ANTI-HYPERTENSIVE AGENTS

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ANTI-HYPERTENSIVE AGENTS

• Dr.V.V.Gouripur, B.Sc, MBBS, MD

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Hypertension

• Elevation of arterial blood pressure above 140/90
  mm Hg. Can be caused by
• an underlying disease process (secondary
  hypertension)
• Renal artery stenosis
• Hyperaldosteronism
• pheochromocytoma
• idiopathic process (primary or essential
  hypertension)

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Hypertension-Persistent 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

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Hypertension

• What Causes High Blood Pressure?
• Cause unknown in 90 to 95 of cases Primary
  Hypertension
• Secondary Hypertension 5 to 10
• Kidney Abnormalities
• Narrowing of certain arteries
• Rare tumors
• Adrenal gland abnormalities
• Pregnancy

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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.

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Autonomic and Renal Regulation of Blood
Pressure
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• 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).

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• 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.

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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.

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Treatment Rationale

• Short-term goal of antihypertensive therapy
• Reduce blood pressure
• Primary (essential) hypertension
• Secondary 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)

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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

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Antihypertensive Drugs
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classification

• 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.

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Thiazides and Other Diuretic Agents

• Chlorothiazide
• hydrochlorothiazide
• Benzfluothiazide
• Chlorthalidone
• Metalozone
• Antihypertensive action
• Prevent Na retention and reduce plasma and
  extracellular fluid volumes.
• Direct vasodilator action,

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Site of action of diuretics
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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

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• 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

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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.

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Use

• Treatment of essential hypertension
• Treatment of edema
• Treatment of diabetes insipidus
• Treatment of hypercalciuria

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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.

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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.

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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 a or ß adrenergic receptors
• C) decreased availability of neurotransmitter
  released from adrenergic postganglionic
  sympathetic neurons and,
• D) blockade of SNS neurotransmission at the
  level of autonomic ganglia.

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Centrally Acting Sympatholytics

• Drugs that decrease sympathetic nervous system
  outflow from the central nervous system).
• Eg. Clonidine,moxanidine,
• Methyl dopa

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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.

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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.

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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.

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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).

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• 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.

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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.

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• 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.

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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.

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• 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

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Sympatholytics Acting on Autonomic Ganglia

• Trimethaphan (Arfonad)
• Mechanism-block nicotinic receptors at autonomic
  ganglia
• Side Effects Toxicity
• Severe postural hypotension
• Diarrhoea

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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.

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Beta-receptor blockers

• (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 a ßreceptor blockade -Labetalol
  (Normodyne

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Uses

• Treatment of hypertension
• Treatment of supraventricular and ventricular
  arrhythmias
• Angina pectoris
• Migraines
• Other

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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 60-80

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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

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Contraindications

• Asthma Never use in asthmatic patients
• Heart failure, Bradycardia
• Intermittent claudication
• Raynauds

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Alpha blockers

• Non selective alpha blockers
• phentolamine
• phenoxybenzamine
• dibenamine
• Selective alpha1blockers
• Prazosin (Minipress)
• doxazosin (Cardura)
• terazosin (Hytrin)
• trimazosin

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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.

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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).

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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

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Calcium Channel Blockers

• Cardioactive
• i. Verapamil (Calan)
• ii. Diltiazem (Cardizem)
• Vasoactive Dihydropyridines
• Nifedipine-( Procardia)
• Amlodipine (Norvasc)
• Felodipine (Plendil)
• Nimodipine (Nimotop)

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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.

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• . Use
• Treatment of hypertension
• Treatment of angina
• Antiarrhythmic

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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.

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• 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

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Side Effects and Toxicity

• Constipation
• Hypotension
• Atrioventricular block
• Decreased cardiac output leading to, or
  worsening, heart failure
• Ankle Edema
• Other

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Contraindications

• Acute MI
• Heart failure, (rate limiting CCBs)
• bradycardia (rate limiting CCBs)

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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).

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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.
• ?-adrenergic blockers and thiazide diuretics also
  limit symptoms.

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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 10-20
  of patients receiving prolonged therapy with high
  doses

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minoxidil (Rogaine)

• Side Effects and Toxicity
• Tachycardia, palpitations, angina and edema when
  doses of beta-blockers and diuretics are
  inadequate.
• Headache, sweating, and hypertrichosis are
  relatively common.
• .

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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

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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.

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• Nitroprusside (Nipride) - parenterally
  administered vasodilator used in treating
  hypertensive emergencies and severe cardiac
  failure dilates both arterioles and venules
  resulting in decreased peripheral resistance and
  venous return. Solutions are light sensitive and
  metabolized to cyanide.
• Fenoldopam (Corlopam) - Dopamine receptor
  agonist Administered by continuous IV infusion

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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

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Angiotensin-II plays a central role in organ
damage
Atherosclerosis Vasoconstriction Vascular
hypertrophy Endothelial dysfunction
Stroke
Hypertension
A-II AT1 receptor
LV hypertrophy Fibrosis Remodelling
Heart failure MI
DEATH
GFR Proteinuria Aldosterone release Glomerular
sclerosis
Renal failure
Preclinical data LV left ventricular MI
myocardial infarction GFR glomerular
filtration rate
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• Contraindications
• Renal artery stenosis
• Renal failure
• Hyperkalaemia
• Adverse Drug reactions
• Cough
• first dose hypertension
• taste disturbance
• renal impairment
• Angioneurotic oedema

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• Drug-Drug Interactions
• NSAIDs
• Precipitate acute renal failure
• Potassium supplements
• Hyperkalaemia
• Potassium sparing diuretics
• Hyperkalaemia

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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

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Use

• Treatment of hypertensionManagement of
  congestive heart failureAcute MI

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BHS Guidelines

• Young Elderly(low renin)
• A B C D
• A ACE Inhibitor/AT II Blockers
• B Beta Blocker
• C Calcium Channel Blocker
• D Diuretic

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Less commonly used agents

• Alpha-adrenoceptor antagonists
• Doxazosin
• Centrally acting agents
• Methyldopa
• Moxonidine
• Vasodilators
• Hydralazine
• Minoxidil

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• 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 doesnt control BP
• Then use the two together
• A single agent will control BP in 40-50 of
  patients

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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.

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• 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.

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• 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.

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• 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
  beta-blockers or ACE inhibitors.

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• 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

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THE END

• THANK YOU