Sutomo Tanzil

Dept.of Pharmacology, Faculty of

Medicine, Sriwijaya University
1. Preload : governed by the ventricular end-
diastolic volume, which is related to venous
return
2. Heart rate : modulated mainly by ANS
3. Myocardial contractility
4. Afterload : the systolic wall tension in the
ventricle; this reflects the resistance to
ventricle emptying within both the heart and
the peripheral circulation.
a CO inadequate to meet the metabolic demands of
the body during exercise (& ultimately also at rest).
Oedema of peripheral tissues (swelling of the legs) &
the lungs (breathlessness) is an important
consequence of cardiac failure.
Etiology: IHD, or by volume overload (leaky valves,
arteriovenous shunts) or pressure overload (HT).
50% of those w/ most severe HF are dead in 6 mths,
& of those w/ mild/moderate are dead in 5 yrs
Loop diuretics (eg.furosemide)
ACEIs (captopril, enalapril)
-blockers (metoprolol) : low dose in stable patients.
Spironolactone
Digoxin :for HF w/ rapid AF.It is also indicated in
patients who remain symptomatic despite th/ w/ loop
diuretics & ACEI.
Isosorbide mononitrate reduces preload & hydralazine
reduces afterload. Used in combination, these prolong
life, but less effectively than ACEI.They are used when
ACEI are contraindicated or not tolerated.
Why should be treated? Usually asymptomatic.
Non-pharmacological or pharmacological
treatment?
Hypertensive emergency: diastolic pressure
over 120 mmHg or there is encephalopathy
malignantoraccelerated hypertension: 90%
die within 1 year if not treated.


a sustained increase in BP140/90
The risk of fatal/nonfatal CVD is lowest w/ BP < 120/80
ISH (systolic BP > 140 to 160 mmHg w/ diastolic BP < 90 mmHg)
is confined to people over 60 years of age.








Normal: BP < 120/80 mmHg
Prehypertension: BP 120/80 -139/89
mmHg
Hyp.stage 1 : 140/90 -159/99 mmHg
Hyp.Stage 2 : 160/100 mmHg

Nonpharmacological th/ : weight loss,
restricting Na intake, increasing aerobic
exercise, lifestyle changes,and less
consumption of alcohol .
Optimal target : <140/85 mmHg( uncom-
plicated HT). With target organ damage
or DM: 130/80 mmHg
Drugs reduce CO by inhibiting myocardial contractility
or by decreasing ventricular filling pressure.
Drugs reduce peripheral resistance by relaxing arterial
smooth muscle or by interfering w/ the activity of
systems that produce arterial vasoconstriction.
Concurrent use of drugs from different classes is a
strategy for achieving effective control of BP while
minimizing dose-related ADRs.
For some AH drugs, on average about two-thirds of
patients will have a meaningful clinical response,
whereas about one-third of patients will not respond to
the same drug.

AH drugs by their primary
site of mechanism of action
Diuretics (HCT,chlorthalidone,indapamid)
Beta-blockers (atenolol,bisoprolol,propranolol)
Alfa-blockers (prazosin,terazosin,doxazosin)
Mixed --blockers (labetalol,carvedilol)
Centrally acting agents(methyldopa,clonidine)
Adrenergic neurone blocking agents (reserpine)
ACE inhibitors (captopril,enalapril,lisinopril)
CCB (amlodipine,verapamil, diltiazem)
Vasodilators (hydralazine, minoxidil, nitroprusside)
AIIRA (losartan,candesartan,valsartan, irbesartan)
Renin inhibitors ( aliskiren)

A diuretic is preferred initial th/ for stage 1 HT .
Stage 2 HT require a diuretic & another drug from a
different class. Some patients may require 4 different
classes of drugs to reach their goal
HT w/ CHF should be treated w/ a diuretic, ACEI
/AIIRA, spironolactone, and BB..
ACEI / AT
1
RA are the first-line drugs in th/ of HT w/ DM
HT w/ symptomatic BPH benefit from an
1
-blocker .
HT w/ recurrent migraine attacks benefit from a BB.
Patients w/ ISH benefit particularly from diuretics and
CCBs





Early th/ is important for hypertensives w/
retinal haemorrhages,exudates or
papilloedema.
Rapid BP reduction is potentially dangerous,
since it can lead to cerebral underperfusion
and ischaemic damage
Oral atenolol or nifedipine are the most widely
recommended treatments, which gradually
reduce the BP over 24 hrs or more.
Diastolic BP >130 mmHg
Eventhough the diastolic BP should be lowered below 120 mmHg
within 24 hours, it must not be faster than that.
If the BP is lowered very rapidly, it may cause cerebral
hypoperfusion and ischaemic damage with stroke and/or death.
if not urgent :a BB (eg.atenolol) is a drug of choice, or a
CCB(eg.amlodipine) if the BB is contraindicated.
In life-threatening cases :(e.g. w/ encephalopathy/acute
dissecting aneurysm/LV failure/preeclampsia) : Na- nitroprusside .
alternatives : hydralazine i.v./i.m., labetalol iv infusion / bolus.



The risk to mother & fetus is not great until the
BP reaches 150/100 mmHg or more.
Safe drugs:methyldopa, nifedipine, & labetalol.
In the 2
nd
trimester, diuretics & BB are still
contraindicated, since they may retard fetal
growth, while ACEIs /AIIRAs may cause
oligohydramnion, renal failure, hypotension &
intrauterine death



occurs after 20 weeks of gestation. It
presents as hypertension, w/ oedema
and proteinuria or hyperuricaemia, in
previously normotension womens.
Methyldopa 0,51 gr 3 x daily or
Nifedipine 5-20 mg 3x daily.
Other alternatives : hydralazine or
labetalol

Org.nitrates(glyceryl trinitrate /
nitroglycerin, isosorbide dinitrate/
mononitrate)
Ca antagonists( diltiazem, verapamil)
Beta-blockers (atenolol, bisoprolol,
metoprolol, propranolol)
Nicorandil
Metabolism modifiers eg. ranolazine,
trimetazidine.
ON dilates capacitance vessels.
Therapeutic doses also dilate resistance
vessels .
Coronary dilatation opposes coronary artery
spasm in variant angina
Myocardial O
2
consumption is reduced
because of the reduced cardiac pre-load &
after-load.
Experimentally,glyceryl trinitrate diverts blood
from normal to ischaemic areas of myocardium
by dilating coronary collateral vessels.


Important in prophylaxis of angina
Work by reducing cardiac O
2

consumption
Avoided in variant angina because they
increase coronary spasm
Contraindications : bronchial asthma,
peripheral vascular diseases, congestive
heart failure.

Ca antagonists/CCB
Block Ca
2+
entry by preventing opening
of voltage-gated L-type Ca channels
verapamil, diltiazem,
nifedipine,amlodipine
Mainly affect heart & vascular smooth
muscle, inhibiting the Ca
2+
entry caused
by depolarization in these tissues
verapamil is relatively cardioselective;
nifedipine is vascular smooth-muscle
selective & diltiazem is intermediate
Ca antagonists/CCB
Vasodilating effect (dihydropyridines): on resistance
vessels, causing reduced after-load. CA also dilate
coronary vessels.
Effects on heart (verapamil,diltiazem) : anti-
dysrhythmic action (atrial tachycardias), because of
impaired AV conduction & reduced contractility.
Clinical uses : antidysrhythmic th/ (verapamil),
preventing angina (diltiazem) & hypertension
(amlodipine).
ADRs :headache,constipation(verapamil) & ankle
oedema (dihydropyridines).There is a risk of causing
HF or heart block, especially w/ verapamil
Acute attacks in chronic stable angina:
sublingual nitroglycerin, isosorbide
mononitrate ,isosorbide dinitrate
Prophylaxis : glyceryl trinitrate (topical
application), isosorbide mononitrate/
dinitrate, beta-blockers, CCB, potassium
channel openers (eg.nicorandil)

If symptoms are not controlled by optimal
doses of a single drug, then a
combination of a BB w/ a CCB (not
verapamil), or a BB/CCB w/ a long-acting
nitrate can be given.
triple therapy (eg.BB+CCB+ a nitrate)
has not been proven to be better than 2
agents, but may sometimes give further
symptomatic benefits.
aspirin (80 mg daily) reduces the risk of myocardial
infarction by about 35 %
Th/ of hypercholestrolaemia reduces the risk of MI and
the need for surgical revascularisation by 30 %.
Coronary artery bypass grafting (CABG) improves
long-term prognosis compared w/ medical treatment
Percutaneous transluminal coronary
angioplasty(PTCA) is currently used for symptom relief
only. PTCA is followed by a restenosis rate of about
40% at 6 months. This is reduced to about 20% by the
use of a bare-metal stent, but w/ no difference in the
risk of MCI or sudden death.
Drug-eluting stents (w/ sirolimus) reduced the
risk of restenosis at 6 months to about 6%.
Insertion of a coronary stent is accompanied by
intensive antiplatelet therapy (aspirin +
clopidogrel for 6 weeks) to minimise early in-
stent thrombosis.The addition of a glycoprotein
IIb/IIIa antagonist (abciximab) is common for
high-risk procedures, especially in the th/ of
those w/ an acute coronary syndrome.
Drug of choice : s.l.glyceryl trinitrate 0.5 mg.
Symptomatic relief can be achieved within 1-2
minutes & the effect lasts in 30 minutes. ADRs
:palpitation, headache, flushing, dizziness, &
postural hypotension.
Sometimes two tablets are required to relieve
anginal pain.
The patient should be told to see his doctor if
the pain still persist within several minutes.
Clinical use of
anticoagulants
Heparin (often as LMWH) is used
acutely for short-term action
Warfarin is used for prolonged therapy
Indications : deep vein thrombosis/
venous thromboembolism/recurrent
pulmonary embolus; AF; prosthetic heart
valves; clotting in extracorporeal
circulation; unstable angina.
Antiplatelet drugs
Aspirin
Dipyridamole
Thienopyridine derivatives (ticlopidine,
clopidogrel)
GP IIb/IIIa receptor antagonists
(abciximab)
Epoprostenol (PGI
2
)

Aspirin
Inactivates COX-1 by irreversible acetylation.
Reduces both TXA
2
& PGI
2
synthesis . However,TXA
2
synthesis does not
recover until the affected platelets is replaced in 7-10 days.
Higher doses are needed to inhibits COX in the endothelium than in
platelets,because platelets are exposed to aspirin in the portal blood,
whereas systemic vasculature is partly protected by presystemic
metabolism of aspirin in the liver. Consequently, low doses of aspirin
decrease the synthesis of TXA
2
without drastically reducing PGI
2

synthesis.
Other NSAIDs also inhibit COX but have a shorter duration of inhibitory
action because they cannot acetylate COX, so that their action is
reversible.
The FDA has approved the use of 325 mg/d for primary
prophylaxis of AMI but urges caution in this use of
aspirin by the general population, except when
prescribed as an adjunct to risk factor management by
smoking cessation & lowering of blood cholesterol &
blood pressure.
Meta-analysis of many published trials of aspirin &
other antiplatelet agents confirms the value of this
intervention in the secondary prevention of vascular
events among patients w/ a history of vascular events.
Dipyridamole
In clinical trials, dipyridamole reduced the
risk of stroke & death in patients w/ a
history of ischaemic stroke or TIA by
around 15%
The beneficial effects of aspirin &
dipyridamole were additive
Headache is the commonest adverse
effect of dipyridamole, but unlike aspirin,
it causes no excess risk of bleeding
A newer PDE inhibitor that promotes
vasodilatation & inhibition of platelet
aggregation.
It is used primarily to treat intermittent
claudication
Clopidogrel
inhibits ADP-induced aggregation through an
active metabolite.
Like ticlopidine, it can cause rash or diarrhoea,
but neutropenia is no more common than w/
aspirin.
In one large trial, clopidogrel was slightly more
effective than aspirin (325 mg/day) in reducing
a composite outcome of ischaemic stroke,
myocardial infarction or vascular death.
The effects of clopidogrel and aspirin are
additive in reducing major vascular events in
patients w/ acute coronary syndrome.
The GPIIb/IIIa complex function as a receptor
mainly for fibrinogen . Activation of this
receptor complex is the final common
pathway for platelet aggregation.
Abciximab is a MAB directed against the GP
IIb/IIIa complex. It is approved for use in
percutaneous coronary intervention & in acute
coronary syndromes.
Eptifibatide & tirofiban inhibit ligand binding
to the GP IIb/IIIa receptor by their occupancy of
the receptor.
The main drug is aspirin. Other drugs w/
different actions (e.g.dipyridamole,
clopidogrel) can be additive in their effects.
Uses mainly relate to arterial thrombus .
Epoprostenol(PGI
2
) is sometimes
administered parenterally to prevent
thrombosis during haemodialysis in patients in
whom heparin is contra-indicated.
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rd
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