SPESIALIT

E
OBAT:
antihipert
ensi
ARIFAH SR
I WAHYUN
I, M.SC, AP
T
2016
 BP regulation operates in a
negative feedback system
Baroreceptors and
chemoreceptors in the carotid
Blood arteries and aortic arch detect
changes in arterial blood
Pressur pressure and in pO2, pCO2 and
H+.
e Increased BP results in increased
review stretch of vessels; activation of
vagus and stimulation of medulla
via sympathetic or
parasympathetic pathways.
 Control of blood pressure
Mean BP is controlled by changing total
peripheral resistance and or cardiac output.
P = CO x TPR (compare Ohms law)

Cardiac output is controlled by sympathetic and para

sympathetic nerves which effect:
heart rate
force of contraction

TPR controlled by nervous and chemical means to

effect constriction/dilatation of
arterioles and venules
Factors determining ABP :
Blood Pressure = Cardiac Output X Peripheral Resistance

(BP) (CO) (PR)

Flow Diameter of
arterioles
BP depends on:
1. Cardiac output CO = SV X HR.
2. Peripheral resistance.
3. Blood volume.
 Heart rate, stroke volume and cardiac output

The pulse rate is not the only way of measuring the heart.
Stroke volume is the amount of blood pumped
out of the left ventricle per beat.

Cardiac output is the amount of blood pumped

out of the left ventricle of the heart per minute.

Cardiac output can be calculated by multiplying

the stroke volume by the heart rate:
cardiac output = stroke volume heart rate

What is the cardiac output of someone with a

heart rate of 60 bpm and stroke volume of 90 ml?

5 of 36 Boardworks Ltd 2006

 Hypertension & regulation of blood pressure
Normal regulation of blood pressure
BP CO PVR
Arterial blood
pressure Cardiac
output Peripheral
Vascular resistance
arteriolar
tone

Blood
volume
Heart Contractility Filling
rate pressure
Venous
tone
Baroreceptors and sympathetic nervous system
Renin-angiotention-aldosterol system (RAAS)
BP review

Normally, when the arterial blood pressure is elevated

1. Kidneys will excrete more fluid
2. Fluid loss will result in decreased ECF volume and blood
volume
3. Decreased blood flow to the heart will reduce cardiac
output
4. Decreased CO reduces arterial blood pressure
5. Vascular endothelium produces vasodilating substances
(nitric oxide, prostacyclin) which reduce blood pressure

7 of 36 Boardworks Ltd 2006

Drugs to treat hypertension

5 primary classes
1. Diuretics
2. Calcium channel blockers
3. Angiotesin converting enzyme (ACE)
inhibitors
4. Autonomic nervous system agents
5. Direct acting vasodilators

8 of 36 Boardworks Ltd 2006

 BP = CO x PVR

cardiac factors circulating volume

heart rate 1. Beta Blockers salt ACEis
2. CCBs
contractility 3. C.A. Adrenergics aldosterone Diuretics

Key:

CCB = calcium channel blockers

CA Adrenergics = central-acting adrenergics
ACEis = angiotensin-converting enzyme inhibitors
 BP = CO x PVR

Hormones Peripheral Sympathetic

1. vasodilators Receptors
2. ACEIs alpha beta
3. CCBs 1. alpha blockers 2. beta blockers

Central Nervous System Local Acting

1. CA Adrenergics 1. Peripheral-Acting Adrenergics
 Evolution of
Antihypertensive Therapies
Effectiveness

Tolerability

1940s 1950 1957 1960s 1970s 1980s 1990s 2001

Direct -blockers ARBs VPIs

ACE
vasodilators inhibitors Others
Peripheral Thiazides
sympatholytics diuretics
Central 2
Ganglion
agonists Calcium
blockers antagonists-
Calcium
Veratrum DHPs
antagonists-
alkaloids
non DHPs Vasopeptidase inhibitors (VPIs) are a new
class of antihypertensive agents that block
-blockers both angiotensin-converting enzyme (ACE)
and neutral endopeptidase
DIURETIC
 Diuretics
Action
0 Reduce blood volume through urinary
excretion of water and electrolytes
Bagaimana meningkatkan ekskresi
urine?
Filtrasi Glomerular atau reabsorbsi
Tubular
0 Electrolyte imbalances can occur
(mainly hypokalemia)
0 Depends on type of diuretic
 1. Diuretics
Selection of diuretcs

Normally used in severe hypertension, in renal

insufficiency and in cardiac failure or
cirrhosis.

Normally used in mild or moderate

hypertension with normal renal and cardiac
function.

Useful to avoid excessive potassium depletion.

Be careful increase blood pressure Nephron, a functional unit of kidney

 Diuretics
0 Most efficient: Loop 0 Most widely
or High-ceiling prescribed: Thiazides
0 Mild to moderate HTN-
primarily
0 Reduce edema
0 Hydrodiuril
assosiated with hydrochlorothiazide
CHF (HCTZ)
0 Hypokalemia
0 Hypokalemia 0 Potassium supplement-
0 KCL supplement KCL
given 0 Apo-hydro, Oretic,
0 Lasix, Demadex, Aquazide H.
Bumex
1. Diuretics
2) Clinical application: diuretics alone for mild or moderate
essential hypertension. Combine with sympathoplegic and
vasodilator drugs to control the tendency toward sodium
retention caused by these agents.
Dosing considerations (thiazide vs. Furosemide)
100 - 200 mg thiazide diuretics are more natriurectic but the same
effect of anti-hypertension is the same as 25 50 mg thiazide
diuretcs.
A threshold amount of body sodium depletion may be sufficient for
anti-hypertensive efficacy.
The blood pressure response to loop diuretics continues to increase at
doses many times greater than the usual therapeutic dose.
1. Diuretics
Adverse effects of diuretcs

Hypokalemia: K+ depletion (except for potassium sparing

diuretcs); may be hazardous in persons taking digitalis, who
have chronic arrhythmias, acute myocardial infarction or
left ventricular dysfunction. Restriction of dietary Na+ intake
will minimize K+ loss.
Mg2+ depletion;
Impair glucose tolerance, induce hyperglycemia;
Increase serum lipid concentrations, induce
hyperlipidemia;
Hyperuricemia, precipitate gout.
 Diuretics
0Potassium-sparing:prevent
hypokalemia
0Mild HTN
0Used in combination with other
diuretics
0No supplement taken
0Watch for hyperkalemia
Potassium-Sparing Diuretics
e.g : amiloride, triamterene, and spironolactone.
Termasuk diureik lemah, aksinya pada collecting
ducts.

Amiloride dan triamterene mengeblok Channel Na +

sehingga mengurangi Na + yang masuk melalui
membran luminal dan mengurangi reabsorpsi NaCl.

Aldosterone antagonist (Spironolactone,

eplerenone)
0 Aldosterone induces the expression of Na/K-
ATPase and Na+ channel
0 Spironolactone and eplerenone blocks aldoserone
receptor reduces Na+ reabsorption and
20 K+
secretion
Types and Names of
Diuretics
Type Example Sites of Action

Thiazides Hydrochlorothiaz Distal convoluted

tubule
ide

Loop diuretic Ethacrynic acid Loop of Henle

Furosemide

K+ - sparing Spironolactone, Collecting tubule

eplerenone
Amiloride, triamteren
 Diuretics (cont)

4. Adverse Reactions 5. Contraindications

dizziness,
electrolyte hypersensitivity,
compromised kidney
imbalance/depletio
function
n cardiac glycosides (K+
hypokalemia, effects)
hypovolemia,
hyperlipidemia, hyponatremia
hyperglycemia
(Thiazides)
gout Quis
The antihypertensive effect of these agents used alone may be limited by
retention of Na+ by the kidney and expansion of blood volume. So
sympathoplegic antihypertensive drugs are most effective when used
concomitantly with a diuretic.

2.
Sympath
oplegic
agents
Adrenergic Blockers

Types of adrenoceptors
Alpha-1
Vasoconstriction
Increased peripheral resistance
Increased blood pressure

Alpha-2
Inhibition of norepinepherine release
Inhibition of insulin release
Beta-Blockers

Types of Adrenoceptors
Beta-1
Tachycardia
Increased lipolysis
Increased myocardial contractility
Beta-2
Vasodilation (in skeletal vasculature)
Slightly decreased peripheral resistance
Bronchodilation
Increased muscle and liver glycogenolysis
Increased release of glucagon
Molecular Mechanism of Action of Sympathomimetics

27
lpha-adrenergic blockers
Non selective alpha blockers are not used in chronic
essential hypertension (phenoxybenzamine,
phentolamine), only used sometimes as in
phaechromocytoma
Specific alpha-1 blockers like prazosin, terazosin and
doxazosine
PRAZOSIN is the prototype of the alpha-blockers

Reduction in t.p.r and mean BP also reduction in

venomotor tone and pooling of blood reduction in CO
Does not produce tachycardia as presynaptic auto (alpha-
2) receptors are not inhibited
 Peripheral Adrenergic Antagonists
Drugs: prazosin (Minipres); terazosin (Hytrin), doxazosin (Cardura )
1. Site of Action- peripheral arterioles, smooth muscle
2. Mechanism of Action
Competitive antagonist at a-1 receptors on vascular
smooth muscle.
1 stimulation cause VC : Vasoconstriction in the
skin & viscera cause increase TVR causing increase BP So,
hypertension may be treated by blocking 1
3. Effects on Cardiovascular System
Vasodilation, reduces peripheral resistance

Stimulate alpha1 receptors -> hypertension

Block alpha1 receptors -> hypotension
only class of antihypertensive agents
that may have the combined effect of
LDL-cholesterol, (HDL)-cholesterol,
and improving insulin sensitivity
 Peripheral Adrenergic Antagonists, cont.
4. Adverse effects
nausea; drowsiness; postural hypotenstion;

5. Contraindications : Hypersensitivity
6. Therapeutic Considerations
no reflex tachycardia; small 1st dose;
dapat untuk pasien : diabetes, asthma, and/or
hypercholesterolemia
mild to moderate hypertension
Sering dikombinasi dengan diuretic, antagonist

Doses: Available as 0.5 mg, 1 mg, 2.5 mg, 5 mg etc. dose:1-4

mg thrice daily (Minipress/Prazopress)
Central Sympatholytics (-2 Agonists)
Drugs: clonidine (Catapres), methyldopa (Aldomet)

0 Site of Action : CNS medullary, Cardiovascular

centers
0 Mechanism of Action
0 CNS a-2 adrenergic stimulation
0 Peripheral sympathoinhibition
0 Decreased norepinephrine release
0 Pharmacological roles: -methylnorepinephrine and
clonidine both bind more tightly to 2 than to 1
adrenoceptors. They bind to presynaptic 2
adrenoceptor to reduce catecholamine release Bind to
postsynaptic 2 adrenoceptor to inhibit activity of
appropriate neurons. Clonidine also binds to
nonadrenoceptor site, the imidazoline receptor,
0 Effects on Cardiovascular System
0 Decreased NE-->vasodilation--> Decreased TPR
-2 Agonists
Methyldopa : Clonidine:
metabolize to - After i.v brief rise in
methyldopamine and blood pressure (direct
- stimulation of
methylnorepinephrin adrenoceptors in
arterioles) and flowed
e;
by a more prolonged
Its antihypertensive hypotension
action appears to be (stimulation of
due to stimulation of adrenoceptors in
central medulla).
adrenoceptors by Clonidine lowers heart rate
methylnorepinephrin and cardiac output more than
-2 Agonists

Clonidine -METHYL DOPA

Stimulate central 2
adrenoceptors 2-agonist
Decreasing PVR Valuable in treating
Useful in hypertension
hypertensive
complicated by renal
disease patients with renal
Sedation & drying of the insufficiency
nasal mucosa
Rebound hypertension
In pregnant women
 drenergic Antagonists
Drugs: propranolol (Inderal); metoprolol (Lopressor)
atenolol (Tenormin); nadolol (Corgard);
pindolol (Visken)
1. Sites of Action
1 : eye, kidney, heart
2 : lung, vascular system,
metabolic system
 drenergic Antagonists, cont.
2. Mechanism of Action
competitive antagonist at adrenergic receptors

1 Reduce heart rate, blood pressure, myocardial

contractility, myocardial oxygen consumption

selective blocker : atenolol, metoprolol

2 Menghambat relaksasi otot di sirkulasi

sistemik, paru dan GI system
Non selective blocker : propranolol, carvidelol,
sotalol, Timolol
 drenergic Antagonists, cont.

3. Effects on Cardiovascular System

a. Cardiac-- HR, SV CO
b. Renal-- Renin Angiotensin II TPR

4. Adverse Effects
impotence; bradycardia;
fatigue; exercise intolerance;

5. Contraindications
asthma; diabetes; bradycardia;
hypersensitivity
 drenergic Antagonists, cont.
6. Therapeutic Considerations
Selectivity
nadolol (Corgard) non selective, but 20 hr 1/2 life
metoprol (Lopresor) selective, 3-4 hr 1/2 life
Risky in pulmonary disease even selective b-1,
Available as mixed a/b blocker available-labetalol
(Trandate, Normodyne)
Use post myocardial infarction- protective
Use with diuretic- prevent reflex tachycardia
PHARMACOKINETICS

REST
VASODILA
T OR
 Relax smooth muscle in
blood vessels resulting in
dilation and decreased
peripheral vascular
Vasodi resistance
lators Reduce afterload so helpful
in heart failure
May cause sodium and
water retention
VASODILATORS
Classification of Vasodilators

Venous Venous
Nitrates Vasodilator

Mixed
Calcium Antagonists
-adrenergic Blockers
ACEI
Nitroprusside

Arterial
Arterial
Vasodilator Minoxidil
Hydralazine
NOguanylatesiklaseAKTIF MOAVasodilators
produksiintraselularcGMP
meningkatproteinkinaseGAKTIF
mengaktifkanfosfataseyang
menginaktivasimyosinrantairingan.Hasil PelepasanNO
akhirnyaadalahrelaksasiototpolos dariendothelium
pembuluhdarah,yangmemungkinkan
relaksasi
pembuluhdarahuntukmembesar
nitroprusside
activationof 1
dopamine Hiperpolarisasiotot
receptors
3
NO polosmelalui
fenoldopam pembukaanchannel
DA K+penurunanCa2
2

+intraseluler

Na+ Ca++ K+ minoxidil

diazoxide
Ca++
hydralazine
 Vasodilators,Cont
1.Effectoncardiovascularsystemvasodilation,decreaseTPR
2.AdverseEffects
reflextachycardia
IncreaseSymNSactivity(hydralazine,minoxidil,diazoxide)
lupus(hydralazine) hypertrichosis(minoxidil)
cyanidetoxicity(nitroprusside)
3.TherapeuticConsiderations
nitroprussideivonly
hydralazinesafeforpregnancy
diazoxideemergencyuseforseverehypertension

Uses:1)Moderatehypertensionwhen1 stlinefailswithbetablockersand
diuretics2)HypertensioninPregnancy,Dose2550mgOD
 Vasodilators
Na Diazo Minoxi Hidral
nitropr xide dil azine
uside
Arterio& Siteof
venodilator Arteriodilator action

Releaseof Openingof Openingof Direct Mechani

(NO) potassium K+channels smof
activation channels insmooth action
ofGC muscle
intracell membranes
ularcGMP

Intravenous Rapid Oral Routeof

infusion intravenou admin.
s
Nanitropruside Diazoxide Minoxidil Hidralazine

1.Hpertensive 1.Moderatesevere Th
emergency hypertension
era
2.Severe
heart failure
2.Treatme
nt of
2.correcti
on of
peu
2.Hyperten
sive
hypoglyce
mia due
baldness
(kebotak
tic
pregnant
woman
to
insulinom
an) use
a s
1.Methemoglobind Inhibitinsulin Hypertricho
uringinfusionNanitropruside
releasefromDiazoxide sis.
Minoxidil Hidralazine Continue
2.Cyanidetoxicity cellsofthe Vasodilator
3.Thiocyanate pancreas s
toxicity causing
SeverehyperglycemiaHypotension,reflextachycardia,
hypotension palpitation,angina,saltand Adverse
Contraindic
waterretention(edema) effects
Contraindicat atedin
edindiabetic females
RAAS
50
The renin-angiotensin-aldosterone system
(RAAS)

Angiotensinogen
Renin
Angiotensin I (AI)
ACE
Angiotensin II (AII)

AT1 receptor AT2 receptor

RAAS
Angiotensinogen
Renin t-PA
Bradykinin ACE A I Cathepsin G
Tonin
Degradation CAGE A II
products Cathepsin G
Chymase

AT1 receptor AT2 receptor

Hypertrophy/proliferation Antiproliferation
Vasoconstriction Antifibrotic
Sympathetic stimulation NO Release
Aldosterone release Differentiation
Vasopressin Vasodilation
ANTIHYPERTENSIVE DRUGS

DRUGS AFFECTING RAAS [renin angiotensin aldosterone

system]-

RENIN INHIBITOR: Beta blockers [Propranolol,

Atenolol, etc], aliskiren

ACE INHIBITORS: Enalapril, Ramipril

ANGIOTENSIN II RECEPTOR [AT1-receptor] BLOCKERS:

Eprosartan, Losartan

ALDOSTERONE ANTAGONIST [ potassium sparing

diuretic ]: Spironolactone
SITE ACTION ACE I AND ARB

ACEI
ACE INHIBITORS
Angiotensin
Converting
Enzyme (ends in PRIL)

captopril enalapril benzapril

(Capoten) (Vasotec) (Lotensin)
 4. Agents that block RAASs

the ACE inhibitors, Captopril, Enalapril, Lisinopril, benazepril,

fosinopril, moexipril, perindopril, quinapril, ramipril, and
trandolapril
Pharmacokinetics & Dosage

Food reduce their bioavailability diminum pada saat perut

kosong
All are pro-drugs, converted to the active agents by hydrolysis
in the liver (Except Captopril).
The half-life of enalaprilat is about 11 hours.

Lisinopril has a half-life of 12 hours

All of the ACE inhibitors except fosinopril and moexipril are

eliminated primarily by the kidneys;
4. Agents that block RAASs

(1) the Adverse effects of ACE inhibitors:

() Severe hypotension (esp. hypovolemic due to diuretics, salt
restriction, or gastrointestinal fluid loss).
() Acute renal failure (particularly in patients with bilateral renal artery
stenosis or stenosis of the renal artery of a solitary kidney),
() Hyperkalemia
() Dry cough and angioedema.
() During the second and third trimesters of pregnancy because of the
risk of fetal hypotension, anuria, and renal failure, sometimes
associated with fetal malformations or death.
() Captopril may cause neutropenia or proteinuria.
() Minor toxic effects like altered sense of taste, allergic skin rashes,
and drug fever
ACEI
Clinical uses
More eff ective in treatment
of hypertension in
conditions associated with
high plasma renin activity (
young & white people ).
Safely used in patients with
ischemic heart disease.
Are useful in treating
patients with diabetic
nephropathy
Treatment of heart failure.
Contraindications
During the second and
third trimesters of
pregnancy because of
the risk of fetal
hypotension,anuria,renal
failure, fetal
malformations and death.
Bilateral renal artery
stenosis or stenosis of
the artery of a solitary
kidney
DRUG
INTERACTIONS ACE
IWith potassium-sparing diuretics
NSAIDs impair their hypotensive
effects
by blocking bradykinin-mediated
vasodilatation.
 Nama Obat Dosis
ACE I
Captopril 12,5-25 mg 2-3
times/daily
enalapril, 5-20 mg OD
Ramipril Start with low
dose; 2.5 to 10
mg daily
Lisinopril available as 1.25,
2.5, 5, 10 1nd 20
mg tab start
with low dose
2-ANGIOTENSIN RECEPTOR
BLOCKING AGENTS

Mechanism of action :
Block AT 1 receptors.
Advantages over ACEI :
They have no effect on bradykinin
system: No cough,wheezing or
angioedema.
Complete inhibition of angiotensin
action compared with ACEI
Losartan is the specific AT1 blocker
LOSARTAN
Pharmacokinetic:
Absorption not aff ected by food but unlike ACEIs its
bioavailability is low. Orally eff ective. Has a potent active
metabolite
High fi rst pass metabolism
Carboxylated to active metabolite E3174
Highly bound to plasma protein
Do not enter brain
Adverse eff ects:
Foetopathic like ACEIs not to be administered in
pregnancy
Rare 1 st dose eff ect hypotension
Low dysgeusia and dry cough
Lower incidence of angioedema
Long half-life, taken once daily.
Available as 25 and 50 mg tablets
 LOSARTAN

Theoretical superiority over ACEIs:

Cough is rare no interference with bradykinin and other
ACE substrates
Complete inhibition of AT1 alternative remains with
ACEs
Result in indirect activation of AT2 vasodilatation
(additional benefi t)
Clinical benefi t of ARBs over ACEIs not known
However, losartan decreases BP in hypertensive which
is for long period (24 Hrs)
heart rate remains unchanged and cvs refl xes are not
interfered
no signifi cant eff ect in plasma lipid profi le, insulin
sensitivity and carbohydrate tolerance etc
Mild uricosuric eff ect
 CALCIUM
CHANNEL
BLOCKER
S
 Calcium Channel Blocking
Agents
Useful in hypertension as dilate
peripheral arteries and decrease
peripheral vascular resistance by
relaxing vascular smooth muscle
Monotherapy or in combination
Tolerated well in renal failure
Calcium Channel Blockers
Examples
Verapamil Very

Procardia (nifedipine)-HTN
Nice

Cardizem (diltiazem)-arrythmias
Drugs
3. Vasodilators
(7) Calcium Channel Blockers

Verapamil, diltiazem, and the dihydropyridine family (amlodipine,

felodipine, isradipine, nicardipine, nifedipine, and nisoldipine)

Nifedipine and the other dihydropyridine agents are more selective

as vasodilators and have less cardiac depressant effect than verapamil
and diltiazem.

Diltiazem has intermediate actions.

Sustained-release calcium blockers or calcium blockers with long

half-lives provide smoother blood pressure control and are more
appropriate for treatment of chronic hypertension.
Calcium Channel Blockers - Classification

diltiazem & verapamil

nifedipine
(and other
dihydropyridines)
Inhibit calcium influx into arterial smooth muscles &
cardiac muscles.
Dihydropyridine group (amlodipine, nifedipine) are
more selective as arteriodilators ( decreasing
afterload)
Verapamil &Diltiazem are more selective as cardiac
depressant ( decreasing C.O) .
Calcium Channel Blockers
SIDE EFFECTS
BP
Bradycardia
May precipitate A-V block
Headache
Abdominal discomfort
Peripheral edema
Calcium Channel Blockers

Advantages:
Unlike diuretics no adverse metabolic effects but mild
adverse effects like dizziness, fatigue etc.
Do not compromise haemodynamics no impairment of

work capacity
No sedation or CNS effect

Can be given to asthma, angina and PVD patients

No renal and male sexual function impairment

No adverse fetal effects and can be given in pregnancy

Minimal effect on quality of life

76
79
NEWER
Antihyper
tensive
Drugs
Newer Antihypertensive Drugs

Aliskiren is a novel, completely nonpeptide, orally active renin

inhibitor that blocks the first and rate-limiting step of the renin-
angiotensin system
Alagebrium, an advanced glycation end product (AGE) crosslink
breaker, has been shown to reduce SBP in patients with uncontrolled
systolic hypertension,
progestin drospirenone and 17beta-estradiol (DRSP/E2),
developed for postmenopausal hormone replacement therapy, has been
shown to lower both clinic and ambulatory SBP in postmenopausal
women
Anticoagulants

Xa

Prothrombin
Thrombin (IIa)
Anticoagulants

Xa

Prothrombin
Thrombin (IIa)

Fibrinogen
Fibrin
Anticoagulants

Xa

Prothrombin
Thrombin (IIa)

Fibrinogen
Fibrin

Plasminogen Plasmin

Fibrin
Degradation
Products
Fibrinolytics clot busters
Antithrombin III
Xa

Heparin
Prothrombin
Thrombin
-

Fibrinogen
Fibrin

Plasminogen Plasmin

Fibrin
Streptokinase Degradation
tPA; rPA; tNK Products
Anticoagulants
Antithrombin III
Warfarin - Xa
Heparin
Prothrombin
Thrombin
-

Fibrinogen
X
Fibrin

Plasminogen Plasmin

Fibrin
Degradation
Products
ARGATROBAN
88

Approved June 2000

direct thrombin inhibitor
Indications:
1. Prophylaxis/treatment of thrombosis in heparin-induced
Thrombocytopenia (HIT)
2. Percutaneous coronary intervention (PCI)
Dosing:
Intravenous infusion
Dose adjustment for moderate hepatic impairment
Argatroban 125 mg in 125 mL aqueous sodium chloride solution
(1 mg/mL) is intended for administration to adult patients
ARGATROBAN
89

Kinetic parameters
Half-life ~45 mins
Primarily excreted in feces (biliary
INR (International Normalized Ratio) monitoring
Combined effect with warfarin
ADRs:
Major bleeding (~5%)
Allergic reactions (?%)
Bivalrudin (Angiomax )
90

Approved December, 2000

Inhibits thrombin by binding to catalytic site and
binding site
Indications:
Unstable angina patients undergoing PCI
Used only in combination with aspirin
Intravenous (bolus + infusion)
Dose adjusted according to body weight
Bivalrudin (Angiomax )
91

Kinetic parameters
Cleared renally and by proteolytic cleavage

Half-life ~25 mins

Dose adjustment in renal impairment

ADRs
Major bleeding (~3.5%)
Back pain (42%), pain, nausea (15%)headache, hypotension
(12%)
Extended-release Niacin/Lovastatin (Advicor)
92

Approved 2001
Inner core of extended-release niacin + lovastatin outer
core
Mechanism
Lovastatin: HMG-CoA enzyme inhibitor
Niacin: decreased esterification of hepatic
triglycerides
Indication
Primary hypercholesterolemia
Mixed dyslipidemia
Nesiritide (Natrecor)
93

Human B-type natriuretic peptide

Vasodilating, natriuretic, and diuretic properties
Indication
Acutely decompensated CHF who have dyspnea at rest or with
minimal activity
Dosing
IV bolus 2 g/kg followed by IV infusion of 0.01 g/kg/min

Prime IV tubing with infusion of 25 mL

If hypotension:
reduce or discontinue dose
May be prolonged (up to hours)
once stabilized can restart at 30% lower dose
94
Nesiritide (Natrecor)
95

Incompatibilites
Heparin, insulin, ethacrynate sodium, bumetanide,
enalaprilate, hydrlazine, furosemide
Do not administer through same IV catheter
Do not administer through central heparin-coated catheter
Kinetic parameters
Half-life ~18 mins
ADRs
Hypotension (11 to 35%); symptomatic ~4 to 17%
Worsening renal function (Scr, azotemia)
Increased mortality?
Olmesartan (Benicar)
96

Approved April, 2002

7th angiotensin-receptor blocker (ARB) to be
approved
Blocks angiotensin-2-receptor which prevents
vasoconstrictor and aldosterone-secreting effects
Indication
Treatment of HTN along or in combination
Olmesartan (Benicar)
97

Kinetic parameters
olmesartan medoxomil converted completely to olmesartan
No metabolism
Mean BP reductions
SBP 13.2 mmHg/DBP 7.3 mm Hg (Chrysant SJ Hum
Hypertens 2003; 17:425-432.)
Dosing
20 mg daily starting dose; titrate to 40 mg daily
Lower starting dose with diuretics or volume depletion
Serum electrolytes & renal function at initiation, one week,
then periodically
Olmesartan (Benicar)
98

ADRs
Hyperkalemia
Dizziness
Worsening renal function
GI upset
Angioedema
Availability
5, 20, 40 mg tablets
Eplerenone (Inspra)
99

Approved September, 2002

Binds mineralcorticoid receptor and blocks binding
of aldosterone (component of Renin-Angiotensin-
aldosterone system)
Lowers BP
Increases serum K+
Indications
CHF post-MI
Hypertension (alone or combination)
Eplerenone (Inspra)
100

Kinetic parameters
Peak concentratios at 1.5 hrs (no food affect)
Metabolized by CYP3A4
Half-life 4 to 6 hrs
Mean BP reductions (Pratt, et al. Am J Hypertension
2002; 15(2):213A.)
randomized controlled trial over 16 wks
SPB 12.8 mmHg/DBP 10.3 mmHg
Eplerenone (Inspra)
101

ADRs
Hyperkalemia

Dizziness

Headache

25 and 50 mg tablets
Rosuvastatin (Crestor)
102

Approved August, 2003

Inhibits 3-hydroxy-3methylglutaryl-coenzyme A
(HMG-CoA)
Enzyme involved in rate limiting step in cholesterol synthesis
Most potent inhibitor
Indication
Hyperlipidemia and mixed hyperlipidemia (adjunct to diet)
Rosuvastatin (Crestor)
103

Kinetic parameters
Not extensively metabolized (~10% by CYP2C9)
Half-life ~19 hrs

Dose
Initial dose 10 mg daily (also options: 5 mg or 20
mg)
Titrate to 40 mg daily
Rosuvastatin (Crestor)
104

ADRs
Hepatotoxicity
LFTs prior to and at 12 weeks, then, periodically
Myopathy
GI (diarrhea, dyspepsia, N & V)
CNS (headache)
Tablets: 5, 10, 20, and 40 mg
Amlodipine/atorvastatin (Caduet )
105

Approved January, 2004

Long-acting calcium antagonist (amlodipine) +
potent statin (atorvastatin)
Indication
Treatment where both amlodipine (HTN, chronic stable angina
or variant angina) and atorvastatin (hyperlipidemia) are
appropriate
Availability (amlodipine/atorvastatin)
Tablets: 5/10, 5/20, 5/40, and 5/80 mg
Tablets: 10/10, 10/20, 10/40, 10/80 mg
Isosorbide dinitrate/hydralazine (BiDil)
106

Approved June, 2005

Indication
CHF treatment in black patients
Dose
1 tablet TID initially, titrate to 2 tabs TID
ADRs
Headache
Dizziness
Availability
Tablets 20 mg ISDN/37.5 mg Hydralazine)
107
108
What is the Cardiac output of a man with a BP =
120/70, pulse = 70/min, cardiac index = 3.2 litres,
and stroke volume of 70 ml?

A. 500 ml/min
B. 1.5 litres/min
C. 3.5 litres / min
D. 5 litres/min
E. 7 litres/min
BACK
SOAL

Example(s) of "high-ceiling" diuretic(s):

A. triamterene (Dyrenium)

B. spironolactone (Aldactone)

C. bumetanide (Bumex)

D. amiloride (Midamor)

E. chlorothiazide (Diuril)
 Adverse effect(s) associated with thiazide
diuretic use:
A. gout

B. Potassium depletion

C. both

D. neither
 1. Diuretics
a. Work to lower BP initially by decreasing peripheral
vascular resistance
b. Thiazide diuretics are potassium sparing
c. Are effective in lowering Bp by 20 25 mmHg in most
patients
d. BP response to thiazides continues to increase at doses
greater than usual therapeutic dose.
e. Diuretics may impair glucose tolerance
0 Propranolol

A. Is a B1 specific blocker
B. Causes prominent postural hypotension
C. Inhibits the stimulation of renin
production by catecholamines
D. Has a half life of 12 hours
E. Has no effect on plasma glucose
Propranolol may cause all
of the following EXCEPT:
A. Bradycardia
B. bronchiolar constriction
C. Hyperglycemia
D. reduced myocardial contractility
E. prevention of the dilation of vessels caused
by circulating epinephrine

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