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Curriculum Vitae

Nama : Prof. Dr. dr. Rozaimah Zain-Hamid, MS, SpFK


Fakultas Kedokteran, USU, Medan * Staf Pengajar Program S2 Biomedik & Program Administrasi Kebijakan Kesehatan; Program S3 Kedokteran, Sekolah Pascasarjana, USU, Medan * Wakil Ketua Komisi Nasional Etika Penelitian Kesehatan (KNEPK), Republik Indonesia

Pekerjaan : * Guru Besar Tetap Departemen Farmakologi dan Terapeutik,

Riwayat Pendidikan: * Dokter (dr), dari Fakultas Kedokteran, USU. Medan * Magister Sains (MS), Ilmu Kedokteran Dasar (Basic Medical Sciences), dari Fakultas Pascasarjana, Universitas Indonesia, Jakarta * Doktor (Ph.D), Farmakologi Klinik (Clinical Pharmacology), dari Institute of Post-graduated Studies, Universiti Sains Malaysia, Malaysia * Spesialis Farmakologi Klinik (Sp.FK), dari Dewan Penilai Kepakaran Persatuan Dokter Ahli Farmakologi Klinik Indonesia (PERDAFKI) Pusat, Jakarta.

ROZAIMAH ZAIN-HAMID

Department of Pharmacology and Therapeutics Faculty of Medicine Universitas Islam Sumatera Utara

Sustained arterial hypertension


Damages blood vessels in kidney, heart, brain etc

Renal failure, coronary disease and stroke


Zain-Hamid, R; Faculty of Medicine UISU.

Elevated blood pressure

Multifactorial: Genetic inheritance, psychological stress, environmental & dietary factors

Zain-Hamid, R; Faculty of Medicine UISU.

Epidemiologic studies of hypertension

The risk of damages to kidney, heart, brain are directly related to extent of blood pressure elevation

Zain-Hamid, R; Faculty of Medicine UISU.

Epidemiologic studies of hypertension

Even mild hypertension (blood pressure 140/90 mm Hg) in young or middle-aged adults

The risk of eventual end organ damage


Zain-Hamid, R; Faculty of Medicine UISU.

Epidemiologic studies of hypertension


Other positive risk factors: Smoking, hyperlipidemia, diabetes, manifestations of end organ damage at the time of diagnosis, and family history of cardiovascular disease

The risk of eventual end organ damage


Zain-Hamid, R; Faculty of Medicine UISU.

Effective pharmacologic lowering of blood pressure

Prevent damages of blood vessels

Morbidity and mortality rate


Zain-Hamid, R; Faculty of Medicine UISU.

BP = CO x PVR
BP = Blood Pressure

CO = Cardiac Output
PVR = Peripheral Vascular Resistance

Zain-Hamid, R; Faculty of Medicine UISU.

Sites of blood pressure control

1.RESISTANCE (arterioles) 2. CAPACITANCE (venules) 3. PUMP OUTPUT (heart) 4. VOLUME (kidneys)

Zain-Hamid, R; Faculty of Medicine UISU.

Renal

Contribute to maintain blood pressure

Regulating the volume of intravascular fluid

Zain-Hamid, R; Faculty of Medicine UISU.

Baroreflexes, mediated by sympathetic nerves + Humoral mechanism (renin-angiotensin-aldosterone system)

To coordinate function of 4 control sites

Maintain normal blood pressure


Zain-Hamid, R; Faculty of Medicine UISU.

Regulation of normal blood pressure


A. Baroreflex :

Stretching of blood vessels ( blood pressure)


stimulation

Carotid Baroreceptor
inhibition

Release of central sympathomimetics


Zain-Hamid, R; Faculty of Medicine UISU.

Regulation of normal blood pressure


B. Renal response in blood pressure regulation Renal perfusion pressure renal arteriole pressure
receptor stimulation

Redistribution of renal blood supply

renin production
angiotensin II production

Salt & water reabsorption

Direct peripheral vasoconstriction

aldosterone synthesis

Zain-Hamid, R; Faculty of Medicine UISU.

Regulation of blood pressure in hypertensive

Baroreceptors & Renal blood volume-pressure control system

To be set at a higher level of blood pressure


Zain-Hamid, R; Faculty of Medicine UISU.

ANTIHYPERTENSIVE AGENTS
1.Diuretics (alter sodium & water balance):
depleting body sodium & blood volume

2. Sympathoplegic agents :
peripheral vascular resistance inhibiting cardiac function venous pooling in capacitance vessels
Zain-Hamid, R; Faculty of Medicine UISU.

ANTIHYPERTENSIVE AGENTS
3. Direct vasodilators:
relaxing vascular smooth muscle

4. Agents that block production action of angiotensin:


peripheral vascular resistance &
blood volume

or

Zain-Hamid, R; Faculty of Medicine UISU.

Sites of action of the major classes of antihypertensive drugs


1.CNS / Vasomotor Center :
methyldopa, clonidine, guanabenz & guanfacine

2. Sympathetic nerve terminals :


guanethidine, guanadrel & reserpine

3. Symphatetic ganglia :
trimetaphan

4. - receptors of heart :
propranolol & other -blockers
Zain-Hamid, R; Faculty of Medicine UISU.

Sites of action of the major classes of antihypertensive drugs


5. Blood vessels : 5.1. -receptors of vessels :

prazosin & other 1-blockers

5.2. Vascular smooth muscle :


hydralazine, minoxidil, nitroprussid, diazoksid, verapamil & other Ca++ channel blocker

Zain-Hamid, R; Faculty of Medicine UISU.

Sites of action of the major classes of antihypertensive drugs 6. Renal :

6.1. Renal tubulus :


thiazides, etc

6.2. - receptor of juxtaglomerular cells that release renin :


propranolol & other -blockers

6.3. Angiotensin Converting Enzyme :


captopril & other ACE inhibitors
Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive agent: Drugs that alter sodium & water balance (Diuretics)

Zain-Hamid, R; Faculty of Medicine UISU.

Diuretics
Therapeutic end point in treating hypertension

Daily natriuresis
Zain-Hamid, R; Faculty of Medicine UISU.

Diuretics

To oppose the tendency toward sodium retention in a relatively sodium-depleted patient

Zain-Hamid, R; Faculty of Medicine UISU.

Diuretics
Potassium loss is coupled to reabsorption of sodium

Restriction of dietary sodium intake potassium loss


Zain-Hamid, R; Faculty of Medicine UISU.

Diuretics
blood volume & cardiac output
Peripheral vascular resistance may

After 6-8 weeks


Cardiac output return to normal
Peripheral vascular resistance may
Zain-Hamid, R; Faculty of Medicine UISU.

Diuretics
Effective in blood pressure by 10-15 mm Hg in most patients

Diuretics alone

Adequate treatment for mild or moderate essential hypertension


Zain-Hamid, R; Faculty of Medicine UISU.

Treatment for mild or moderate hypertension and normal renal & cardiac function

Thiazide diuretics Treatment for severe hypertension

Diuretics + sympathoplegic + vasodilator drugs


Zain-Hamid, R; Faculty of Medicine UISU.

More powerful diuretics : acting on the loop of Henle


Severe hypertension, when multiple drugs with sodium - retaining properties are used
Renal insufficiency, when GFR < 30 or 40 mL/min.

Cardiac failure or cirrhosis, where sodium retention is marked


Zain-Hamid, R; Faculty of Medicine UISU.

Potassium sparing diuretics

To avoid excessive potassium depletion, particularly in patients taking digitalis

To enhance the natriuretic effects of other diuretics

Zain-Hamid, R; Faculty of Medicine UISU.

Thiazide diuretics
More natriuretic at higher doses ( >100 200 mg hydrochlorothiazide)

When used as a single agent, lower doses (25 50 mg) exerts as much antihypertensive effect do higher doses
Zain-Hamid, R; Faculty of Medicine UISU.

Most common adverse effect of diuretics


Potassium depletion ( hypokalemia) Magnesium depletion Impair glucose tolerance

serum lipid & uric acid concentration

Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive agent: Drugs that alter sympathetic nervous system function

Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs that alter sympathetic nervous system function


1. Centrally acting sympathoplegic
2. Inhibition transmission through autonomic ganglia 3. Reducing release of norepinephrine from sympathetic nerve endings 4. Block postsynaptic adrenoceptors
Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs that alter sympathetic nervous system function

1. Centrally acting sympathoplegic

Cause sedation & mental depression, disturbances of sleep (nightmare)

Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs that alter sympathetic nervous system function

2. Inhibition transmission through autonomic ganglia

Produce toxicity from inhibition of parasympathetic regulation, in addition to profound sympathetic blockade
Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs that alter sympathetic nervous system function

3. Reducing release of norepinephrine from sympathetic nerve endings

Cause effect similar to those of surgical sympathectomy


(inhibition of ejaculation, hypotension that is increased by upright posture & after exercise)
Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs that alter sympathetic nervous system function

4. Block postsynaptic adrenoceptors

Produce a more selective spectrum of effects depending on the class of receptor to which they bind
Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs that alter sympathetic nervous system function

Used alone may be limited by retention of sodium & expansion of blood volume More effective when used concomitantly with a diuretics
Zain-Hamid, R; Faculty of Medicine UISU.

Adrenoceptor antagonist

Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive drugs :
Block postsynaptic adrenoceptors (adrenoceptor antagonist)

- adrenoceptor-blocking agents
(propranolol, metoprolol, nadolol, carteolol, atenolol, pindolol, acebutolol, labetalol)

- adrenoceptor-blocking agents
(prazosin & other -blockers)
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (propranolol)
Indication:
Mild to moderate hypertension

Severe hypertension
preventing the reflex tachycardia that often results from treatment with direct vasodilator
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (propranolol)
Mechanism of action:
Antagonizes 1and 2 - adrenoceptors First administration CO (bradycardia)

Continued treatment peripheral resistance


Inhibits the stimulation of renin production by cathecolamine (mediated by 1- receptors) Depression of the renin angiotensin aldosterone system
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (propranolol)
Pharmacokinetics :
Peroral first pass metabolism;
T : 3-6 hours

Withdrawal syndrome : nervousness, tachycardia, intensity of angina &BP

Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (propranolol)
Side effects :
Predictable extension of - blocking action occur in patients with myocardial reserve, asthma, peripheral vascular insufficiency & diabetes Other side effects : diarrhea, constipation, nausea, vomiting, mental depression, nightmares, insomnia etc
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (propranolol)

Plasma triglycerides & HDL-cholesterol, which theoretically could contribute to atherogenesis

Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (metoprolol)
Equipotent to propranolol as a 1- blockers
More selective to 1- receptor than propranolol asthmatic patients, diabetes and other peripheral vascular disease Inhibiting stimulation 2 reseptor 50-100 fold less potent than propranolol

Cardios selectivity is not complete: eksaserbasi asma


Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (nadolol, carteolol, atenolol)

Nadolol & carteolol non selektif 1-blocker Atenolol & betaxolol selective - 1 blocker & longer T once a day dosages to obtain a satisfactory therapeutic effect should dosage 4-5/day Renal function nadolol, carteolol & atenolol
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers (labetalol)

BP systemic vascular resistance without significant alteration in HR or CO

Has -blocking action & - blocking action, ( : = 3 : 1)


For treatment hypertension with pheochromocytoma & hypertensive emergency
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers
(Prazosin, terazosin & doksazosin)

Pharmacokinetic
- First pass metabolism

Zain-Hamid, R; Faculty of Medicine UISU.

(Prazosin, terazosin & doxazosin)


Mechanismof action
Blocking 1 in arterioles & venules BP arterioles & venules dilatation 1- receptors selectivity produce less reflex tachycardia Retention of salt & fluid occurs when these drugs are administered without diuretics
Zain-Hamid, R; Faculty of Medicine UISU.

- blockers

(Prazosin, terazosin & doxazosin)


Pharmacokinetic : First pass metabolism (liver) Side effects :

- blockers

postural hypotension first dose should be small & administered at bedtime


Other side effects : dizziness, palpitation, & headache
Zain-Hamid, R; Faculty of Medicine UISU.

ACE-inhibitors
(Angiotensin Converting Enzyme- Inhibitors)

Zain-Hamid, R; Faculty of Medicine UISU.

ACE- Inhibitors

Captopril, enalapril, lisinopril


Benazepril, fosinopril, quinapril,
ramipril
(Long-acting members of ACE-inhibitors)
Zain-Hamid, R; Faculty of Medicine UISU.

ACE- Inhibitors
(Captopril)

Mechanism of action :
Inhibitory action on renin - angiotensin system
Stimulation kalikrein - kinin system

Zain-Hamid, R; Faculty of Medicine UISU.

ACE- Inhibitors
(Captopril)

Mechanism of action :
Improved intrarenal hemodynamics glomerular efferent arteriole resistance

intraglomerular capillary pressure


Zain-Hamid, R; Faculty of Medicine UISU.

ACE- Inhibitors
(Captopril)

Pharmacokinetics :
Bioavailability : +70 % & decreased by 30 - 40 % (if drug take with the food) T : 3 hours

Blood levels correlate poorly with clinical response


Zain-Hamid, R; Faculty of Medicine UISU.

ACE- Inhibitors
(Captopril) Side effects :
Severe hypotension
(hypovolemia diuretics, salt limited, dirrhea)

Other side effects :


Acute renal failure, hyperkalemia, cough

Contra indication :
pregnancy (malformation)
Zain-Hamid, R; Faculty of Medicine UISU.

Conclusions :
Effective pharmacologic lowering BP has been shown to prevent damage to blood vessels & reduce morbidity and mortality

Antihypertensive agents give different mechanisme to regulate blood pressure Combination of antihypertensive agents is necessary to optimize hypertension therapy
Zain-Hamid, R; Faculty of Medicine UISU.

Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive agent: Centrally acting sympathoplegic drugs

Methyldopa Clonidine

Zain-Hamid, R; Faculty of Medicine UISU.

Antihypertensive agent: Centrally acting sympathoplegic drugs

Methyldopa & clonidine slightly different hemodynamic effects :


clonidine lowers heart rate & cardiac output more than does methyldopa
they may act primarily on different populations of neurons in vasomotor center of the brain stem
Zain-Hamid, R; Faculty of Medicine UISU.

Methyldopa
Useful for mild to moderately severe hypertension
peripheral vascular resistance, with variable in heart rate & cardiac output Sometimes cause postural hypotension (orthostatic hypotension) One potential advantage of methyldopa is renal vascular resistance
Zain-Hamid, R; Faculty of Medicine UISU.