SPESIALIT

E
OBAT:
antihipert
ensi

ARIFAH SR
I WAHYUN
I, M.SC, AP
T
2012

BP review
Any condition that affects heart rate,
stroke volume or peripheral vascular
resistance affects arterial blood
pressure
Compensatory mechanisms to
maintain balance between
hypotension and hypertension

BP review
BP regulation operates in a negative feedback
system
Baroreceptors and chemoreceptors in the carotid
arteries and aortic arch detect changes in arterial
blood pressure and in pO2, pCO2 and H+.
Increased BP results in increased 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

Hypertension & regulation of blood pressure

Normal regulation of blood pressure
BP
Arterial blood
pressure

Heart
rate

CO
Cardiac
output

Contractility

PVR
Peripheral
Vascular resistance

Filling
pressure

Baroreceptors and sympathetic nervous system

Renin-angiotention-aldosterol system (RAAS)

arteriolar
tone

Blood
volume
Venous
tone

Factors determining ABP :

Blood Pressure = Cardiac Output X Peripheral Resistance

(CO)
Flow

(BP)

BP depends on:

(PR)
Diameter of
arterioles

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?

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0 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.
B.
C.
D.
E.

500 ml/min
1.5 litres/min
3.5 litres / min
5 litres/min
7 litres/min

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

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Basic pharmacology of
antihypertension drugs

BP = CO x PVR
cardiac factors
heart rate
contractility

1. Beta Blockers
2. CCBs
3. C.A. Adrenergics

circulating volume
salt

ACEis

aldosterone

Diuretics

Key:
CCB = calcium channel blockers
CA Adrenergics = central-acting adrenergics
ACEis = angiotensin-converting enzyme inhibitors

BP = CO x PVR

Hormones
1. vasodilators
2. ACEIs
3. CCBs

Peripheral Sympathetic
Receptors
alpha
beta
1. alpha blockers 2. beta blockers

Central Nervous System

1. CA Adrenergics

Local Acting
1. Peripheral-Acting Adrenergics

MAJOR ANTIHYPERTENSIVE
DRUGS
1) Diuretics
a) Thiazides and congeners.
b) Loop diuretics.
c) Potassium-sparing diuretics.
d) Carbonic Anhidrase Inhibitor
e) Osmotic Diuretic
2) Sympathoplegic agents
f) Centrally acting
sympathoplegic drugs
g) Ganglion blocking agents
h) Adrenergic neuron-blocking
agents
i) Adrenoceptor antagonists .

3) Vasodilators
- Nitric oxide releasers.
- Potassium channel
openers.
- Calcium channel blockers.
4) Angiotensin inhibitors
and antagonists.
- Angiotensin Converting
Enzyme (ACE) inhibitors.
- Angiotensin receptor
antagonists.

Evolution of
Antihypertensive Therapies
Effectiveness
Tolerability
1940s

1950

1957

1960s

-blockers

Direct
vasodilators
Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids

1970s

1980s

ARBs
ACE
inhibitors

Thiazides
diuretics
Central 2
agonists
Calcium
antagonistsnon DHPs

-blockers

1990s

2001

VPIs
Others

Calcium
antagonistsDHPs
Vasopeptidase inhibitors (VPIs) are a new
class of antihypertensive agents that block
both angiotensin-converting enzyme (ACE)
and neutral endopeptidase

DIURETIC

DIURETIC

Adalah obat-obat yang bekerja

meningkatkan ekskresi air dan Na.

pada

ginjal

untuk

Bagaimana meningkatkan ekskresi urine?

Filtrasi Glomerular atau reabsorbsi
Tubular
Tujuan penggunaan diuretic
1. Menjaga jumlah volume urine yang
dikeluarkan ( e.g.: renal failure)
2. Untuk mengurangi edema (e.g.: heart
failure, liver failure; nephrotic syndrome)
3. Untuk mengontrol tekanan Darah .
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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 (cont)
1. Site of Action
Renal Nephron
2. Mechanism of Action
Urinary Na+ excretion
Urinary water excretion
Extracellular Fluid
and/or Plasma Volume

3. Effect on Cardiovascular System

Acute decrease in CO
Chronic decrease in TPR, normal CO
Mechanism(s) unknown

A. Diuretics Osmosis

Osmotic Diuretics (e.g.: Mannitol)

Mekanisme aksi : merupakan senyawa hidrofilik
yang mudah disaring melalui glomerulus dengan
sedikit penyerapan kembali, dengan demikian
meningkatkan keluaran urin melalui osmosis ..
Pemberian: Diberikan secara i.v
Adverse Reactions:
dehidrasi
Hypernatremia karena yang diekskresikan lebih banyak
air daripada garam elektrolit.
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B. Carbonic anhydrase inhibitors

Carbonic Anhydrase Inhibitors
(Acetazolamide (Oral) ;
Dorsolamide (Ocular) ;
Brinzolamide (Ocular)

Acetazolamide inhibits carbonic

anhydrase (CA) manly in proximal tubules.

H2O + CO2

CA

H2CO3

H2CO3 + H+

Mekanisme aksi : Menurunkan

reabsorbsi bikarbonat pada tubulus
proksimal melalui inhibisi katalis
hidrasi CO2 dan reaksi dehidrasi.
Na+ yang meningkat akan dialirkan
nefron distal, meningkatkan sekresi
K
ESO Acetazolamide: Sedasi,
Acidosis; Renal stone (Phosphate
and Calsium stone) ;
Hyperchloremia, hyponatremia dan
hypokalemia

Thiazide Diuretic

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); hypokalemia 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
hyperlipidemia;

lipid

Hyperuricemia, precipitate gout;

concentrations,

induce

Potassium-Sparing Diuretics

e.g : amiloride, triamterene, and spironolactone.

Termasuk diureik lemah, aksinya pada saluran pengumpulcollecting
ducts.
Amiloride dan triamterene mengeblok Channel Na +
sehingga mengurangi Na + yang masuk melalui membran luminal dan
mengurangi reabsorpsi NaCl.

Aldosterone antagonist (Spironolactone, eplerenone)

Aldosterone induces the expression of Na/K- ATPase and Na +

channel
Spironolactone and eplerenone blocks aldoserone receptor
reduces Na+ reabsorption and K+ secretion
26

Mechanisms of Action: Collecting tubule

and potassium-sparing diuretics

Two cell types in

collecting tubule
1. Principal cells transport
Na, K, water
2. Intercalated cells
secretion of H+ and HCO3
3. Blocking Na+ movement in
also prevents K+ movement
out

Diuretics (cont)
4. Adverse
Reactions
0
0

0
0
0
0

dizziness,
electrolyte
imbalance/depleti
on,
hypokalemia,
hyperlipidemia,
hyperglycemia
(Thiazides)
gout

5.
Contraindications
0
0

hypersensitivity,
compromised
kidney function
0
cardiac
glycosides (K+
effects)
0
hypovolemia,
0
hyponatremia

Types and Names of

Diuretics
Type
Example
Sites of Action
Osmotic agents

Mannitol

Proximal tubule
Descending loop
Collecting duct

Carbonic
anydrase inhib.

Acetazolamide

Proximal tubule

Thiazides

Hydrochlorothiaz
ide

Distal convoluted
tubule

Loop diuretic

Ethacrynic acid
Furosemide

Loop of Henle

K+ - sparing

Spironolactone
Amiloride

Collecting tubule

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

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

35

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 are used

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 autoregulation of NA release

remains intact

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 :
metabolize to methyldopamine and
methylnorepinephrin
e;
Its antihypertensive
action appears to be
due to stimulation of
central
adrenoceptors by
methylnorepinephrin

Clonidine:
After i.v brief rise in
blood pressure (direct
stimulation of
adrenoceptors in
arterioles) and flowed
by a more prolonged
hypotension
(stimulation of
adrenoceptors in
medulla).
Clonidine lowers heart rate
and cardiac output more than

-2 Agonists
Clonidine

Stimulate central 2

adrenoceptors
Decreasing PVR
Useful in hypertension
complicated by renal
disease
Sedation & drying of the
nasal mucosa
Rebound hypertension

-METHYL DOPA

2-agonist
Valuable in treating
hypertensive
patients with renal
insufficiency
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

Reduce heart rate, blood pressure, myocardial

contractility, myocardial oxygen consumption

selective blocker : atenolol, metoprolol

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

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.
B.
C.
D.
E.

Bradycardia
bronchiolar constriction
Hyperglycemia
reduced myocardial contractility
prevention of the dilation of vessels caused
by circulating epinephrine

VASODILA
T

OR

Vasodilators
Relax smooth muscle in blood
vessels resulting in dilation and
decreased peripheral vascular
resistance
Reduce afterload so helpful in heart
failure
May cause sodium and water
retention

VASODILATORS

Classification of Vasodilators
Venous
Nitrates

Mixed
Calcium Antagonists
-adrenergic Blockers
ACEI
Nitroprusside
Arterial
Vasodilator

Arterial
Minoxidil
Hydralazine

Venous
Vasodilator

MOAVasodilators

NOguanylatesiklaseAKTIF
produksiintraselularcGMP
meningkatproteinkinaseGAKTIF
mengaktifkanfosfataseyang
menginaktivasimyosinrantairingan.Hasil
akhirnyaadalahrelaksasiototpolos
pembuluhdarah,yangmemungkinkan
pembuluhdarahuntukmembesar

activationof
dopamine
receptors

PelepasanNO
dariendothelium
relaksasi

nitroprusside

NO

fenoldopam

DA

Hiperpolarisasiotot
polosmelalui
pembukaanchannel
K+penurunanCa2
+intraseluler

Na+ Ca++ K+ minoxidil

hydralazine

Ca++

diazoxide

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&
venodilator

Arteriodila Arteriodilat Arteriodil

tor
or
ator

Releaseof
nitricoxide
(NO)
NOactivati
onof
guanylyl
cyclase

intracell
Intravenous
ularcGMP
infusion

Openingof Openingof
potassium potassium
channels
channelsin
smooth
muscle
membranes
Rapid
intravenou
s

Oral

Siteof
action

Direct

Mechani
smof
action

Oral

Routeof
admin.

Na
Diazoxide Minoxidi Hidralazin
nitropru
l
e
side
1.Hperte
nsive
emergen
cy

1.Hyperte
nsive
emergenc
y

1.Moder
ate
severe
hyperten
sion

1.Moderat
esevere
hypertensi
on.

2.Severe 2.Treatme 2.correct

heart
ntof
ionof
failure hypoglyce baldness
miadue (kebotak
to
an)
insulinom

Th
era
peu
2.Hyperte
tic
nsive
pregnant
use
woman
s

1.Methemoglobind Inhibitinsulin
Hypertric
uringinfusionNanitropruside
releasefromDiazoxide

Minoxidil
Hidralazine Continue
hosis
.
2.Cyanidetoxicity cellsofthe
Vasodilator
3.Thiocyanate
pancreas
s
toxicity
causing
Severehyperglycemia
Hypotension,reflextachycardia,

hypotension

palpitation,angina,saltand
waterretention(edema)
Contraindic

Contraindicat
edindiabetic

atedin
females

Adverse
effects

RAAS

60

The renin-angiotensin-aldosterone system

(RAAS)
Angiotensinogen
Renin
ACE

Angiotensin I (AI)
Angiotensin II (AII)

AT1 receptor

AT2 receptor

RAAS
Bradykinin

Angiotensinogen
Renin
A
I
ACE

t-PA
Cathepsin G
Tonin

Degradation CAGE
A II
products
Cathepsin G
Chymase

AT1 receptor
Hypertrophy/proliferation
Vasoconstriction
Sympathetic stimulation
Aldosterone release
Vasopressin

AT2 receptor

Antiproliferation
Antifibrotic
NO Release
Differentiation
Vasodilation

ANTIHYPERTENSIVE DRUGS
DRUGS AFFECTING RAAS [renin angiotensin aldosterone
system] RENIN INHIBITOR: Beta blockers [Propranolol,
Atenolol, etc]
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
(Capoten)

enalapril
(Vasotec)

benzapril
(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

Contraindications

More eff ective in treatment

of hypertension in
conditions associated with
high plasma renin activity (
young & white people ).

During the second and

third trimesters of
pregnancy because of
the risk of fetal
hypotension,anuria,renal
failure,
fetal
malformations and death.

Safely used in patients with

ischemic heart disease.
Are useful in treating
patients with diabetic
nephropathy
Treatment of heart failure.

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
ACE I
Captopril
enalapril,
Ramipril

Lisinopril

Dosis
12,5-25 mg 2-3
times/daily
5-20 mg OD
Start with low
dose; 2.5 to 10
mg daily
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

85

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 reninangiotensin 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
Plasminogen

Fibrin

Plasmin
Fibrin
Degradation
Products

Fibrinolytics clot busters

Antithrombin III
Xa
Heparin
Prothrombin

Thrombin

Fibrinogen
Plasminogen
Streptokinase
tPA; rPA; tNK

Fibrin

Plasmin
Fibrin
Degradation
Products

Anticoagulants
Warfarin

Antithrombin III

Xa
Heparin

Prothrombin

Thrombin

Fibrinogen
Plasminogen

X
Fibrin

Plasmin
Fibrin
Degradation
Products

ARGATROBAN
94

Approved June 2000

direct thrombin inhibitor
Indications:
1.

2.

Prophylaxis/treatment of thrombosis in heparin-induced

Thrombocytopenia (HIT)
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
95

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 )
96

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 )
97

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)

98

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)
99

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

100

Nesiritide (Natrecor)
101

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)
102

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)
103

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)
104

ADRs

Hyperkalemia
Dizziness
Worsening renal function
GI upset
Angioedema

Availability

5, 20, 40 mg tablets

Eplerenone (Inspra)
105

Approved September, 2002

Binds mineralcorticoid receptor and blocks binding

of aldosterone (component of Renin-Angiotensinaldosterone system)

Lowers BP
Increases serum K+

Indications

CHF post-MI
Hypertension (alone or combination)

Eplerenone (Inspra)
106

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)
107

ADRs
Hyperkalemia
Dizziness
Headache

25 and 50 mg tablets

Rosuvastatin (Crestor)
108

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)
109

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)
110

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 )
111

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)

112

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)

113

114