Antihypertensive Drugs

Nafrialdi

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 Mechanisms of Blood Pressure Regulation
Blood Presure

Cardiac Peripheral
Output Resistance

Heart Rate Stroke Vascular Vessel

volume tone elasticity

Myocardial Blood
contractility volume

Parasympathetic Sympatethic RAAS Local Factors 2

 Parasympathetic:
 Heart rate ↓  Cardiac output ↓  BP ↓
 Sympathetic:
 Heart rate ↑
 Contractility ↑  BP ↑
 Vascular tone ↑
 RAAS:
 Vascular tone ↑
 Blood volume ↑  BP ↑
 Local factors:
 Vasodilator: EDRF, Prostacylin (PGI2)  BP ↓
 Vasocostrictor: Ang. II, Endothelin  BP ↑

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 Blood Pressure Classification
(JNC VI, 1997)
Cathegory DBP SBP
Optimal < 80 < 120
Normal < 85 < 130
High normal 85-89 130-139
Hypertension
Grade 1 (mild) 90-99 140-159
Grade 2 (moderate) 100-109 160-179
Grade 3 (severe) > 110 > 180
Isolated systolic HT < 90 > 140
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 Blood Pressure Classification
(JNC VII, 2003)

BP classification SBP DBP

(mmHg) (mmHg)
Normal < 120 < 80
Prehypertension 120-139 80-89

Stage 1 140-159 90-99

hypertension
Stage 2 > 160 > 100
hypertension

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 Cardiovascular Risk Factors
 Hypertension
 Cigarette smoking
 Obesity (BMI > 30 kg/m2)
 Physical inactivity
 Dyslipidemia
 Diabetes mellitus
 Microalbuminuria or estimated GFR < 60 ml/min.
 Age (>55 yrs for men, > 65 yrs for women)
 Family history of premature CV disease
(men under age 55 or women under age 65)

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 Target Organ Damage

 Heart: left ventricular hypertrophy, heart

failure, angina, myocardial infarction
 Brain: stroke

 Kidney: hypertensive nephropathy

 Vessel: atherosclerosis

 Eye: hypertensive retinopathy

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Treatment Strategy

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Non Pharmacologic Treatment

 Lifestyle modification
 Weight reduction (if over weight/obese)
 Adopt DASH eating plan (rich in fruit and
vegetables, and lowfat diet)
 Dietary sodium reduction
 Moderation of alcohol consumption
 Stop smoking
 Regular physical activity
 Stress avoidance

DASH: Dietary Approach to Stop Hypertension 11

Sites of action of major
classes of
antihypertensive drugs

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 Pharmacologic Treatment
 First line: 6 groups
 Diuretics
 Beta blockers
 ACE-inhibitors
 Ang II receptor blockers (ARB)
 Ca antagonist
 Alpha blockers* (considered first line in JNC VI but not
in JNC VII)
 Second line: 3 groups
 Adrenergic neuron inhibitors
 Central α2- agonist
 Direct vasodilator 13
 I. DIURETICS
 Mechanisms of action:
 Diuresis, natriuresis  blood volume ↓
 cardiac output ↓  BP ↓
 Na+ in serum & vascular smooth muscle ↓
 vascular resistance ↓  BP ↓
3 groups of diuretics:
 I.a. Thiazide
 I.b. Loop diuretics
 I.c. Potassium sparing diuretics

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 I.a. THIAZIDE DIURETICS
Hydrochlorthiazide (HCT), Bendroflumethiazide,
Chlortalidon , Indapamid
 Onset of anti hypertensive effect: 2-3 days
 Maximum effects: 2-4 weeks
 Drug of choice for mild to moderate HT, and
HT with low renin activity (elderly)
 Much less effective in renal insufficiency
 Frequently used in combination with other anti
HT drugs:
 Prevents water retention by other anti HT drugs
 Potentiation with other anti HT drugs
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 Adverse effects
 Hypokalemia  digitalis toxicity ↑
 Hyponatremia, hypomagnesemia

 Hyperuricemia  precaution in gout arthritis

 Hyperglycemia, hypercholesterolemia  not ideal

for DM and dyslipidemia
 Hypercalsemia (rare)  might be beneficial for
retarding osteoporosis
 Sexual dysfunction

 Caution: not effective in renal failure

 Interaction: NSAIDs reduces anti HT effects of
diuretics
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I.b. Loop Diuretics (high ceiling diuretics)
 FUROSEMIDE
 Strong and rapid diuretic effect
 Effective for HT with renal failure
 Firt line drug for heart failure
 Side effects:
 ≈ Thiazide
 Except Hypocalsemia

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 I.c. Potassium Sparing Diuretics
Spironolactone, Triamteren, Amiloride
 Weak diuretics
 Generally used in combination with other diuretic
 Reduces the risk of hypokalemia by other diuretic
 May risk hyperkalemia:
 In renal failure

 In combination with ACE-Inhibitor/ARB, NSAID

 Spironolactone is an aldosteron antagonist

 Drug of choice for hyper aldosteronism

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 II. Beta-Blocker
 Mechanism: inhibition of b1 receptors
 Heart  decreases cardiac output ↓

 Juxtaglomerular cells  renin secretion ↓

 Clinical use:
 Mild to moderate HT

 HT with coronary artery disease

 HT with supraventricular arrhythmia

 HT with tachycardia

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 Adverse effects
 Bronchospasm
 Bradycardia
 Impotency
 Peripheral vascular disturbances
 Unfavourable effect on lipid profile
 Masking hypoglycemic symptoms
 Decrease renal function
 Contraindications
 Asthma, COPD
 Peripheral vascular disease
 AV block grade 2-3
 Sick sinus syndrome

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 III. ACE-inhibitor dan ARB
Angiotensinogen ACE-inhibitor

Angiotensin I Bradykinin

ARB ACE

Angiotensin II Inactive
peptide

AT1 receptor AT2 receptor

•Vasoconstriction •Vasodilatation
•Aldosterone secretion •Nitric oxide secretion
•Vascular/cardiac remodelling •Anti remodelling
•Sympathetic stimulation

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 ACE-Inhibition:
 AngII ↓ : vasodilatation  BP ↓
: aldosterone ↓  Na+ and water retention ↓
 Bradykinin ↑  vasodilatation
 Clinical use:
 First line drug for mild, moderate and severe HT
 HT with heart failure
 Hypertensive crisis
 HT in diabetes, dyslipidemia, and DM nephropathy
 Longterm use: cardioprotective, vasculoprotective

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 Adverse effects:
 Dry cough (10-20%)
 Angio udem, skin rash, dysgeusia
 Hypotension (first dose phenomen)
 Risk of Hyperkalemia:
 In renal failure
 If combined with K+ Sparing Diuretics or NSAID
 Embryotoxic
 Contraindication
 Pregnancy
 Lactation  risk of renal failure in the fetus
 Bilateral stenosis of Renal artery or unilateral stenosis in
single kidney
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Drugs Prodrug/a Active form Hepatic Eliminatio Daily
ctive Metabolism n Dosing
Captopril Active - + Kidney 2-3 x

Lisinopril Active - - Kidney OD

Perindopril Prodrug Perindoprilat + Kidney OD

Enalapril Prodrug Enalaprilat + Kidney OD/ 2x

Ramipril Prodrug Ramiprilat + Kidney OD/ 2x

Quinapril Prodrug Quinaprilat + Kidney OD/ 2x

Silazapril Prodrug Silazaprilat + Kidney OD

Benazepril Prodrug Benazeprilat + Kidney OD/ 2x

Fosinopril Prodrug Fosinoprilat + Kidney + OD

bilier

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 IV. Angotensin Receptor Blockers (ARB)
Losartan, Valsartan, Irbesartan, Candesartan, Telmisartan
 Mechanism of action:
 Blockade of Ang II (AT1) receptor.

  Vasodilatation

  Aldosterone ↓

  Decreasing Ang II-mediated sympathetic

activation
  Prevents vascular and cardiac hypertrophy
(vasculo- and cardio protective)

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 Angotensin Receptor Blocker (ARB)
 Side effects ≈ ACE-I, except:
 No dry cough

 No angio-edema

 Indications and contraindications = ACE-I

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 V. Calsium Channel Blocker

Inhibition of Ca++ influx

 Blood vessels  vasodilatation

 Heart  negative inotropism, negative

dromotropism
  not recommanded in the presence of heart
failure

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 Three groups of CCB
 1. Dihydropyridine (DHP):
 (nifedipine, amlodipine, nicardipine, felodipine, lasidipine,
nitrendipine, …)
Vasculo selective:
 Predominant vasodilatory effect
 Minimal cardiac effects
 2. Diphenylalkilamin: - verapamil
 More cardioselective:
  Decreases myocardial contractility and conduction

 3. Benzothiazepin: - diltiazem
 Cardioselective
  Decreases myocardial contractility and conduction

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 Pharmacokinetics:
 Nifedipine:
 Rapid oral absorpton  rapid BP ↓
 Short T1/2  needs 3-4 x daily dosing
 Amlodipine:
 Slow absorption
 Long T1/2  once daily
 First pass metabolism (all CCB)
 Extensive hepatic metabolism (>90%): all CCB 
precaution in liver failure
 Minimal renal excretion  relatively save for renal
failure
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 INDICATIONS
 Hypertension: dihydropiridine, verapamil,
(diltiazem: rare)
 Hypertensive crisis: nifedipine (sublingual),
nicardipine iv
 Angina pectoris: verapamil, diltiazem, nifedipine
(short acting)
 Arrhythmia: verapamil, diltiazem
Note: Short acting Nifedipin is not recommanded for maitenance therapy
of HT

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 Adverse effects
 Nifedipine:
 Hipotension  risk of myocardial and cerebral
ischemia
 Tachycardia

 Head ache, flushing, peripheral edema

 Verapamil, diltiazem:
 Bradicardia, constipation

Contraindication
 Heart failure (except amlodipine)

 Precaution in liver cirrhosis

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 VI. Alpha-blocker
Prazosin, terazosin, bunazosin, doxazosin
 Blockade of a-1  vasodilatation
 Positive effect on lipid profile (LDL ↓ , HDL ↑)

 Decreases insulin resistance

CLINICAL USAGE
 Mild to moderate HT

 Benign prostatic hypertrophy (HT or not)

 HT with DM /dyslipidemia

 HT with peripheral vascular disease

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 ADVERSE EFFECTS
 Orthostatic hypotension (first dose phenomene:
often w/ prazosin)
 Start low dose, before bed time

 Tachycardia

 Head ache

 Peripheral edema

 Prazosin, terazosin, bunazosin: short halflife  2-3 x

daily
 Doxazosin: longer half life  once daily

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 Second line drugs
 I. ADRENERGIC BLOCKING AGENTS
(Reserpin, Guanetidin)
 Mechanism:
 Reserpin: inhibits NE transport into nerve vesicles
 Guanetidin: Shift NE out of vesicles
  depletion of NE vesicles
 Low dose Reserpin + HCT: effective and very cheap
 Side effects:
 Sedation, deppression
 Nasal congestion
 Peptic ulcer

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  II. Central α-agonist
(Clonidin, methyldopa, guanfasin)
 sympathetic outflow ↓  cardiac output ↓
 Methyldopa: D.O.C for pregnant women

 Side effects:
 Dry mouth, sedation, dizziness
 Sexual dysfunction
 Fluid retention  decreased effects
 Withdrawal effect can lead to hypertensive
crisis
 Interaction: Tricyclic antideppressants,
sympathomimetic drugs  reduces effects

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 III. DIRECT VASODILATORS
 Hydralazin: Mechanism ?
Indications: - HT emergency
- HT in glomerulonephritis
- HT in eclampsia
 Minoxidil & Diazoxide: Potassium channel opener
 Malignant HT
 HT in glumerulonephritis
 Hypertensive encephalopathy
Adverse effects
 Hydralazin: lupus like syndrome, tachycardia, flid
retenton, angina pectoris
 Minoxidil: hirsutism
 Diazoxide: hyperglycemia  for insulinoma
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 Antihypertensive in special conditions

Pregnancy
 Methyldopa: choice
 Beta blocker: atenolol, metoprolol, labetalol (relatively safe)
 CCB: widely used in preeclampsia/ eclampsia, sinergisme
with MgSO4
 Hydralazin: preeclampsia/eclampsia
 ACE-I and ARB: contraindication

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Antihypertensive in special conditions
Hypertensive emergency
 Oral drugs: captopril, nifedipine
 Parenteral drugs: clonidin, nitroglycerin, hydralazin,
furosemide

Renal failure
 CCB, furosemide, clonidine, alpha blocker, hydralazine,
NTG  safe
 ACE-I /ARB  CI if hyperkalemia, stop if creatinine
increases
 B-blocker  tends to reduce renal function

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Antihypertensive in special conditions
Liver cirrhosis
 CCB: not recommanded

Asthma
 Beta-blocker: contraindicated

DM/dyslipidemia
 Choice : ACE-I /ARB
 B-blocker, thiazide: not recommanded
 CCB. a-blocker, clonidine: safe

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