ANTIHIPERTENSI

PENDAHULUAN

Hipertensi adalah peningkatan tekanan darah (sistole > 140 mmHg, diastole > 90 mmHg). Klasifikasi berdasarkan JNC VII, 2003. TD ditentukan oleh : cardiac output dan peripheral vascular resistance. Organ yang berpengaruh : jantung, pembuluh darah, ginjal.

pathophysiopharmacology of hypertension
CNS BR

HEART

SYMPATHETIC NERVE

BP

1 BV
KIDNEY
Ag Renin A-I ACE A-II

Ca++ Retention Na & water Aldosteron

First-line antihypertensive drugs

Diuretics

blockers

ACE inhibitors

1blockers

Ca antagonists

Angiotensin II antagonists

Combination Therapies

-adrenergic blockers and diuretics ACE inhibitors and diuretics Angiotensin II receptor antagonists and diuretics Calcium antagonists and ACE inhibitors Other combinations

Drugs used in hypertension

The four major groups of antihypertension drugs :
1. 2. 3.

4.

Diuretics Sympathoplegics Vasodilator Angiotensin antagonis

Sympathoplegics

Sympathoplegics sympathetic nerve function in several ways Effects : reduction of venous tone, Heart rate (HR), contractile force of the heart, Cardiac Output (CO) & total peripheral resistance Compensatory responses & adverse effects are marked Classification : - Baroreceptor-sensitizing agents - CNS-active agents - Ganglion-blocking drugs - Postganglionic Sympathetic nerve terminal blockers - Adrenoceptor blockers

Baroreceptor-sensitizing agents

Effects : reducing sympathetic outflow and increasing parasympathetic outflow No currently available drugs act at this site .

CNS-Active Agents

Prototype : Alpha2-selective agonists (clonidine, methildopa) Effects : reducing sympathetic outflow by activation of 2 receptors in the CNS The drugs readily enters the CNS when given orally Methildopa is prodrug; it is converted to methilepinephrine in the brain. Tox : salt retention, rebound hypertension (sudden dicontinuation of clonidine), hematologic immunotoxicity-hemolytic anemia (methyldopa), sedation (both drugs)

Ganglion-blocking drugs

Prototype : nicotinic blockers (trimetaphan, hexamethonium) Effects : extremely powerful BP-lowering Tox : - salt retention. - blurred vision, constipation, urinary hesitancy, sexual dysfunction (PS blockade). - sexual disfunction, orthostatic hypotension (Simpathetic blockade).

Postganglionic sympathetic nerve terminal blockers

Prototype & mechanism of action: Reserpine (deplete the adrenergic nerve terminal of its NE stores). Guanethidine (block release of the stores). In high dose these drugs are very efficacious but produce a high incidence of adverse effects. Have long duration action. Toxicity : behavioral depression (discontinuation of reserpin), orthostatic hypotension & sexual dysfunction(guanethidine).

Adrenoceptor Blockers

Prototype : -blockers (prazosin-a selective agent, phentolamine, phenoxybenzamine), -blockers (propanolol) Mechanism of action : Reduce vasc resistance & venous return (alphablocker). Reduce CO, decrease vasc resistance, reduce angiotensin levels The non-selective -blockers are of no value in chronic hypertension because of excessive compensatory responses, especially tachycardia

Vasodilator

Drugs that dilate blood vessels by acting directly on smooth muscle cells. Four major mechanism : - release of nitric oxide. - opening of potassium channels. - blockade of calcium channels. - activation of D1 receptor.

Vasodilator
Hydralazine & Minoxidil They have more effects on arterioles than on venous. Orally active & suitable for chronic therapy. Mechanism of action : release of nitric oxide from endothelial cells (hydralazine) potassium channel opener (minoxidil) Toxicity : tachycardia, salt&water retention, drug-induced lupus erythematosus (hydralazine) severe compensatory response, hirsuitisme, pericardial abnormality (Minoxidil)

Vasodilator
Ca-channel Blocker Prototype : nifedipine, verapamil, diltiazem They are effective venodilator because they are orally active, suitable for chronic hypertension of any severity. They produce fewer compensatory response.

Vasodilator
Nitroprusside & Diazoxide Mechanism of action :

nitroprussid release of nitric oxide. diazoxide opens potassium channels, thus hyperpolarizing and relaxing smooth muscle

These drugs given parenterally, used in hypertensive emergencies Toxicity :

excessive hypotension, tachycardia, cyanide toxicity (nitroprusside). hypotension, hyperglycemia (because this drug reduces insulin release), salt&water retention

Fenolopam Mechanism of action : D1 receptor activation (arteriolar vasodiation) Given by IV infusion, used in hypertensive emergencies

Angiotensin Antagonists

The groups : Angiotensin Converting Enzyme (ACE) inhibitor (captopril). angiotensin II receptor blockers (losartan, valsartan, irbosartan, candesartan). These drugs are given by oral administration Effects : ACE-inhibitor : a reduction in blood levels of angiotensin II and aldosterone, probably an increase endogenous vasodilators of the kinin family Toxicity : ACE inhibitor : cough, renal damage in patient with preexisting renal vasc disease, renal damage in the fetus. Angiotensin II receptor blockers : fetal renal toxicity, potassium retention These drugs are absolutely contraindicated in pregnancy

DIURETIK

Renal Transport Mechanism

Proximal convoluted tubule (PCT) : - reabsorption of amino acids, glucose, & numerous cations, NaCl, NaHCO3 - Carbonic anhydrase is the enzyme required for the bicarbonate reabsorption process on the brush border and in the cytoplasm Thick portion of the ascending limb of the loop of Henle (TAL) - Pumps NA, K, & Cl out of the lumen into the interstitium of the kidney - A major site of calcium and magnesium reabsorption

Renal Transport Mechanism

Distal convoluted tubule (DCT) - pumps Na & Cl out of the lumen of the nephron via the carier - reabsorption of Calcium under the control of parathyroid hormone (PTH) Cortical collecting tubule (CCT) - the last tubular site of sodium reabsorption - controlled by aldosterone - the primary site of acidification of the urine and of potassium excretion - Reabsorption of water under the control ADH

Diuretics

These drugs lower Blood Pressure (BP) by reduction of Blood volume (BV). The most important diuretics for hypertension therapy are The Thiazides and The loop diuretics. The Thiazides adequate in mild hypertension. The Loop diuretics adequate in moderate, severe & malignant hypertension. Compensatory responses to BP-lowering are minimal.

Carbonic Anhydrase Inhibitors

Prototype : Acetazolamide. This diuretics are sulfonamide derivatives Mechanism of action : inhibition of carbonic anhydrase in the brush border and intracelluler carbonic anhydrase in the PCT. This inhibition occurs in other tissues of the body as well as in the kidney Effects : - bicarbonate diuretics - body bicarbonate depleted, and metabolic acidosis results. - resulting in significant potassium wasting Clinical Uses : - treatment of glaukoma (major application) - must be administered orally - also used to prevent acute mountain (high-altitude) sickness. - their diuretic effect only use if edema is accompanied by significant metabolic alkalosis. Toxicity : drowsiness, paresthesias, allergy (uncommon), formattion of renal stones (alkalinization of the urine may cause precipitation of calcium salts), renal potassium wasting, encephalopathy because of increased ammonia reabsorption.

Loop Diuretics

Prototype : Furosemide, bumetanide, torsemide(These are sulfonamide derivatives), ethacrinic acids Mechanism of action : inhibit the cotransport of Na, K, & Cl. The loop diuretics are relatively short acting Effects : - produce a massive NaCl diuresis edema fluid rapidly excreted, Blood volume significantly reduced - the diluting ability of the nephron is reduced - Ca excretion is significantly increased - moderately effective uricosuric (Ethacrinic acid) - significant potassium (K) wasting and excretion H+ hypokalemic alkalosis - Inhibition of prostaglandin synthesis by AINS will decreases of the effficacy of diureticsespecially loop diuretic (because of prostaglandin are important in maintaining glomerular filtration)

Loop Diuretics

Clinical Use : - treatment of edematous states (eg, heart failure, ascites) - acute pulmonary edema - treatment of severe hypercalcemia (that induced by malignancy) note : diuresis without volume replacement will result in hemoconcentration Toxicity : - induce hypokalemic metabolic alkalosis - cause hypovolemia and CV complication - ototoxicity - may cause sulfonamide allergy

Thiazide Diuretics

Prototype : Hydrochlorotiazide (HCT). All the members of this group are sulfonamide derivatives Mechanism of action : inhibit Na, Cl transport in the early segment of DCT Effects : - produce moderate sodium and chloride diuresis - hypokalemic metabolic alkalosis may occur - reduce intracellular sodium & promotes sodium-calcium exchangeurine calcium content decrease - reduce BP (reduction blood volume, reduce vasc resistance)

Thiazide Diuretics

Clinical use : hypertension, chonic therapy of edematous (CHF), chronic renal calcium stone formation Toxicity : - massive diuresis with hyponatremia - potassium wasting - hyperglycemia (in diabetic patient) - increase of serum uric acid and lipid levels - potential sulfonamide allerginicity

Potassium-Sparing Diuretics

Prototype : spironolactone, a steroid derivative; amiloride, triamterene Mechanism of action : a pharmacologic antagonist of aldosterone in the collecting tubules Effects : - increase in sodium clearance - decrease in K & H+ excretion (potassium-sparing diuretics) - may cause hyperkalemic metabolic acidosis Clinical use : - potassium wasting caused by chronic therspy with loop or thiazide diuretics - Aldosteronism (that may occur in cirrhosis, heart failure) Toxicity : hyperkalemia, gynecomastia, and anti-androgenic effects

Osmotic Diuretics

Prototype : Mannitol (given by IV), glycerin, isosorbide, and urea(rarely used) Mechanism of action : they poorly reabsorbed from the tubule, remains in the lumen and holds water by virtue of its osmotic effect. Effects : - the volume of urine is increased - reduce brain volume and intracranial pressure by osmotically extracting water from the tissue into the blood. A similar effects occurs in the eye Clinical use : - to maintain high urine flow - reducing IOP in acute glaucoma - reducing ICP in neurologic conditions Toxicity : hyponatremia, pulmonary edema (caused by removal of water from intracellular compartment), headche, nausea, & vomiting

Antiduretic Hormone Agonists

Prototype : ADH (vasopressin), desmopressin. They are must given parenterally Mechanism of action : facilitates water reabsorption from the collecting tubule by activating of adenyl cyclase Effects : reduce in urine volume and increased its concentration. Clinical use : pituitary diabetes insipidus Toxicity : hyponatremia (a large water load), hypertension in large doses

Antidiuretic Hormone Antagonists

Prototype : Demeclocycline, lithium (given orally adm) Mechanism of action : inhibit the action of ADH Clinical Use : Syndrome of inappropriate of ADH secretion (SIADH) Toxicity : bone and teeth abnormalities in children (demeclocycline)

1% dari penderita hipertensi akan mengalami krisis hipertensi dengan gangguan kerusakan organ seperti :

Infark serebral (24.5%) Ensefalopati (16.3%) Perdarahan intraserebral/sub-araknoid (4.5%) Gagal jantung akut dgn edema paru (36.8%) Miokard infark akut/angina tidak stabil (12%) Diseksi aorta (2%) Eklampsia (4.5%) Ginjal (1%)

DEFINISI

Krisis hipertensi adalah suatu keadaan peningkatan tekanan darah yang mendadak (sistole >180 mmHg dan/atau diastole >120 mmHg), yang diperoleh dengan sekurang kurangnya dua kali pengukuran, dengan jarak 1-2 menit, pada penderita hipertensi, yang membutuhkan penanggulangan segera

KLASIFIKASI HIPERTENSI KRISIS

1. Hipertensi emergensi Kenaikan tekanan darah mendadak yang disertai kerusakan organ target yang progresif disebut hipertensi emergensi. Pada keadaan ini diperlukan tindakan penurunan tekanan darah yang segera dalam kurun waktu menit/jam. 2. Hipertensi urgensi Kenaikan tekanan darah mendadak yang tidak disertai kerusakan organ target disebut hipertensi urgensi. Penurunan tekanan darah pada keadaan ini harus dilaksanakan dalam kurun waktu 24-48 jam. Kedua jenis krisis hipertensi ini perlu dibedakan dengan cara anamnesis dan pemeriksaan fisik, karena baik faktor risiko dan penanggulangannya berbeda.

Manifesfasi klinis krisis hipertensi:

a. Bidang neurologi:
Sakit kepala, hilang/kabur penglihatan, kejang, defisit neurologis fokal, gangguan kesadaran (somnolen, sopor, koma).

b. Bidang mata:
Funduskopi berupa perdarahan retina, eksudat retina, edema papil.

c. Bidang kardiovaskular:
Nyeri dada, edema paru.

d. Bidang ginjal:
Azotemia, proteinuria, oliguria.

e. Bidang obstetri:
Preklampsia dengan gejala berupa gangguan penglihatan, sakit kepala hebat, kejang, nyeri abdomen kuadran atas, gagal jantung kongestif dan oliguri, serta gangguan kesadaran/gangguan serebrovaskular.

VI. TATALAKSANA KRISIS HIPERTENSI

Penatalaksanaan krisis hipertensi sebaiknya dilakukan di rumah sakit, namun dapat dilaksanakan di tempat pelayanan primer sebagai pelayanan pendahuluan dengan pemberian obat anti hipertensi oral.
Sebelum RS
Di RS

Transportasi

Sebelum Rumah Sakit

Obat-obatan yang beredar di Indonesia

Obat-obatan yang digunakan pada hipertensi emergensi

A.Clonidin (Catapres) IV B.Diltiazem (Herbesser) IV C.Nicardipin (Perdipin) IV D.Labetalol (Normodyne) IV E.Nitroprusside (Nitropress, Nipride) IV

Clonidin (Catapres) IV (150 mcg/ampul)

Clonidin 900 mcg dimasukkan dalam cairan infus glucosa 5% 500cc dan diberikan dengan mikrodrip 12 tetes / menit, setiap 15 menit dapat dinaikkan 4 tetes sampai tekanan darah yang diharapkan tercapai.

Bila target tekanan darah tercapai pasien diobservasi selama 4 jam kemudian diganti dengan tablet Clonidin oral sesuai kebutuhan. Clonidin tidak boleh dihentikan mendadak, tetapi dosis diturunkan perlahan-lahan oleh karena bahaya rebound phenomen, dimana tekanan darah naik secara cepat bila obat dihentikan.

Diltiazem (Herbesser) IV (10 mg dan 50 mg/ampul)

Diltiazem 10 mg IV diberikan dalam 1-3 menit, kemudian diteruskan dengan infus 50 mg/jam selama 20 menit. Bila tekanan darah telah turun >20% dari awal, dosis diberikan 30 ug/Jam sampai target tercapai Diteruskan dengan dosis maintenance 5-10 mg/jam dengan observasi 4 jam kemudian diganti dengan tablet oral. Perlu perhatian khusus pada penderita dengan gangguan konduksi jantung dan gagal jantung.

Nicardipin (Perdipin) IV (2 mg dan 10 mg/ampul)

Nicardipin diberikan 10-30 mcg/kgBB bolus.

Bila tekanan darah tetap stabil? diteruskan dengan 0.5- 6 mcg/kgBB/menit sampai target tekanan darah tercapai.

Labetalol (Normodyne) IV* Labetalol diberikan 20-80 mg IV bolus setiap 10 menit atau dapat diberikan dalam cairan infus dengan dosis 2 mg/menit. Nitroprusside (Nitropress, Nipride) IV* Nitroprusside diberikan dalam cairan infus dengan dosis 0.25-10.00 mcg/kg/menit Hati hati, fotosensitif. Obat harus dilindungi dari cahaya, misalnya dengan kain/ plastik hitam. * Obat-obat ini belum beredar resmi di Indonesia

KRISIS HIPERTENSI PADA KEADAAN KHUSUS:

A. Krisis Hipertensi pada Gangguan Otak B. Krisis Hipertensi pada Penyakit Jantung C. Krisis Hipertensi pada Penyakit Ginjal D. Krisis Hipertensi pada Gangguan Endokrin E. Krisis Hipertensi pada Kehamilan F. Krisis Hipertensi pada Pengguna Napza

Obat-obat parenteral untuk penanganan hipertensi emergensi pada edema paru dan sindroma koroner akut