6.1. Antihipertensi

8/13/2019 6.1. Antihipertensi

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ANTIHIPERTENSI


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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.


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CNS

HEART

BV

SYMPATHETICNERVE

1

1

KIDNEY

1 ReninAg

A-I A-II

ACE

Ca++

Aldosteron

Retention

Na & water

BR

2BP

pathophysiopharmacology of hypertension


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First-line antihypertensive drugs

Diuretics

blockers

1blockers

ACE inhibitors

Angiotensin II antagonists

Ca antagonists


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Combination Therapies

-adrenergic blockers and diuretics

ACE inhibitors and diuretics

Angiotensin II receptor antagonists anddiuretics

Calcium antagonists and ACE inhibitors

Other combinations


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Drugs used in hypertension

The four major groups of antihypertension drugs :

1. Diuretics

2. Sympathoplegics

3. Vasodilator4. Angiotensin antagonis


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Sympathoplegics

Sympathoplegics sympathetic nerve function inseveral 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


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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

Methildopais prodrug; it is converted tomethilepinephrine in the brain.

Tox: salt retention, rebound hypertension (suddendicontinuation of clonidine), hematologicimmunotoxicity-hemolytic anemia (methyldopa),sedation (both drugs)


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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).


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Adrenoceptor Blockers

Prototype : -blockers (prazosin-a selective agent,phentolamine, phenoxybenzamine), -blockers(propanolol)

Mechanism of action : Reduce vasc resistance & venous return (alpha-

blocker).

Reduce CO, decrease vasc resistance, reduce

angiotensin levels The non-selective -blockers are of no value in

chronic hypertension because of excessivecompensatory responses, especially tachycardia


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Vasodilator

Drugs that dilate blood vessels by actingdirectly on smooth muscle cells.

Four major mechanism :

- release of nitric oxide.

- opening of potassium channels.

- blockade of calcium channels.

- activation of D1 receptor.


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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-inducedlupus erythematosus (hydralazine)

severe compensatory response, hirsuitisme,pericardial abnormality (Minoxidil)


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Vasodilator

Ca-channel Blocker

Prototype : nifedipine, verapamil, diltiazem

They are effective venodilator because they areorally active, suitable for chronic hypertensionof any severity.

They produce fewer compensatory response.


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Vasodilator

Nitroprusside & Diazoxide

Mechanism of action : nitroprussid release of nitric oxide.

diazoxide opens potassium channels, thus hyperpolarizing and relaxingsmooth 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 (arteriolarvasodiation)

Given by IV infusion, used in hypertensive emergencies


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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 thekidney

- A major site of calcium and magnesium reabsorption


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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 potassiumexcretion

- Reabsorption of water under the control ADH


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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 Thiazidesadequate in mild hypertension.

The Loop diureticsadequate in moderate, severe

& malignant hypertension. Compensatory responses to BP-lowering are

minimal.


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Carbonic Anhydrase Inhibitors

Prototype : Acetazolamide. This diuretics are sulfonamide derivatives

Mechanism of action : inhibition of carbonic anhydrase in the brush border and intracellulercarbonic anhydrase in the PCT. This inhibition occurs in other tissues of the body as well asin 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 potassiumwasting, encephalopathy because of increased ammonia reabsorption.


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Loop Diuretics

Prototype : Furosemide, bumetanide, torsemide(These are sulfonamidederivatives), ethacrinic acids

Mechanism of action : inhibit the cotransport of Na, K, & Cl. The loop diureticsare relatively short acting

Effects :

- produce a massive NaCl diuresis edema fluid rapidly excreted, Blood volumesignificantly 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 ofdiureticsespecially loop diuretic (because of prostaglandin are important inmaintaining glomerular filtration)


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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 inhemoconcentration

Toxicity :

- induce hypokalemic metabolic alkalosis

- cause hypovolemia and CV complication

- ototoxicity

- may cause sulfonamide allergy


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Thiazide Diuretics Prototype : Hydrochlorotiazide (HCT). All the members of

this group are sulfonamide derivatives

Mechanism of action : inhibit Na, Cl transport in the earlysegment of DCT

Effects :

- produce moderate sodium and chloride diuresis

- hypokalemic metabolic alkalosis may occur

- reduce intracellular sodium & promotes sodium-calciumexchangeurine calcium content decrease

- reduce BP (reduction blood volume, reduce vasc resistance)


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Thiazide Diuretics

Clinical use : hypertension, chonic therapy ofedematous (CHF), chronic renal calcium stoneformation

Toxicity :

- massive diuresis with hyponatremia

- potassium wasting

- hyperglycemia (in diabetic patient)

- increase of serum uric acid and lipid levels- potential sulfonamide allerginicity


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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 thiazidediuretics

- Aldosteronism (that may occur in cirrhosis, heart failure)

Toxicity : hyperkalemia, gynecomastia, and anti-androgenic effects


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Osmotic Diuretics

Prototype : Mannitol(given by IV),

glycerin, isosorbide, and urea(rarely used)

Mechanism of action : they poorly reabsorbed from the tubule, remains inthe 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 extractingwater 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 waterfrom intracellular compartment), headche, nausea, & vomiting


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Antiduretic Hormone Agonists

Prototype : ADH (vasopressin), desmopressin. They aremust given parenterally

Mechanism of action : facilitates water reabsorptionfrom 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


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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 inchildren (demeclocycline)


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1% dari penderita hipertensi akan mengalami krisishipertensi 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%)


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DEFINISI

Krisis hipertensiadalah suatu keadaan

peningkatan tekanan darah yang mendadak

(sistole >180 mmHg dan/atau diastole >120

mmHg), yang diperoleh dengan sekurangkurangnya dua kali pengukuran, dengan jarak

1-2 menit, pada penderita hipertensi, yang

membutuhkan penanggulangan segera


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KLASIFIKASI HIPERTENSI KRISIS1. H ipertensi emergensi

Kenaikan tekanan darah mendadak yang disertai kerusakanorgan target yang progresif disebut hipertensi emergensi. Padakeadaan ini diperlukan tindakan penurunan tekanan darah yangsegera dalam kurun waktu menit/jam.

2. H ipertensi urgensiKenaikan tekanan darah mendadak yang tidak disertaikerusakan organ target disebut hipertensi urgensi.

Penurunan tekanan darah pada keadaan ini harus dilaksanakandalam kurun waktu 24-48 jam.

Kedua jenis krisis hipertensi ini perlu dibedakan dengan caraanamnesis dan pemeriksaan fisik, karena baik faktor risiko dan

penanggulangannya berbeda.


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VI. TATALAKSANA KRISIS

HIPERTENSI

Penatalaksanaan krisis hipertensi sebaiknya

dilakukan di rumah sakit, namun dapat

dilaksanakan di tempat pelayanan primersebagai pelayanan pendahuluan dengan

pemberian obat anti hipertensi oral.

Sebelum

RS

Di

RSTransportasi

Sebelum Rumah Sakit


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Obat-obatan yang beredar di Indonesia

Sebelum Rumah Sakit


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Obat-obatan yang digunakan pada

hipertensi emergensi

A.Clonidin (Catapres) IV

B.Diltiazem (Herbesser) IVC.Nicardipin (Perdipin) IV

D.Labetalol (Normodyne) IV

E.Nitroprusside (Nitropress, Nipride) IV

Cl idi (C t ) IV


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Clonidin (Catapres) IV

(150 mcg/ampul)

Clonidin 900 mcg dimasukkan dalam cairan infus glucosa 5%500cc dan diberikan dengan mikrodrip 12 tetes / menit, setiap15 menit dapat dinaikkan 4 tetes sampai tekanan darah yangdiharapkan tercapai.

Bila target tekanan darahtercapai pasien diobservasi selama 4jam kemudian diganti dengan tablet Clonidin oral sesuaikebutuhan.

Clonidin tidak boleh dihentikan mendadak, tetapi dosisditurunkanperlahan-lahan oleh karena bahaya rebound

phenomen, dimana tekanan darah naik secara cepat bila obatdihentikan.


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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.


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Labetalol (Normodyne) IV*

Labetalol diberikan 20-80 mg IV bolus setiap 10

menit atau dapat diberikan dalam cairan infus dengandosis 2 mg/menit.

Nitroprusside (Nitropress, Nipride) IV*

Nitroprusside diberikan dalam cairan infus dengandosis 0.25-10.00 mcg/kg/menit

Hatihati, fotosensitif. Obat harus dilindungi daricahaya, misalnya dengan kain/ plastik hitam.

* Obat-obat ini belum beredar resmi di Indonesia


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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


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

6.1. Antihipertensi

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