Anti-Hypertensive Drugs

HTN (Hypertension) is Chronic elevation in blood pressure > 140/90 mmHg ANTIHYPERTENSIVE DRUGS are those drugs used to combat hypertension.

CLASSIFICATION- Anti hypertensives 1st Line Anti-hypertensive drugs

1. ACEI : CAPTOPRIL, ENALAPRIL,RAMIPRIL A

2. ANGIOTENSIN BLOCKERS : LOSARTAN,CANDESARTAN, VALSARTAN

3. BLOCKERS : PROPANOLOL, ATENOLOL 4. CCBs : VERAPAMIL,DILITIAZEM, NIFEDIPINE B C

5. DIURETICS
THIAZIDES: HYDROCHLOROTHIAZIDE,CHLORTHALIDONE

D
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HIGH CEILING:FUROSEMIDE K- SPARING: SPIRONOLACTONE,AMILORIDE

Other Anti-hypertensives
6. + BLOCKERS: LABETALOL, CARVEDILOL 7. ADRENERGIC BLOCKERS: PRAZOSIN, TERAZOSIN 8. CENTRAL SYMPATHOLYTICS: CLONIDINE, METHYL DOPA 9. VASODILATORS : Arterioles- HYDRALAZINE, Minoxidil, Diazoxide Venous + Arteriole- SOD. NITROPRUSSIDE, Nicorandil, blockers 10. Newer drugs- Natriuretic peptides, Fenoldopam 11. Obsolete agents- Reserpine, Guanethidine, Trimethaphan
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Antihypertensive drugs
BP = CO X PVR CO = HR X SV Anatomical sites for regulating BP 1. Arterioles 2. Heart 3. Post-capillary venules 4. Kidney
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DIURETICS -THIAZIDES

MECHANISM OF ACTION:1.Diuresis reduces plasma and e.c.f vol by 5-15% leads to decreased CO 2. Despite compensatory mech. fall in BP is maintained by a slowly developing reduction in PVR. 3. Reduction in PVR is due to persisting sod and vol. deficit 4. Fall in B.P develops over 2-4 weeks
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HIGH CEILING DIURETICS

Prototype FUROSEMIDE. Weaker than THIAZIDES. Fall in b.p dependent on reduction in plasma vol and CO Indications -when HTN is complicated by 1.CRF thiazides are ineffective. 2. Coexisting refractory CHF. 3.Resistance to combination regimes containing a thiazide or marked fluid retention due to use of potent vasodilators 4. Hypertensive emergencies.
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Merits of DIURETICS as Anti HTN

1. 2. 3. 4. 5. 6. 7. Once a day dosing + flat DRC. No fluid retention. No tolerance. Low incidence of postural HTN. Less CNS side effects. Effective in isolated systolic HTN. Decreased risk of hip fracture in elderly & post menopausal pts.
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Demerits of Diuretics as Anti-HTN

1.Hypokalemia. 2.Erectile dysfunction in males. 3.Carbohydrate intolerance(inhibition of insulin release). 4.Dyslipidemia. 5.Hyperuricemia(inhibit urate excretion). 6.Increased incidence of sudden cardiac death- Tdp.
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POTASSIUM SPARING DIURETICS Spironolactone or amiloride lower b.p slightly. Used in conjunction with a thiazide (1) to prevent pot.loss. (2) to augment Anti-HTN action.

Vasoconstriction Sympathetic system Aldosterone release Vent. hypertrophy(Remodelling)

AT1

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ACE INHIBITORS (ACEI)

Pharmacological actions: vasodilatation sympathetic activation Na+ & water retention Heart remodelling Bradykinin

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ACE INHIBITORS (ACEI)

Drugs: Captopril Enalpril- 2.5- 10mg OD (prodrug) Ramipril Perindopril Lisinopril Fosinopril
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ACE INHIBITORS (ACEI)Therapeutic Uses

1. 2. 3. 4. 5. Mild to Moderate CHF HTN (+ DM) / 1st line MI LVH Diabetic Nephropathy

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ACE INHIBITORS (ACEI)

ADR1. Hyperkalemia 2. Postural HTN 3. Cough 4. Laryngeal angioedema 5. Dysgeusia 6. Granulocytopenia 7. Fetotoxic

C/I Pregnancy Bilateral renal artery stenosis D.i Pot. Sparing diuretics Pot. Supplements

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ACE INHIBITORS (ACEI)

1st choice of drug in essential and renovascular HTN. Improve RBF. Retard diabetic nephropathy. Capacity to regress LVH. Most appropriate A-HTN in patients with diabetes, nephropathy,LVH,CHF,post MI cases. More effective in younger HTN. Dose = 2.5 10 mg/day (Enalapril). S/E dry persistent cough.

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AT1 Receptor BLOCKERS (ARB)

Drugs Losartan (50mg/day) Irbesartan Telmisartan Valsartan Therapy HTN- Early action and progresses to peak at 2-4 wks CHF D.i- K+

Merits: No cough / No angiooedema

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CALCIUM CHANNEL BLOCKERS

Classification 1.dihydropyridines amlodipine 2.phenylalkylamine- verapamil 3.benzothiazepine- diltiazem They lower the B.P by decreasing peripheral resistance without compromising cardiac output.

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Advantages of CCBs 1.Quick onset of action. 2.Can be administered once a day. 3.No sedation or CNS effects. 4.Not contraindicated in asthma and angina 5. Do not impair renal perfusion. 6. Do not effect male sexual function. 7. No effect on plasma lipid profile,uric acid level,electrolyte balance. 8. No adverse foetal effects.
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Disadvantages of CCBs
1. Negative inotropic/dromotropic action of diltiazem may worsen CHF & cardiac conduction defects.
2. By smooth muscle relaxant action- worsen GERD. May accentuate bladder voiding difficulty in males.
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3.

 BLOCKERS
Response develops over 1-3 wks. Cardioselective- Atenolol / Metoprolol Non-cardioselective- Plol/ Pindolol Others- Carveidilol / Celiprolol Drugs with ISA cause less reduction of H.R and C.O ,but lower vascular resistance by beta 2 agonism. Non selective beta blockers decrease RBF 20 and GFR.

Demerits- BLOCKERS

C/I-Peripheral vascular disease / ----. Unfavourable efffect on lipid profile. Fared poorly on quality of life. Rebound HTN occurs on sudden discontinuation of beta blockers.

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ADVANTAGES- BLOCKERS
Absence of postural HTN. No Bowel alteration. No Salt and water retention. Less S/E. Low cost. Once a day regimen. Cardioprotective potential.
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VASODILATORS
Arteriolar vasodilators Hydralazine, Minoxidil, Diazoxide

Arteriolar & venous vasodilators Sodium nitroprusside Adrenergic blockers- eg., Prazosin Nicorandil

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ARTERIOLAR VASODILATORS
Hydralazine-

MECHANISM OF ACTION: Endothelium dependent may involve generation of NO and stimulation of cGMP.

USES:
drug of choice in acute severe hypertension in pregnancy

CHF ( + ISDN)
Emergency HTN- IV Hydralazine

ADVERSE EFFECTS:

reflex sympathetic activation (reflex tachycardia, peripheral edema, IHD)

extreme hypotension

Lupus erythematosus
CONTRAINDICATIONS: CAD

multiple CVS risk factors

elderly patients

ARTERIOLAR VASODILATORS
Minoxidil (Prodrug)-

MECHANISM OF ACTION: K+ channel opener relax VSM PVR BP. USES: Adjuvant use in HTN Male patterened Alopecia ADR:

reflex sympathetic activation

diffuse hirsutism (minoxidil) hypertrichosis (minoxidil)

ARTERIOLAR VASODILATORS
Diazoxide-

MECHANISM OF ACTION: K+ channel opener relax VSM PVR BP. USES: Emergency HTN ADR: reflex sympathetic activation Hyperglycaemia

ARTERIOLAR AND VENOUS: eg. Sodium nitroprusside

MECHANISM OF ACTION :
NO released from endothelium dilatation of arterioles and venules cardiac output , t.p.r. USES:

hypertensive emergencies
CHF with pulmonary edema acute aortic dissection controlled hypotension during anesthesia

Sodium nitroprusside ADVERSE EFFECTS :

hypotension palpitation weakness nervousness

vomiting
lactic acidosis

disorientation
thiocyanate toxicity

 ADRENERGIC BLOCKERS eg. prazosin, doxazosin

MECHANISM OF ACTION:
block action of nor-epinephrine on vascular adrenergic receptors Dilates both resistance and capacitance vessels ((arteriolar & venodilaor) BP

USES :
in conjugation with diuretics and blockers drug of second line

ADVERSE EFFECTS ( ADRENERGIC BLOCKERS): postural hypotension ( first dose effect) headache

drowsiness
dry mouth

weakness
palpitation fluid retention nasal blockage blurred vision

CENTRAL SYMPATHOLYTICS
IMIDAZOLE DERIVATIVE- CLONIDINE -METHYL DOPA MOA:- Stimulation of pre-synaptic 2 receptors. Decrease sympathetic outflow Plasma NA declines heart rate and cardiac output t.p.r. and BP USES : add on therapy non emergent HT in pregnancy(-METHYL DOPA)

ADVERSE EFFECTS (Central Sympatholytics):

1. 2. 3. 4. sedation dry mouth depression autoimmune hemolytic anaemia

5.
6.

lupus erythrematosus
rebound hypertension

7.

orthostatic hypotension

Management of Hypertension
BP category Normal SBP (mm Hg) < 120 DBP (mm Hg) < 80 NonPharma T/t Encourge life style changes Drug therapy
No Anti-HT drugs

PreHypertensive

120-139

80-89

No Anti-HT drugs except compelling indications ABCD & combinations ABCD & combinations
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Stage-I HT Stage-II HT

140-159 > 160

90-99 > 100

Non-Pharmacological treatment in the management of HT

Salt restriction Diet- saturated fats / Fibre / calcium Alcohol & abstain from smoking Control DM Control Obesity Exercises- brisk walk for 30mins x 5days/wk Relaxation / meditation / Yoga

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DRUG THERAPY

SBP > 140 / DBP > 90

Pt. young (< 55yrs) & not Black

A or B

Pt. Old (> 55yrs) & Black

C or D

A + C or D Or B + C or D A or B + C + D
A or B + C + D + blocker or spironolactone
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Individualization of anti-hypertensive therapy

Diuretics- Elderly / Blacks/ post-menopausal osteoporosis(Thiazides) ACEI- CHF/ LVH/ DM/ post MI CCB- Angina/ PVD/ elderly/ isolated HT/ Blacks -blockers- Angina/ post MI/ tachyarrythmias/ anxiety/ migraine -blockers- BPH/ poor lipid profile Pregnancy- -methylDOPA/ nifedipine/ vasodialtors

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Management of Hypertensive Emergencies

Requires in BP within 1 hr. DBP > 130 High risk of end organ damage Emergencies include- HT encephalopathy
- HT Nephropathy - Intra-cranial hemorrhage - Aortic dissection - Pre-eclampsia / Eclampsia - Pulmonary edema - Unstable angina / MI
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Management of HT Emergencies
Goal- to reduce BP by 25%(not more) within mins to 1 hr.
- excessive reductions- IHD / Cererbral & Renal ischaemia

Parenteral drug therapy- Sod. Nitroprusside

- IV NTG - Furosemide - Enalprilat - Labetalol - Fenoldapam - Esmolol - Phentolamine + -Blocker (Atenolol-50mg oral)

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