anti hypertensive drugs seminar
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ANTIHYPERTENSIVE DRUGS
Prepared by:
Dr. Vidushi Sharma
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Definition
According to JNC VII :
HYPERTENSION is defined as systemic blood
pressure of 140/90 mm of Hg. Or more on two
separate occasions measured at least one to
two weeks apart.
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Epidemiology
Most common cardiovascular disease.
The prevalence of hypertension increases
with advancing age . Worldwide prevalence estimates for
hypertension may be as much as 1 billion
individuals &
approximately 7.1 million deaths per year
may be attributable to hypertension.
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Etiology:
1. Primary / essential / idiopathic HTN:Cause unknown: 90 95 % of the cases
familial incidence-30%
2. Secondary hypertension:
Underlying cause known: 5-10% of the cases
Renal artery stenosis, renal parenchymal ds.
Hyperaldosteronism, coarctation of aorta
pheochromocytoma,
eclampsia410/25/2010
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Risk Factors:
Family History
Age
High salt-intake
Low potassium intake
Obesity BMI>30
Excess alcohol consumption
SmokingStress
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Diagnosis
Repeated , reproducible measurements
of elevated blood pressure is diagnostic.
Headache (especially upon waking)
EpistaxisDizziness
Tinnitus
Unsteadiness
Blurred visionDepression
Nocturia
Retinopathy,
papilledema (on fundoscopy)
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Grades of Hypertension
(JNC VII)
BP classifications Systolic BP (mmHg) Diastolic BP (mmHg)
Normal =100
7
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MAJOR FACTORS INFLUENCING BLOOD PRESSURE:
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Anatomic sites of BP control
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1. Baroreceptor reflex arc
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2. Humoral control
3. Local hormones10/25/2010
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Vasomotor Sympathetic HEART(1) HR , CO
center ganglion VESSELS() PVR
BP
Decreased Angiotensinogenpressure in activation Renin
renal arterioles. Of JG cells release Angiotensin I
BP Blood Aldosterone Angiotensin II
vol. secretion
BP PVR vasocontriction AT I recp.
REGULATION OF BLOOD PRESSURE 1110/25/2010
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Renin Angiotensin Aldosterone
System (RAAS)
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Inhibitors of RAAS
1. Blockers of Renin secretion Blockers, Clonidine
2. Renin Inhibitors
Enalkiren , Remikiren3. ACE Inhibitors
Captopril Perindopril
Enalapril QuinaprilLisinopril Trandolapril
Ramipril Fosinopril
Benazipril Moexipril1410/25/2010
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Individual drugs
Captopril
Short half life, must be dozed more frequently.
only ACEIs available in oral & parentral form.
Enalapril
pro-drug (t1/2 35hrs) converted to Enalaprilat
(t1/2 10 hrs)-twice daily for effective 24hrs BP control
Quinapril
newer agents, long half life. OD dose
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Therapeutic use
Hypertension
Heart failure
Post MI
Diabetic nephropathy
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Side -effects
Hypotension ( after 1st dose)
Dry brassy cough (commonest)
ARF (C.I B/L renal stenosis)
Hyperkalemia
Fetopathic ( fetal hypotension, anuria, renal
failure, malformations, neonatal death)
Angioneurotic oedema- rare but fatal
minor S/E- neutropenia, cholestatic type
hepatotoxicity, glycosuria, proteinuria.1710/25/2010
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Interactions
K sparing diuretics / K supplements
hyperkalemia.
NSAIDS impair bradykinin induced
vasodilation.
Increased plasma lithium & digoxin levels .
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Angiotensin II (AT 1) Receptor
Antagonist {ARBS}
Losartan, valasartan, candesartan, irbesartan ,
telmisartan.
Diifers from ACEIs:
1. No effect on bradykinin - more selective
2. More complete inhibition of AT1 receptoractivation . Alternate pathways ACEIs.
3. Activation ofAT 2 receptors.
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Therapeutic use:
Alternative to ACEIs
no cough , angioneurotic oedema , dysguesia.
S/E:
Fetal toxicity
ARF
hyperkalemia
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CALCIUM CHANNEL BLOCKERS
a) Phenylalkylamines
VERAPAMIL (t1/2- 6hrs)
b) Benzothiazepines
DILTIAZEM ( t1/2- 3-4 hrs)c) Dihydropyridines
Short Acting-(t1/2-2-6hrs)
NIFEDIPINE & NICARDIPINE , NIMODIPINE Intermediate Acting(t1/2-8-12hrs)- NITRENDIPINE
Long Acting( t1/2- 30-50hrs) - AMLODIPINE
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MECHANISM OF ACTION:
Ca influx through calcium channels
smooth & cardiac muscle
contraction
CCBs stabilises channel in inactivated state.
NET RESULT:
smooth ms. relaxation - vasodilatation
cardiac ms.- SA Node- contractilityAV Node- conduction
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SELECTIVITY:
Verapamil- cardioselective
Diltiazem-. intermediateNifedipine-relatively vascular smooth ms.
Cardiac depressant effects :
Verapamil>diltiazem>nifedipine
Coronary artery dilator effects :nifedipine>verapamil>diltiazem
Vasodilatory effects :nifedipine>verapamil>diltiazem
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Nifedipine
vasoselective preload , Natriuretic effect- no diuretic
Half life 2-6 hrs ( short acting) --- reflex tachycardia
Nimodipine
Crosses BBB
Amlodipine
long acting - ODno reflex tachycardia.
Verapamil
no reflex tachycardia- direct ve chronotropic effect.
alpha blocking action- peripheral vasodilatation.
USE: HTN ( mild to moderate) mostly in combinations.
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ADRs
Headache, dizziness, facial flushing,
hypotension.nifedipine- reflex tachycardia, difficulty invoiding
Verapamil- bradycardia.
Interactions:
verapamil, diltiazem not with Beta blockers,Cardiac depressants- Quinidine
increase plasma digoxin levels
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VASODILATORS
Arteriolar-
Hydralazine, Minoxidil
Dizoxide & Fenoldopam
HYDRALAZINE:
MOA
Direct vasodilators. Opens K channel + NO
generation + c GMP stimulation.
MINOXIDIL
More potent , longer acting2610/25/2010
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DIZOXIDE
open k channels
FENOLDOPAM Agonist of dopamine D1 receptors
Peripheral arterial dilation and natriuresis
S/E
Flushing, headache,nausea, vomiting, tachycardia,nasal congestion, reflex tachycardia
+ minoxidil hypertrichosis.+ dizoxide- hyperglycemia, hyperuricemia, fluid
retention
+ fenoldopam- increased IOP.2710/25/2010
USE: Severe HTN. In Hypertensive emergencies
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SODIUM NITROPRUSSIDE
non selective vasodilatorMOA-
releases NO
NO activates the guanylyl cyclase-cyclic GMP-PKG pathway, leading to vasodilation .
P/K- continuous intravenous infusion
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Pharmacological effect:
Pooling arterial impedence.
S/E:
Headache, flushing.Serious toxicity CN & thiocynate- metabolic acidosis,arrhythmias. in renal insufficiency
USES:Hypertensive emergencies- aortic dissection
during surgeries
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DIURETICS
High ceiling/ medium efficacy:Furosemide, Bumetanide, toresamide,
piretanide, ethacrynic acid & indacrinone.
Medium efficacy :Benzothiadiazines ( thiazides):
Hydrochlorothiazide, chlorothiazide, benzthiazide,
clopamide.
Thiazide like :Chlorthalidone, xipamide, indapamide, metolazone,quinethazone
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Weak/ Adjunctive diuretics:
Carbonic Anhydrase Inhibitors:Acetozolamide, ethoxzolamide, dorzolamide
Potassium Sparing diuretics:Aldosterone antagonists- Spironolactone, eplerinone
Inhibitors of renal epithelial Na channels- Amiloride,Triamterone.
Osmotic Diuretics:
Mannitol, Glycerol
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LOOP DIURETICS
Block NaK2Cl Cotransport at TAL
Relative potency: bumetanide>
toresamide>furosemide> indacrinone
USES:
In severe HYPERTENSION with cardiac &
renal insufficiency
Indacrinone- Hypertensives with gout
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TOXICITIES
Hypokalemic metabolic alkalosis Ototoxicity
Hyperuricemia
Hypomagnesemia Allergic reactions
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THIAZIDE DIURETICS
Block Na/ Cl cotransport at DCT
USES:
In HTN for longer durations at
smaller doses + K supplements .
Heart failure
INDAPAMIDE
More potent & longer acting >
Hydrochlorthiazide.
In diabetic hypertensives
Intrinsic vasodilatory activity
Lesser S/E
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TOXICITIES:
Hypokalemic metabolic alkalosis
Hyperuricemia
hyperglycemia
hyperlipidemia
allergic rxn.
To be avoided :
Hypertensives with DM, gout, hyperlipidemia, renalinsufficiency & pregnancy.
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POTASSIUM SPARING DIURETICSALDOSTERONE ANTAGONISTS
Na INFLUX INHIBITORS
USES
Along with other diuretics to
prevent hypokalemia
Eplerinone more selective less S/E
TOXICITIES:
Hyperkalemia
Hyperchloremic metabolic acidosisGynaecomastia
ARF
Renal stones
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Beta blockers
Non selective:
Propranolol , Sotalol, NadololOxprenolol, Pindolol
(Pindolol and oxprenolol have ISA also)
Selective:
Acebutolol,Esmolol,atenolol,
bisoprolol,metoprolol,nebivolol,betaxolol,celiprolol
(Celiprolol and acebutalol possess ISA also)
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MOA:
1. 1 blockade- HR, FOC, conduction velocity
Cardiac output
2. 1 blockade- Renin secretion
3. Presynaptic recp.-central sympathetic outflow
4. Prostacyclin synth. In vascular bed.
5. Natriuretic peptides secrn.6. Peripheral presynaptic recp. blockade
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Quite effective in mild to moderate HT.
IDDM
Bronchial asthma & COPD
Variant Angina
CCF
PVDs
S/E- bradycardia, rebound HTN after abruptwithdrawl, adverse serum lipid profile
( not with drugs having ISA)
To be avoided in hypertensives with:
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Cardioselective blockers:
Safer in PVD, asthmatics, unfavourable lipid profile.
S/E: rebound HTN after abrupt withdrawl
( not with drugs having ISA)
Atenolol:
doesnt cross BBB.
Nevivilol:
+ vasodilating effect.
Esmolol:
Ultrashort acting IV for HTNsive emergencies.
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Alpha blockers:
Non selective: Phentolamine & phenoxybenzamine
Selective Alpha 1 blockers:doxazosin
phentolamineindoraminphenoxybenzamineprazosinterazosintolazoline
Alpha + Beta blockersbucindololcarvedilollabetalol
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Non selective : cause reflex tachycardia.
Selective:
Less tachycardia
E1 blockers reduce serum triglycerides & LDL
cholesterol, increase HDL cholesterol.
USE:
Selective E1--- Hypertensives with BPH &
Hyperlipidemia & diabetics
Labetelol- in hypertensive emergencies
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Centrally acting Antihypertensives:
Clonidine: E
agonist
decrease central sympathetic outflow.
Used
In moderate HTNS/E
Rebound HTN after abrupt withdrawl
Methyldopa
false transmitter.
DOC in HTN during pregnancy
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Treatment of Hypertension
To prevent morbidity & mortality
ass. with persistent raised BP by
lowering to an acceptable level.
CVD, TIA, stroke, encephalopathy.
LVH, CHF
CAD, Angina , M.I, sudden cardiac death.
Dissecting aneurysms
Glomerulopathy, Renal failure.
GOAL
Preventing target organ damage & complications:
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Weight loss of as little as 10 lbs (4.5 kg) reduces BPand/or prevents hypertension in a large proportion ofoverweight person - ideal is to maintain normal body
weight
Diet rich in fruits, vegetables, low fat dairy products witha reduced content of dietary cholesterol as well assaturated and total fat.
Dietary Approaches to Stop Hypertension (DASH) eating plan:
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Rule out correctable secondary causes ofhypertension 1st.
Non Pharmacological change for essential HTN:
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Rich in potassium and calcium content
Dietary sodium should be reduced to no more than100 mmol per day (2.4 g of sodium).
Limited alcohol intake to no more than 1 oz (30 mL)of ethanol/per day.
Quit smoking
Regular aerobic physical activity such as briskwalking at least 30 minutes per day most days of theweek.
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Compelling indications for the use of
antihypertensive drugs:
Heart failure
High coronary artery disease risk
H/o MI in the past H/o stroke in the past
Diabetes Mellitus
Chronic renal disease.
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BP Classification Life stylemodification
Initial drug therapy
Without compelling
indications
with compelling
indications
NORMAL ENCOURAGE
PREHYPERTENSION YES NO HTNsive DRUGSINDICATED
Drug(s) for the
compelling indications
STAGE 1 HTN YES THIAZIDES FOR MOST,MAY CONSIDER ACEIs/ARBs,
B BLOCKERS , CCBs ,
COMBINATIONS
Drug(s) for thecompelling indications
other antihypertensive
drugs (diuretics, ACE
inhibitor, ARB, beta-
blocker, CCB) as
needed
STAGE 2 HTN YES 2-drug combination for
most (usually thiazide &
ACE Is or ARB or beta-
blocker or CCB)
--------do--------
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JNC VII MANAGEMENT OF HTN :
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Angina-
- blockers, CCBs Avoid- Vasodialtors Asthma/ COPD-
- CCBs, diuretics, ARBs Avoid- ACEIs, blockers
BPH-
DOC- alpha blockers avoid- CCBs
CHF-
- Diuretics, ACEIs Avoid- CCBs except amlodipine
DM-
- ACEIs, avoid- blockers,
CONCOMITTANT ILLNESS:
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Post MI-
- beta blockers, ACEIs
PVD-
- CCBs, alpha blockers avoid- Beta blockers
Renal Insufficiency:
- CCBs, Diuretics avoid- ACEIs.
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Combination TherapyBP regulated by multiple factors-
- to block one increases compensatory activity of other.
Monotherapy not effective:
Diuretics, vasodilators, CCBs, ACEIs blockers, clonidine, methyldopa
Sympathetic inhibitors & vasodilators DiureticsVasodilators Beta blockers
ACEIs/ ARBs Diuretics
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Hypertension in pregnancy
To be avoided: Diuretics: blood volume
uteroplacental defecit( placentalinfarcts, miscarriages)
ACEIs/ ARBs: fetopathic
Non selective blockers- L.B.W, placentalsize, neonatal bradycardia.
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Drugs safer in pregnancy
Hydralazine
Methyldopa
Dihydropyridine gp. Of CCBs: discontinue
before labour weaken uterine contractions.
Cardioselective blockers
Prazosin & clonidine
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FUTURE TRENDS
Enalkiren , Remikiren Renin inhibitors
poor bioavailability, high first pass metabolism
further improvement. Aliskerin
Gene therapy- 30- 35% essential HTN
familial. Genes ACE & Angiotensinogen.
Omapatrilat , Sompatrilat & fasidotrilat
Vasopeptidase inhibitors.- natriuretic
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Mebifradil:
1st generation. Blocks T type Ca channels.
Gilnidipine:
Blocks both L & T type Ca channels.
Lercanidipine:
3rd generation. Block L type Ca channels
66% NaCl reabs. At PCT efforts to inhibit this
Rolofylline- acts at PCT to block A1 recp.
Aquaporins inhibitors at PCT.
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References
Katzung, Basic andClinical Pharmacology. 11th ed.
Principles of pharmacology . HL sharma KKsharma
The Pharmacological Basis of Therapeutics . Goodmanand Gilman .11th ed.
Essentials of Medical pharmacology. K.D Tripathi 6th
ed.
http//hyper.ahajournals.org/cgi/content/full/42/6/1206
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THANK YOU
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