vessels).
Baroreflex acts in response to any event
that lowers blood pressure including
•Primary reduction in PR
(e.g., vasodilating agent).
•Reduction in intravascular volume.
•Decreased rate and/or contractility of
heart.
Role of kidneys
(Renal Hormonal Control Loop)
– Long-term control of B.P. via regulation of blood volume
» Reduction in renal perfusion causes intrarenal
redistribution of blood flow and increased reabsorption of
salt and water and production of renin.
– Renin
» Enzyme that increases production of Angiotensin II.
» Renin production is stimulated by decreased pressure in
renal arterioles as well as sympathetic neural activity (via
beta-adrenergic receptors).
– Angiotensin II causes:
» Direct constriction of resistance vessels
» Stimulates synthesis of aldosterone in the adrenal cortex.
– Aldosterone - increases renal sodium absorption and
intravascular blood volume.
Treatment Rationale
Short-term goal of antihypertensive therapy:
Reduce blood pressure
• Primary (essential) hypertension
• Secondary hypertension
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
Ways of Lowering Blood Pressure
• Reduce cardiac output (ßblockers, Ca2+ channel blockers)
• Reduce plasma volume
(diuretics)
• Reduce peripheral
vascular resistance
(vasodilators)
Drugs used in treating hypertension
• Drugs used in treating hypertension act by
altering normal homeostatic
mechanisms.
• Efficacy, toxicity, and suitable
combinations of drugs can often be
predicted by consideration of both the
sites and the mechanisms of action of the
agents.
• An understanding of the pharmacology of
the agents provides the rationale for drug
therapy in hypertension
Antihypertensive Drugs
Drugs used in hypertension
Diuretics
Sympathoplegics-
Alpha or beta
receptors
Older oral
Vasodilators
Nerve terminal
Calcium blockers
ganglia
Parenteral
Vasodilators
CNS Sympathetic
outflow
Vasodilators
Angiotensin antagonists
ACE inhibitors
Receptor blockers
classification
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•
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Diuretics-Lower blood pressure by depleting the
body of sodium and reducing blood volume.
Sympatholytic nAgents -Lower blood pressure by
reducing peripheral resistance, inhibiting cardiac
function, and increasing venous pooling in
capacitance vessel (i.e., reducing venous
return).Direc
Vasodilators -Lower blood pressure by relaxing
vascular smooth muscle.
Agents which Decrease Action of Angiotensin
Reduce peripheral resistance from angiotensin
action; angiotensin also decreases aldosterone
release, which will lower blood volume.
Thiazides and Other Diuretic
Agents
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Chlorothiazide
hydrochlorothiazide
Benzfluothiazide
Chlorthalidone
Metalozone
Antihypertensive action
– Prevent Na+ retention and reduce
plasma and extracellular fluid volumes.
– Direct vasodilator action,
Site of action of diuretics
Diuretics play an extremely important role in
antihypertensive therapy.
– Usually well tolerated and
accepted by patients.
– Lower B.P. both at rest and
during exercise, regardless of
body position.
– Favorable hemodynamic effects
Enhance action of other antihypertensive
drugs
»When non-diuretic antihypertensive agents are
used alone to lower B.P., the kidney responds to
the decreased perfusion pressure by retaining
Na+, Cl-, and H20 (leads to expansion of plasma
and extracellular fluid volumes which tends to
offset the original decrease in B.P.).
»Concomitant administration of a diuretic with other
antihypertensive agents is important
Absorption, Metabolism and
Excretion
– All absorbed orally but
hydrochlorothiazide absorbed
more readily than
chlorothiazide.
– Excreted by kidney by the some
mechanism responsible for
secretion of uric acid.
» May cause elevated serum
uric acid.
» Use with caution in gout.
Use
– Treatment of essential
hypertension
– Treatment of edema
– Treatment of diabetes insipidus
– Treatment of hypercalciuria
Adverse Effects
–Hypokalemia –
drowsiness, dizziness, sometimes
fainting, muscle weakness, loss of deep
tendon reflexes.Cardiovascular
complications - arrhythmias,
hypotension.(May have to administer K+.)
–Hyperuricemia - may aggravate gout.
–May induce hyperglycemia and aggravate
diabetes mellitus.
Cautions and contraindications
• May aggravate renal and/or hepatic
insufficiency.
• May aggravate gout and diabetes
mellitus.
• May intensify arrhythmias of digitalis
toxicity.
• May worsen other fluid/electrolyte
imbalances.
• Direct and indirect effects on fetus.
Sympatholytic Drugs that alter SNS
function
• There are a number of different sites of action for
"sympatholytic" antihypertensives which act to interfere with
some aspect of sympathetic nervous system (SNS) activity,
including:
• A) outflow of SNS activity from the brain;
• B) antagonism of α or β adrenergic receptors;
• C) decreased availability of neurotransmitter released
from adrenergic [postganglionic sympathetic]
neurons; and,
• D) blockade of SNS neurotransmission at the level o
autonomic ganglia.
Centrally Acting Sympatholytics
• Drugs that decrease sympathetic
nervous system outflow from the
central nervous system).
• Eg. Clonidine,moxanidine,
Methyl dopa
Methyldopa (Aldomet®)
Mechanism of action - major
antihypertensive action is on the
CNS to decrease SNS outflow from
the brainstem.
Effect due to a metabolite, -methyl
norepinephrine that stimulates
presynaptic 2-adrenergic receptors
to inhibit sympathetic outflow from
vasopressor centers in brainstem.
Side Effects and Toxicity
Bradycardia,
diarrhea,
dry mouth,
failure of ejaculation
Edema
Postural hypotension can develop, but considerably less
frequent and less severe than with reserpine, guanethidine,
ganglionic blocking agent
CNS effects(Unpleasant sedation; persistent lassitude and
drowsiness; vertigo.Extrapyramidal signs, nightmares,
psychic depression (less common than with reserpine).
Lactation - associated with high concentration of prolactin in
plasma.
Idiosyncratic reactions
Drug fever, liver damage
Hemolytic anemic
Sudden withdrawal can cause "rebound" hypertension.
Pharmacokinetics
» Absorbed well from G.I.T. but
there is a large variability of the
extent of absorption among
patients.
» Elimination is largely renal.
» The drug and its metabolites may
interfere with some of the
standard chemical tests for
catecholamines.
Clonidine (Catapres®)
•
Mechanism - Like methyldopa, clonidine is a
central 2-adrenergic agonist.
– Direct stimulation of -adrenergic receptors in
the vasomotor centers of brainstem.
– Results in inhibition of sympathetic activity
– Predominance of parasympathetic activity
Pharmacokinetics
Absorbed well from G.I.T.
Largely excreted by kidney
(60% excreted unchanged,
remainder as metabolites).
–Use
»Treatment of essential hypertension
»Other
–Side Effects and Toxicity
»Similar to those seen with methyldopa;
i.e., bradycardia, dry mouth, sedation,
etc.
»Fluid and sodium retention.
»Occasionally impotence or postural
hypotension may occur.
»Sudden withdrawal can result in
hypertensive crisis.
Sympatholytics Acting on
Postganglionic Sympathetic Neurons
Reserpine (Rauwolfia Alkaloid;
Mechanism - depletion of catecholamines
(NE, DA, Epi) and 5-HT (serotonin) in
both the central and peripheral nervous
system and some other sites.
» Antagonizes the uptake and binding of
NE by storage granules (vesicles).
» NE is then metabolized by MAO in the
neuron.
» Once NE is depleted, sympathetic
discharge is decreased.
» Central as well as peripheral action.
Side Effects and Toxicity
»CNS-Unpleasant sedation and lethargy.
Nightmares, dreams.Depression and
suicide.
»Extrapyramidal signs (rare).
»Increases tone and motility of G.I.T. with
abdominal cramps and diarrhea.
»Bradycardia, miosis, nasal congestion,
flushing.
»Orthostatic (postural) hypotension - may
be severe.
Adrenergic neuron blockers
• Guanethidine (Ismelin®)
– Mechanism
» Prevents release of NE from
vesicles.
» Actions are primarily peripheral (
unlike reserpine, guanethidine
doesn't cross B.B.B.).
» Actively taken up by adrenergic
neuron, replaces NE in vesicle, and
causes gradual NE depletion.
Use - treatment of moderately severe to
severe hypertension.
Side Effects and Toxicity
»Postural hypotension
»May be severe
»Dizziness, weakness
»Intestinal cramping and diarrhea.
»Ejaculatory failure
»Other minor effects - edema, nasal
congestion.
»Drug interactions for guanethidine
Sympatholytics Acting on
Autonomic Ganglia
• Trimethaphan (Arfonad®)
Mechanism-block nicotinic
receptors at autonomic ganglia
Side Effects & Toxicity
Severe postural hypotension
Diarrhoea
Sympatholytics Which Block
Adrenergic Receptors
Beta receptor blockers;
Mechanism - -adrenergic blocking agent
» Decreases C.O. via 1-blocking action
on heart.
» There is evidence that it decreases
sympathetic outflow from CNS but this is
not likely to be primary site of action.
» 1-blocking action inhibits renin
production by juxtaglomerular cells in
kidney.
Beta-receptor blockers
1. (Nonselective) Beta-1 and Beta-2 blockade
» PROPRANALOL
» Timolol (Blocadren®)
» Nadolol (Corgard®)
» Penbutolol (Levatol®)
2. Relatively selective beta-1 blockade (preferred for
patients with asthma or diabetes)
» Metoprolol (Lopressor®)
» Atenolol (Tenormin®)
3 Beta blockers with "Intrinsic Sympathomimetic Activit- Have
less effect on resting heart rate and cardiac output; also less likely to
cause a decrease in HDL cholesterol/LDL cholesterol
» Pindolol (Visken®)
» Acebutolol (Sectral®)
4. Combined α &βreceptor blockade -Labetalol (Normodyne
Uses
»Treatment of hypertension
»Treatment of supraventricular
and ventricular arrhythmias
»Angina pectoris
»Migraines
»Other
Role of beta blockers in hypertension
• Proven benefit in reduction of stroke,
MI
• Commonly used as first line therapy
• When used alone effective in 50-60%
of patients
• When used in conjunction with a
diuretic increase response rate to 6080%
Side Effects and Toxicity
» Bradycardia
» Development of heart failure (usually in patients with
compromised heart function or on other drugs).
» Sudden discontinuation may precipitate rebound hypertension
» Exacerbation of asthmatic symptoms
» Hypotension
» A.V. block
» May be detrimental to diabetics because of two actions:
» masks tachycardia which usually signals hypoglycemia
» intensified hypoglycemic response in diabetics because of
suppression of glycogenolysis.
» Elevated triglycerides and decreased HDL-cholesterol
» Diminished exercise tolerance
Contraindications
–Asthma Never use in asthmatic
patients
–Heart failure, Bradycardia
–Intermittent claudication
–Raynauds
Alpha blockers
Non selective alpha blockers
» phentolamine
» phenoxybenzamine
» dibenamine
Selective alpha1blockers
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»
»
»
Prazosin (Minipress®)
doxazosin (Cardura®)
terazosin (Hytrin®)
trimazosin
Alpha Blockers
– Mechanism
» Blocks postsynaptic alpha adrenoreceptors (1)
in arterioles and venules.
» Selective 1 block allows norepinephrine to act
on presynaptic 2 receptors to exert negative
feedback on its own release.
» Prazosin produces less reflex tachycardia than
nonselective alpha-blockers such as
phentolamine, which blocks 2 receptors as
well as 1 receptors.
» Block of presynaptic 2 “auto-receptors” by
nonselective blockers allows more NE release
following nerve stimulation. Therefore, there is
more NE available to stimulate the heart.
Use
» Essential hypertension; effectiveness
may be increased, if necessary, by use
in combination with other agents, such
as diuretics and beta-blockers, to offset
compensatory actions, i.e., edema,
tachycardia.
» Chronic congestive heart failure
(CHF); used to dilate both resistance
and capacitance vessels (decreases
both afterload and preload).
Side Effects and Toxicity
Usually well tolerated
“
First-dose phenomenon”
with postural hypotension
and syncope occurring shortly after the first
dose.
First dose should be given at bedtime
» Others - dizziness,
palpitations, lassitude,
headache.
Doesn't alter plasma lipid
concentration
Sexual dysfunction is uncommon
Calcium Channel Blockers [
“Cardioactive”
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•
i. Verapamil (Calan®)
ii. Diltiazem (Cardizem®)
“Vasoactive” –
Dihydropyridines
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•
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Nifedipine-( Procardia®)
Amlodipine (Norvasc®)
Felodipine (Plendil®)
Nimodipine (Nimotop®)
Mechanism of action
(Calcium antagonists; slow channel
blockers)
– Inhibits calcium influx in arterial smooth
muscle causing dilation of peripheral
arterioles and reduction of blood
pressure.
– Also inhibits movement of calcium
through channels in myocardial and
specialized conducting tissues of the
heart.
• . Use
–Treatment of hypertension
–Treatment of angina
–Antiarrhythmic
Calcium Channel Blockers
Concern over the use of short acting CCBs
• May increase rate of MI in hypertensive
patients
• The FDA have said that “ short acting
dihydropyridines should not be used as
first line therapy to treat hypertension.”
• Long acting dihydropyridines such as
AMLODIPINE appear safe
• Rate limiting CCBs such as
VERAPAMIL, DILTIAZEM also safe
• CCBs work by
– blocking the L type calcium channels
– selectivity between vascular and cardiac L
type channels
– relaxing large and small arteries and
reducing peripheral resistance
– reducing cardiac output
Side Effects and Toxicity
– Constipation
– Hypotension
– Atrioventricular block
– Decreased cardiac output leading to,
or worsening, heart failure
– Ankle Edema
– Other
Contraindications
– Acute MI
– Heart failure, (rate limiting CCBs)
– bradycardia (rate limiting CCBs)
Vasodilators
(act directly on vascular smooth muscle)
Hydralazine (Apresoline®)
• Mechanism
– Direct relaxation of vascular
smooth muscle is major effect
(arteriole effect greater than effect
on veins).
– Causes reflex cardiac stimulation.
– Increases renin secretion (reflex
sympathetic discharge).
Use
–Used in hypertensive emergencies.
–Used in treatment of essential
hypertension.
»Antihypertensive effect is
optimized by concurrent
administration of a -adrenergic
blocker, (eg, propranolol) to
prevent tachycardia and increased
renin secretion and a diuretic to
counter sodium and water
retention and increased plasma
volume.
Side Effects and Toxicity
–Headache, palpitation, anorexia, nausea,
dizziness, and sweating are common.
–Nasal congestion, flushing, lacrimation,
conjunctivitis, paresthesias, edema, tremors, and
muscle cramps occur less frequently.
–Myocardial stimulation - can produce anginal
attacks.
–Drug fever, urticaria, skin rash, polyneuritis,
anemia, and certain other idiosyncratic reactions
are rare, but require termination of therapy.
–Drug-induced lupus-like syndrome occurs in 1020% of patients receiving prolonged therapy with
high doses
minoxidil (Rogaine®)
Side Effects and Toxicity
– Tachycardia, palpitations, angina
and edema when doses of betablockers and diuretics are
inadequate.
– Headache, sweating, and
hypertrichosis are relatively
common.
.
minoxidil - used topically to
stimulate hair growth
• A 2% solution of minoxidil (Rogaine®) is
used topically to stimulate hair growth in
treatment of male pattern baldness
Vasodilators Used in Treating
Hypertensive Emergencies
• Diazoxide (Hyperstat I.V.®) parenterally administered arteriolar
dilator used to treat hypertensive
emergencies; structurally related to thiazide diuretics but is devoid of diuretic
activity.
• Nitroprusside (Nipride®) - parenterally
administered vasodilator used in treating
hypertensive emergencies and severe
cardiac failure; dilates both arterioles and
venules resulting in decreased periphera
resistance and venous return. Solutions
are light sensitive and metabolized to
cyanide.
• Fenoldopam (Corlopam®) - Dopamine
receptor agonist; Administered by
continuous IV infusion
Angiotensin Converting
Enzymes
ENALAPRIL, LISINOPRIL, RAMIPRIL
• Competitively inhibit the actions of
angiotensin converting enzyme (ACE)
• ACE converts angiotensin I to active
angiotensin II
• Angiotensin II is a potent vasoconstrictor
and hypertrophogenic agent
Angiotensin-II plays a central role in
organ damage
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
A-II
AT1
receptor
LV hypertrophy
Fibrosis
Remodelling
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Stroke
Hypertension
Heart failure
MI
Renal failure
*Preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
DEATH
• Contraindications
– Renal artery stenosis
– Renal failure
– Hyperkalaemia
• Adverse Drug reactions
– Cough
– first dose hypertension
– taste disturbance
– renal impairment
– Angioneurotic oedema
Drug-Drug Interactions
• NSAIDs
– Precipitate acute renal failure
• Potassium supplements
– Hyperkalaemia
• Potassium sparing diuretics
– Hyperkalaemia
Angiotensin II Antagonists
• LOSARTAN, VALSARTAN, CANDESARTAN,
TELMISARTANand
IRBESETRAN
MECHANISM-angiotensin II antagonists
competitively block the actions of angiotensin II
at the angiotensin AT1 receptor
• Advantage over ACE inhibitors
– No cough
Use
• Treatment of hypertension
Management of congestive heart
failure
Acute MI
BHS Guidelines
Young
A
B
A
B
C
D
Elderly(low renin)
C
D
ACE Inhibitor/AT II Blockers
Beta Blocker
Calcium Channel Blocker
Diuretic
Less commonly used agents
• Alpha-adrenoceptor antagonists
– Doxazosin
• Centrally acting agents
– Methyldopa
– Moxonidine
• Vasodilators
– Hydralazine
– Minoxidil
• If there are no contraindications start
treatment according to age and other
pathology
• If elderly with a low dose of
– a thiazide diuretic
– a calcium channel blocker
• If young
– An ACEI
– or beta-blocker
If a single agent doesn’t control BP
– Then use the two together
• A single agent will control BP in 40-50% of
patients
Some Considerations for
Choosing Treatments (unless
otherwise contraindicated).
–Diabetes mellitis
• ACE inhibitors, alpha-antagonists,
and calcium antagonists can be
effective, and have few adverse
effects on carbohydrate
metabolism.
– Hyperlipidemic
• Low dose diuretics have little effect
on cholesterol and triglycerides.
• Alpha-Blockers decrease LDL/HDL
ratio. Calcium-channel blockers,
ACE inhibitors, angiotensin II
receptor blockers have little effect
on lipid profile.( Beta blockers
^lipids)
– Obstructive airway disease
• Avoid beta-blockers.
–Pregnancy
»If taken before pregnancy,
most antihypertensives can be
continued except ACE
inhibitors and angiotensin II
receptor blockers.
»Methyldopa is most widely
used when hypertension is
detected during pregnancy.
»Beta-Blockers are not
recommended early in
pregnancy.
–African origin
• Diuretics have been
demonstrated to decrease
morbidity and mortality, and
hence should be first choice.
• Ca++ blockers and alpha/beta
blockers are effective.
• Patients may not respond well
to monotherapy with betablockers or ACE inhibitors.
–Elderly
• Smaller doses, slower
incremental increases in
dosing, and simple regimens
should be used.
• Close monitoring for side
effects (i.e., deficits in cognition
after methyldopa; postural
hypotension after prazosin) is
appropriate.
• BPH-ALPHA BLOCKERS
THE END
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