Anti Hypertensive Drugs Seminar

8/8/2019 Anti Hypertensive Drugs Seminar

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ANTIHYPERTENSIVE DRUGS

Prepared by:

Dr. Vidushi Sharma

([email protected])

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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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Anti Hypertensive Drugs Seminar

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