DRUGS USED IN THE TREATMENT OF HYPERTENSION

IKE HUSENIKE HUSEN

Depart. Of Pharmacology & TherapyDepart. Of Pharmacology & Therapy

Faculty Of Medicine -Padjadjaran UniversityFaculty Of Medicine -Padjadjaran University

ANTIHYPERTENSIVE DRUGS Principles of blood pressure regulation:Principles of blood pressure regulation:

1.1. Blood pressure is regulated by the Blood pressure is regulated by the following :following :

a.  cardiac outputa.  cardiac output

b. Peripheral vascular resistanceb. Peripheral vascular resistance

c.Volume of intravascular fluid c.Volume of intravascular fluid (controlled at the kidney)(controlled at the kidney)

2. Baroreflexes adjust moment-to- moment 2. Baroreflexes adjust moment-to- moment

blood pressure:blood pressure: Carotid baroreceptors Carotid baroreceptors

3. Reduction in renal perfusion pressure3. Reduction in renal perfusion pressure

Major Factors Influencing Blood Pressure

ARTERIAL BLOOD PRESSURE

ARTERIAL BLOOD PRESSURE

PERIPHERALRESISTANCE

PERIPHERALRESISTANCE

CARDIAC OUTPUT

Heartrate

Contractility

Filling Pressure

BloodVolume

VenousTone

Arteriolar volume

ANTIHYPERTENSIVE DRUGS

1.1. DIURETICSDIURETICS

2.2. SYMPATHOLYTIC DRUGS SYMPATHOLYTIC DRUGS

3.3. VASODILATORSVASODILATORS

4.4. ACEACE INHIBITORS AND INHIBITORS AND

ANGIOTENSIN II RECEPTOR ANGIOTENSIN II RECEPTOR

ANTAGONISTS ANTAGONISTS

5.5. CALSIUM CHANNEL BLOCKERSCALSIUM CHANNEL BLOCKERS

1. DIURETICS

Mechanisms of ACTION & Mechanisms of ACTION & hemodynamic EFFECT :hemodynamic EFFECT :

- Depleting Na- Depleting Na+ + lead to BV lead to BV & & CO, PR CO, PR

may may . . - 6-8 weeks : CO normal ; PR - 6-8 weeks : CO normal ; PR

Figure 3.Actions of thiazide Diuretics

Decrease inBlood pressure

Thiazidediuretics

Thiazidediuretics

Cardiac OutputCardiac Output

Blood VolumeBlood Volume

Sodium, waterretention

Sodium, waterretention

Peripheralresistance

Peripheralresistance

PHARMACOLOGICAL EFFECT PHARMACOLOGICAL EFFECT DiureticsDiuretics::

Natriuretic (especially loop D.)Natriuretic (especially loop D.) KK+ + excretion (esp. excretion (esp.

acetazolamide; except Kacetazolamide; except K++--Sparing D.)Sparing D.)

CaCa++ ++ excretion (esp. loop D. ; excretion (esp. loop D. ; except Thiazide D.) except Thiazide D.)

Water excretion (esp. loop D.)Water excretion (esp. loop D.)

INDICATION : THIAZIDE DIURETICS : Mild or THIAZIDE DIURETICS : Mild or

moderate essential HT with normal moderate essential HT with normal renal & cardiac function.renal & cardiac function.

LOOP DIURETICS :LOOP DIURETICS :a.a.    Severe HT when multiple drugs Severe HT when multiple drugs

with sodium-retaining properties with sodium-retaining properties are used, in combination therapy.are used, in combination therapy.

b.b. Sodium retention : GFR < Sodium retention : GFR < 30ml/mnt, cardiac failure, cirrhosis30ml/mnt, cardiac failure, cirrhosis

POTASSIUM-SPARING DIURETICS : POTASSIUM-SPARING DIURETICS : a.a.    >< excessive potassium depletion>< excessive potassium depletionb.b. Natriuretic effects of other Natriuretic effects of other

diuretics diuretics

TOXICITY/ADVERSE REACTION : Hypokalemia (except for potassium-Hypokalemia (except for potassium-

sparing D.), precaution :sparing D.), precaution : a.a.    Persons taking digitalisPersons taking digitalis b.b. Chronic arrhythmiasChronic arrhythmias c.c.    AMI AMI

HypomagnesiaHypomagnesia Metabolic effect (especially at Metabolic effect (especially at dose): dose):

a.Glucose intolerancea.Glucose intolerance

b.Serum lipid b.Serum lipid c.Uric acid c.Uric acid , precipitate gout, precipitate gout

2. SYMPATHOLYTIC DRUGS2A. 2A. BLOCKERS BLOCKERS

DRUGS:Prazosin, terazosin, doxazosinDRUGS:Prazosin, terazosin, doxazosin

11 blocking agent: relaxation of arterial blocking agent: relaxation of arterial & &

venous smooth muscle PR and venous smooth muscle PR and arterial BP arterial BP

CO, RBF, GFR CO, RBF, GFR min. (tachycardia and min. (tachycardia and

increased renin release don not occur)increased renin release don not occur)

PHARMACOKINETICS & DOSAGE:

Plasma concentration prazosin Plasma concentration prazosin in in patient CHDpatient CHD

owing primarily to reduced 1owing primarily to reduced 1stst pass pass metabolismmetabolism T T 1/21/2 DOSAGEDOSAGE

PrazosinPrazosin 3-4 h3-4 h Dosis initial 1mg 3X sehari (*)Dosis initial 1mg 3X sehari (*)

Dosis dapat ditingkatkan 20-30mg/hDosis dapat ditingkatkan 20-30mg/h

TerazosinTerazosin 12 h12 h Umumnya: sehari sekali (5-20 mg/h)Umumnya: sehari sekali (5-20 mg/h)

DoxazosinDoxazosin 22 h22 h Sehari sekali, dosis initial 1mg/h (*)Sehari sekali, dosis initial 1mg/h (*)

Dosis dapat ditingkatkan sampai 4mg/h Dosis dapat ditingkatkan sampai 4mg/h atau lebih (prn)atau lebih (prn)

(prn): prorenata = bila perlu(*); untuk mencegah hipotensi postural, sinkop

SIDE EFFECT & TOXICITY

11 blockers causes postural blockers causes postural hypotension, and syncope after hypotension, and syncope after the 1the 1stst dose (1 dose (1stst pass effect) pass effect) the 1the 1stst dose should be small and dose should be small and should be administered at should be administered at bedtimebedtime

Other toxicities (rare): dizziness, Other toxicities (rare): dizziness, headache, palpitations, lethargyheadache, palpitations, lethargy

INDICATION :

Mild to moderate HT.Mild to moderate HT. In combination with In combination with

propranolol or a diuretic for propranolol or a diuretic for additive effect.additive effect.

Figure 4. Actions of -adrenoceptor blocking agents (- BLOCKERS)

Activation of B1 adrenoceptors

on heart

Activation of B1 adrenoceptors

on heart

Cardiacoutput

Cardiacoutput

Peripheral resistance

Peripheral resistance

Angiotensin IIAngiotensin IIReninRenin

Decrease inBlood pressure

AldosteronAldosteron

Sodium, water retention

Sodium, water retention

Blood volumeBlood volume

-Adrenoceptor blockers

-Adrenoceptor blockers

2B. Blockers

DRUGS:

Non selectiveNon selective: propranolol, : propranolol, nadolol, carteololnadolol, carteolol

11 blockers (cardioselective): blockers (cardioselective): atenolol, metoprolol (relative), atenolol, metoprolol (relative), betaxolol, bisoprololbetaxolol, bisoprolol

Partial agonist (Partial agonist (-blockers with -blockers with ISA):ISA): pindolol, acebutolol pindolol, acebutolol (cardioselective), penbutolol.(cardioselective), penbutolol.

-blockers with -blockers with -blocking -blocking effect: labetalol & carvediloleffect: labetalol & carvedilol

PHARMACOKINETICS & DOSAGE: Propranolol: Propranolol: Oral doses >> IV doses (1Oral doses >> IV doses (1stst-pass -pass

hepatic metabolic). T ½ 3-6 h.hepatic metabolic). T ½ 3-6 h. Dose started 80mg/d in divided Dose started 80mg/d in divided

doses. Effective antihypertensive doses. Effective antihypertensive dosage 80-480mg/d, once or twice dosage 80-480mg/d, once or twice daily.daily.

Measures of resting bradycardia and Measures of resting bradycardia and reduction in HR during exercise may reduction in HR during exercise may be used as guides in regulating be used as guides in regulating dosage.dosage.

INDICATION:

- HT with SV tachyarrhythmia, - HT with SV tachyarrhythmia, previous MI, A. pectoris, previous MI, A. pectoris, glaucoma, migraine headache.glaucoma, migraine headache.

- It more effective : young - It more effective : young patient > elderly.patient > elderly.

2C. CENTRALLY ACTING ADRENERGIC DRUGS

a.a.    Clonidine (Clonidine (2 2 )) : Mild to : Mild to moderate HT (not responded to moderate HT (not responded to diuretic alone). diuretic alone). Half of drugs: eliminated Half of drugs: eliminated

unchanged in the urine patient unchanged in the urine patient with renal insuff. with renal insuff. DO DO

Toxicity: dry mouth and sedation Toxicity: dry mouth and sedation (frequent and may be severe) (frequent and may be severe)

CI: risk of mental depressionCI: risk of mental depression

b. Methyldopab. Methyldopa : PR : PR BP BP Do :1-2 g/d orally in Do :1-2 g/d orally in

divided/single dosesdivided/single doses Renal insuff. : reduced drug Renal insuff. : reduced drug

clearanceclearance Distribution: CNS (+)Distribution: CNS (+) Toxicity: sedation, drowsiness; Toxicity: sedation, drowsiness;

depression, Vertigo, lactation depression, Vertigo, lactation (included in men)(included in men)

3. VASODILATORS

Vasodilator:Vasodilator:

A.A.    Hidralazine & minoxidil (p.o): Hidralazine & minoxidil (p.o):

long term outpatient Th/long term outpatient Th/

B.B.      P.e : nitroprusside & diazoxide P.e : nitroprusside & diazoxide

Hypertensive Emergencies.Hypertensive Emergencies.

C.C.      Calcium channel blockersCalcium channel blockers

Figure 5Figure 5MEKANISME KERJA

Arteriole relax Renin C

Vasc. Resistance & BP Na+ & water retention

blockers

Baroreflex:Ino & chronotropic (+)Oxygen consumption

Risk: A.pectoris, Mi, Cardiac failure (in predisposed individuals

3A1. Hydralazine

Dilates arteries and arteriole (not Dilates arteries and arteriole (not veins) veins)

   PR and reflex PR and reflex HR & CO. HR & CO.    Pharmacokinetics :Pharmacokinetics :

Bioavailability Bioavailability (25%) (25%) Metabolism : rapid & slow Metabolism : rapid & slow acetylatorsacetylators

Toxicity:Toxicity: headache, anorexia, headache, anorexia, palpitations, Sweating and palpitations, Sweating and flushing  flushing  

Usage:Usage: Th/ moderately severe Th/ moderately severe HT HT

It is almost always as It is almost always as combination combination

with a with a -blockers and diuretics -blockers and diuretics

((see figuresee figure 5: slide 22) 5: slide 22)

3A2. Minoxidil

Dilates arterioles (not venules)Dilates arterioles (not venules) Indication: severe to malignant Indication: severe to malignant

HT that is HT that is

refractory to other refractory to other drugs (p.o)drugs (p.o)

3B. HYPERTENSI EMERGENCY

Diastolic BP > 150 mmHg Diastolic BP > 150 mmHg (uncomplicated p.) or >130 (uncomplicated p.) or >130 mmHg with complications :mmHg with complications :

- Encephalopathy- Encephalopathy

- Cerebral hemorrhage- Cerebral hemorrhage

- Left ventricular failure- Left ventricular failure

- Aortic stenosis- Aortic stenosis Goal Th/ : rapidly reduce blood Goal Th/ : rapidly reduce blood

pressurepressure

3B1. Sodium Nitroprusside (IV)

Vasodilator (V&A) Vasodilator (V&A) reflex reflex tachycardia tachycardia

VR VR decomp. (-) decomp. (-)

COCO(slight)(slight)

or or change change

decomp. (+) CO decomp. (+) CO

PHARMACOKINETICS:

T ½ : in minutes continuous infusion.T ½ : in minutes continuous infusion.

(<1 hour)(<1 hour)

Nitroprusside Nitroprusside cyanide (*) cyanide (*) thiocyanatethiocyanate

(toxic) (toxic) (nontoxic)(nontoxic)

thiosulfatethiosulfate

urineurine

(*) : rhodenase (mithoch. Enzyme)(*) : rhodenase (mithoch. Enzyme)

SIDE EFFECT/TOXICITY:

Metabolite: may produce cyanide, but cyani- Metabolite: may produce cyanide, but cyani- de toxicity is rare. Th/: thiosulphat and rho-de toxicity is rare. Th/: thiosulphat and rho- danase to produce thiocyanate (less toxic and danase to produce thiocyanate (less toxic and eliminated by kidneys).eliminated by kidneys). Per oral: hydrolyzed to cyanide (!!!)Per oral: hydrolyzed to cyanide (!!!) Toxicity related to accumulation of cyanide :- Toxicity related to accumulation of cyanide :- - Metabolic acidosis- Metabolic acidosis

- - Arrhythmias Arrhythmias - - Excessive hypotensionExcessive hypotension - - Death.Death.

3B2. Diazoxide

Direct-acting arteriolar vasodilator. Direct-acting arteriolar vasodilator. Vascular effect Vascular effect hydralazine. hydralazine. For coronary insuff. patients : diazoxide IVFor coronary insuff. patients : diazoxide IV + + blocker (>< reflex activation of the heart). blocker (>< reflex activation of the heart). USAGE: USAGE: Th/ HT emergency, especially:Th/ HT emergency, especially:

- Malignant HT- Malignant HT- HT encephalopathy- HT encephalopathy- Eclampsia- Eclampsia

TOXICITY: TOXICITY: Excessive hypotension Excessive hypotension

3C. Calcium Channel Blockers

ACTION :ACTION :

- Inhibit Ca- Inhibit Ca++ ++ influx into vasc. smooth influx into vasc. smooth muscle muscle

cells cells tones & vasc. resistance tones & vasc. resistance BP BP (vasodilators) (vasodilators)

- Intrinsic natriuretic effect- Intrinsic natriuretic effect

-- Useful in HT with asthma, Useful in HT with asthma, diabetes, anginadiabetes, angina

and peripheral vascular diseaseand peripheral vascular disease

DRUGS :

A. Dihydropyridine family:A. Dihydropyridine family: -  -  NifedipineNifedipine - Isradipine - Isradipine - Nicardipine- Nicardipine - Nisoldipine - Nisoldipine - Amlodipine- Amlodipine - Felodipine - Felodipine -  -  Nimodipine (esp. cerebral Nimodipine (esp. cerebral

vasodilator)vasodilator)Pharmacological effect :Pharmacological effect : - Selective vasodilators - Selective vasodilators - - Cardiac depressant <<< verap./diltiaz.Cardiac depressant <<< verap./diltiaz. -  -  Reflex sympathetic activation: slight Reflex sympathetic activation: slight

tachycardia and slight increases COtachycardia and slight increases CO

B. Verapamil It has the greatest effect on the heart:It has the greatest effect on the heart: Slows cardiac cond. Slows cardiac cond. HR HR , balanced by , balanced by

reflex activation, NET EFFECT : reflex activation, NET EFFECT : moderate moderate

cardiac suppression (HR&CO cardiac suppression (HR&CO )) Contraindicated in patient with Contraindicated in patient with

preexisting depressed cardiac function preexisting depressed cardiac function or AV conduct. abnormalities !!!or AV conduct. abnormalities !!!

Weak vasodilatorWeak vasodilator

C. Diltiazem

It reduces HR (lesser than It reduces HR (lesser than verapamil), verapamil),

BP BP ..

SIDE EFFECT AND TOXICITY :

Excessive inhibition of CaExcessive inhibition of Ca++ ++ influx influx serious cardiac depression :serious cardiac depression :

-        -        Cardiac arrestCardiac arrest - - BradycardiaBradycardia

-        -        AV blockAV block - CHF- CHF

SIDE EFFECT :SIDE EFFECT :

-        -        FlushingFlushing - Headache - Headache

-        -        HypotentionHypotention - Peripheral - Peripheral edemaedema

-        -        ConstipationConstipation - Fatigue- Fatigue

Dilation of Coronary Vessels

Nifedipine

Verapamil

Dilitiazem

Weakaction

Strong action

AV Conduction

Nifedipine

Verapamil

DiltiazemDecreased

Little effect

Increased

Frequency of adverse effects

Verapamil

Dilitiazem

Nifedipine

Infrequent Frequent

4. INHIBITORS OF ANGIOTENSIN

A. ACE-IBHIBITORA. ACE-IBHIBITOR

-   -   CaptoprilCaptopril - Fesinopril- Fesinopril

-   -   EnalaprilEnalapril - Moexipril- Moexipril

-   -   LisinoprilLisinopril - Quinopril- Quinopril

-   -   BenazeprilBenazepril - Ramipril - Ramipril (long (long

acting)acting)

B. ANGIOTENSIN RECEPTOR- BLOCKING AGENTS

B1. Angiotensin Type 1 (ATB1. Angiotensin Type 1 (AT11) Receptor) Receptor

Blocking AgentsBlocking Agents

- Losartan- Losartan

- Valsartan- Valsartan

B2. Analog and competitive Inhibitor B2. Analog and competitive Inhibitor ofof

Angiotensin II : SaralasinAngiotensin II : Saralasin

Fig. Page 16Fig. Page 16

Kininogen

Bradykinin

Vasodilation

VR

BP

inactive

Angiotensin I

Angiotensi II

Vasoconstriction Aldosteron

VR Na+, water retention

BP

* *

**

Hypertrophi &Remodeling cor & vasc.

*Site of ACE blockade (ACE inhibitor)**Site of receptor blockade (angiotensin-Receptor blocking agent

Figure. 6: Effects of ACE inhibitors

Angiotensinogen(2globulin in blood)

Angiotensin I(inactive)

Renin(from kidney)

Decreased angiotensin II

ACE

-

ACE Inhibitors

Output of sympathetic

nervous systemVasodilation of vascular smooth

muscle

Retention of sodium and water

Levels of bradykinin

Decreasedaldosterone production

Decreased blood pressure

4A. ACE INHIBITOR

Pharmacological effect:Pharmacological effect:Captopril:Captopril:

- - VRVR BP BP- - Aldosteron secretion Aldosteron secretion Na Na++ & &

water water retention retention & K & K++ retention retention

- - Bradikinin Bradikinin vasodilation vasodilation- - VasodilatorVasodilator preload preload COCO

EnalaprilEnalapril: bradykinin : bradykinin

Pharmacokinetics & dosage:

Bioavailability captopril p.o: 70% after Bioavailability captopril p.o: 70% after fasting, p.c.:fasting, p.c.: 30-40%, the antihypertensive 30-40%, the antihypertensive action un-affected. Lisinopril is slowly action un-affected. Lisinopril is slowly absorbed.absorbed.

Distribution: captopril: most body tissues, Distribution: captopril: most body tissues, except CNSexcept CNS

Do. : - captopril: 25mg, 2-3 times daily, Do. : - captopril: 25mg, 2-3 times daily, enalapril: 10-20mg once or twice daily, enalapril: 10-20mg once or twice daily, lisinopril: 10-80mg once daily.lisinopril: 10-80mg once daily.

All of ACE inhib. except fosinopril & All of ACE inhib. except fosinopril & moexipril are eliminated primarily by moexipril are eliminated primarily by kidney. kidney.

Toxicity/side effect:

-  -   Severe hypotension after initial Severe hypotension after initial dose (in dose (in hypovolemic due to hypovolemic due to diuretics, salt restric-diuretics, salt restric- tion, or GI fluid tion, or GI fluid loss)loss)

-     -     ARF (particularly in renal stenosis)ARF (particularly in renal stenosis) -     -     HyperkalemiaHyperkalemia -     -     Dry coughDry cough -     -     AngioedemaAngioedema -     -     Altered sense of tasteAltered sense of taste -     -     Allergic skin rashes, Drug feverAllergic skin rashes, Drug fever

Contraindication: Contraindication: 22ndnd and 3 and 3rdrd trimesters of pregnancytrimesters of pregnancy

Drug interaction:Drug interaction:

-  -  Potassium supp./pot.-sparing Potassium supp./pot.-sparing diureticsdiuretics

hyperkalemia hyperkalemia

-  -  NAIDS may impair the hypotensive NAIDS may impair the hypotensive

effect by blocking bradykinineffect by blocking bradykinin

USAGE:

- - Mild-moderate hypertension Mild-moderate hypertension - - Hypertension who were Hypertension who were

refractory to refractory to standard standard multidrug antihypertensive multidrug antihypertensive regimensregimens

- Hypertension with chronic - Hypertension with chronic congestive congestive heart failureheart failure

4B1. Angiotensin Type 1 (AT4B1. Angiotensin Type 1 (AT11) Receptor) Receptor Blocking Agents (Losartan and Blocking Agents (Losartan and

valsartan).valsartan). Effect on bradykinin metabolism Effect on bradykinin metabolism

(selective (selective blockers) blockers) Losartan: uricosuric effectLosartan: uricosuric effect

4B2. Analog and competitive Inhibitor 4B2. Analog and competitive Inhibitor ofof Angiotensin II : SaralasinAngiotensin II : Saralasin Antagonist and also weak agonist Antagonist and also weak agonist

AT IIAT II the effect: unpredictable the effect: unpredictable