DRUGS ACTING ON CARDIOVASCULAR SYSTEm 1.docx

DRUGS ACTING ON CARDIOVASCULAR SYSTEM (UNIT 4)
OBJECTIVES
1) To be able to classify cardiovascular drugs e.g glycosides, anti angina ,antiarrhythmic
drugs, antihypertensive ,anticoagulants, antiplateletes, and hematinics
2) Mode of action
3) Indications and contraindications, side effects
CARDIAC GLYCOSIDES
For cardiac dysrrythmias
Digtalis
William Withering discovered digitalis purpura as the active plant in this mixture.
Digitalis has very narrow dosage window for therapeutic efficacy without toxicity.
Digitalization for dosing digitalis (digoxin [Lanoxin]; digitoxin [Crystodigin]) has been widely
accepted over the years as a means of minimizing toxicity.
Digitalis has become the mainstay of therapy for CHF despite its toxicity and MOA
Mechanism of Action
Digitalis increases contractility (positive inotropy) while decreasing heart rate (negative
chronotropy)/ reducing the pace making rate of SA node. This pharmacological profile results
from indirect as well as direct effects of digitalis glycosides on the heart.
Indirect= enhances vagal tone
Digitalis on conducting system;- the drug is fat-soluble steroid that crosses the blood-brain
barrier and enhances vagal tone thus reducing AV node and bundle of his conduction. .
The slowing and/or conversion of a patient with Supraventricular arrhythmia /tachycardias.
This increased vagal activity increases acetylcholine release, which in turn is coupled to the
opening of a K+channel which results in closing of the L-type sarcolemmal Ca+ channel. Ca+
channel inhibition slows the heart rate and/or converts the rhythm to a sinus mechanism.
There is also increased excitability of ventricular muscle fibres =>to extrasystoles
Oxygen consumption in hrt muscles is reduced =>sufficiency performance of short hrt muscles.
Digoxin induces diuresis due to increased blood flow to the renals with increased GFR,
especially in CCF patients.
direct effects Digitalis binds to the enzyme (Na+,–K+ ATPase ) and inhibits its activity
elevation in intracellular Na+  increase in extrusion of Na+ through the Na+ Ca++ exchanger,
which functions to maintain a relatively constant level of both Na+and Ca++ in the cell. Ideally
the exchanger normally extrudes Ca++ in exchange for Na+. However, In the presence of
increased intracellular Na+extrusion of Na+ exchanging it for extracellular Ca+. This reversal
in the activity of exchanger  increase in intracellular ionized free Ca+ in myocyte enhancing
myocardial contractility.
Toxicity
Nausea, vomiting, anorexia, fatigue,
Characteristic visual disturbance (greenyellow Halos around bright objects).
Cardiac toxicities; tachyarrhythmias and bradyarrhythmias, including supraventricular and
ventricular tachycardia, ectopic beats and atrioventricular (A-V) block.

The most classic (but not most frequent) atrial tachycardia with A-V block.
CNS =Confussion, restlessness, agitation, nightmares acute psychosis
Gynaecomatsia in men and breast enlargement in women as it resemble oestrogen structure
N/B; digoxin poisoning is phenytoin 100mg IV, atropine is effective for bradycardia.
Or in severe cases digoxin specific binding fragment (FAB) is an antibody that inactivates
digoxin.
pk;
Administered po as tablets 0.25mg,or oral solution 0.5mg/ml =30 drops and IV ampoules of
2mls.each 0.25mg/ml
Po well absorbed, effect after 5-30min increasing to 1hr regardless of the route.
Plasma t1/2 =36hrs accumulation occurs effect may persist for 2-3weeks.
Excreted unchanged by the kidneys and the remainder metabolized extensively by the liver.
Dosages; digitalization for digoxin
This process is starting patients on several repeated doses of digitalis over 24 to 36 hours
before establishing a lower daily maintenance dose.
IV preparation is diluted with normal saline or water for injection that 1ml of digoxin + 4ml N/S
= 0.25mg/5ml solution. Each ml =0.05mg.
Dosing for digitalization whether oral or i.v, calculate total digitalization dose per day and give
½ of the loading dose stat and the other half in divided dose 8hly or ¼ of the total dose 8hly.
Dosage; po or IV
 Emergency/ very rapid digitalization
i.v digoxin preparation =250µg/ml or 0.25mg/ml.
Total IV dosage slow iv 0.5mg -0.75mg-1mg over 2hrs then
po digoxin 0.125mg-0.5mg/day( 8hrly) for one day.
Maintain on oral digitalis 0.125mg-0.5mg/day in 1 or 2 divided doses
Aim at the HR of 70-80 b/m
 moderate digitalization for adults
Total dose digoxin tablets 250µg-500µg daily or 0.01mg/kg-0.015mg/kg stat.
Followed by ¼ of the total dose or (62.5µg-500µg daily) in divided doses 6-8hrly. Maintenance is
¼ of the total dose i.e 0.125mg -0.5mg daily (62.5µg-500µg daily) in two divided dose or OD
 Slow digitalization;-
 Day 1 = 0ral digitalis 0.5mg tds
 day 2= 0.5mg bd
 day 3= 0.25mg bd
 Day 4= 0.25 mg OD and maintain on the same.
Summary of total digitalization dose per age in children;-
 Premature babies =0.03mg/kg po
 Full term newborn= 0.03mg/kg-0.5mg/kg po
 Infants up to 2yrs =0.05-0.06mg/kg. po
 Children >2-10 yrs =0.04-0.05mg/kg. po

Clinical Use
 Digitalis in the management of Cardiac failure
 acute pulmonary edema
 Patients with atrial fibrillation.
 supraventricular tachycardia
 Atrial flatter by shortening refractory period of the atrial muscle, thus controlling
ventricular rate.
 phenobarbitone overdose suicide cases
N/b heart rate should not fall<60b/m.
Precaution; elderly due to reduced renal clearance causing more accumulation of the drug.
C/I patients with HR < 60B/M, heart block, myocardial diseases.
Interactions. Digoxin; nifedipine,verapramil, quinidine,amiodarone drugs raises stead state
concentration of the drug therefore lower the dosage when used together as they potentiate
AV block. Thiazides worsen hypokalemia therefore supplement nutritional k+.
ANTIANGINAL DRUGS
Angina pectoris is a clinical manifestation that results from coronary atherosclerotic heart
disease. Characterized by acute imbalance between oxygen requirement of the myocardium
and the available oxygen supply to it.
An angina attack due to increased oxygen demandchronic cardiac ischaemia
Occurs due to an imbalance between myocardial oxygen supply and demand owing to the
inability of coronary blood flow to increase in proportion to increases in myocardial oxygen
requirements.
 Causes= Conditions that increase HR and increased contractility
 Cases that increase ventricular pressure and size.
Drugs used in the cases are those that reduce the pre load or the venus return e.g nitrate beta
adrenoreceptors blockers,ca++ blockers ( verapramil, nifedipine) dilates coronary arteries
,reduce spasm thus reducing afterload.
Angina pectoris due to reduced oxygen supply to myocardiumacute myocardial
ischaemia that is reversible.
May also occur as a result of vasospasm of large epicardial coronary vessels or one of their
major branches.
causes; atheroscelerosis and cholesterosis
Drugs used nitrates like nitroglycerin and ca++ blockers
General principles of management of angina
There are three major components to the treatment of angina:
1 Management of the risk factors for coronary atherosclerosis (e.g. lipid lowering, aspirin,
antihypertensive drugs, cessation of smoking)
2 Treatment of symptoms
3 Preventing or delaying myocardial infarction and death

Drug therapy
i) Acute attack of angina; Short acting drugs nitrites
e.g glyceryl nitrate sublingual or nifedipine sublingual or capsule bite
ii) For prophylaxis; long acting drugs;
1. β-blockers e.g propranolol (Inderal) non selecive, artenolol selective,
N /B resting HR should not go below 55b/m
2. Or ca++ channel blockers ,verapamil (Calan), nifedipine (Adalat), amlodipine (Norvasc).
Indicated in coronary artery spasm,myocardial insufficiency and patients with
bronciospasms. can be used in combination with beta blockers
3. Or long acting nitrate; like isosrbide dinittrate of isosorbide mononitrate orally at night.
4. antiplatelet therapy with ASA which reduces the incidences of myocardial infarction in
unstable angina or with low doses of heparin
5. surgery- coronary bypass surgery /Coronary angiography
a)organic nitrates and nitrites
They are vasodilators
MOA; The denitration of nitrate and nitrites in the smooth muscles cell releases nitrogen and
nitrous oxide ( N O). NO is structurally related to physiological endothelial relaxer factor which
activates enzyme process via cGMP( cyclic guanosine monophosphate)  Alteration of c++
fluxes in the cell and induces smooth muscle relaxation generalized vasodilatation of
vennules capasitance vessels and to less extent (resistance vessels)these effects to cvs;
1. arteriolar vasodilatation  reduced BP and reduced peripheral resistance.
2. peripheral venous dilatation  reduced venous return  reduced BP
3. reduced pulmonary pressure.
All the above  increased HR , Reduced CO and reduced heart workload and reduced oxygen
consumption demand by the heart.
4. Reduced coronary artery spasm
5. Improved blood flow to ischaemic areas.
Pharmacokinetics
Well absorbed orally, intestinal mucosa and skin
Extensive and rapid 1st pass metabolism in the liver by( dinitration). t1/2 varies and may
increase in hepatic insufficiency
Side effects collapse due to fall in BP due to overdose or allergy. Remedy administer when
patient is in supine position, legs higher than the head to restore venous return.
Severe headache due to dilatation of vessels and stretching of sensitive tissues around the
meninges
methaemoglobinaemia in large doses
contraindications; angina due to anaemia and pain due to myocardial infarction

Glyceryl trinitrate/ Nitroglycerin (trinitrin)
This is a short acting drug which is generally kept as a ‘rescue’ treatment for ‘breakthrough’
angina. Ideally, glyceryl trinitrate should be taken to prevent angina.
It is an odourless liquid combined with mannitol making it fairly stable tablet sublingual or
chewed tablet or placed in buccal salcus. Tablet 0.5mg preparation.
Action begins 2-5min after intation and effect lasting 30min. plasma t1/2= 2-3min.
preparations; Sublingual, Transmucosal (buccal), Oral,Ointment (2%),Transdermal and
Intravenous
N/B; not swallowed due to extensive 1st pass metabolism therefore use sublingual,buccal,
nitrolingual spray.
Dosage 0.5mg max 6mg /24hrs. patient in supine positon to avoid collapse.
Tolerance developes with repeated and frequent exposure to organic nitrates is accompanied
by the development of tissue tolerance to the drug’s vasodilating effects thus the patient needs
more and more doses. For prevention use ointment disc paster impregnated with nitroglycerin
as a patch is given 8hly /24hrs in patients with nocturnal angina
Amyl nitrite ampole
It’s a short acting drug and volatile inflammable liquid inhaled through an open mouth after
crashing in a hanky.
Duration of action 15-30min effect in 3-10 min excreted in lungs and some in the kidneys.
SE ;crashing the ampoule has limited its use, skin flushes of the face, intraocular pressure and
methaeglobinaemia
Long acting nitrate
(Isosorbide dinitrate/ cedocard and isosorbide mononitrate)
The clinical pharmacology of isosorbide dinitrate is similar to nitroglycerin, but it is also
effective orally and has a longer half-life of 40 minutes.
Prevents future attacts of angina and for CCF plasma ½ =20min.
preparations sublingual tablets, po tabs
Doses; Isosorbide dinitrate: 10mg tid up to 20mg or 5mg qid. max dose 120 mg /24hrs in two
to three doses.
Isosorbide mononitrate (elantan) slow release po swallow drugs. has less 1st pass metabolism
making it more reliable in systemic bioavailability. t1/2 = 4hrs
dose po Isosorbide mononitrate : 20–120 mg daily in od or two doses not more than 8 hours
apart).
Transdermal GTN: 5–15 mg.
b)Beta-receptor blockers
Β-Blockers approved for clinical use in secondary angina in the United States include
propranolol and nadolol (Corgard) = block both β1- and β2-adrenoceptors equally, while

atenolol (Tenormin) and metoprolol (Lopressor) are cardioselective β 1- receptor antagonists.
MOA; They competively bind at adrenoreceptor inhibiting catecholamines.
Thus counteract dysrhythmia effects of catecholamines (adrenaline and noradrenaline) by
Prolonging refractory period of AV node which prevent tachycardia.
They abolish the rate of automatic firing of the SA node by beta agonists
Their role in angina depends mainly on decreasing myocardial oxygen consumption by:
1 Limiting the increased heart rate associated with exercise and anxiety
2 Limiting the increased force of contraction associated with the same stimuli
3 Increasing the length of diastole, the period during which coronary blood flow occurs
Beta-blockers have been shown to reduce sudden death and re infarction following a
myocardial infarct.
Adverse effects
Lethargy, fatigue, bradycardia and bronchospasm are common side effects.
Rebound worsening of angina due to up regulation of receptors, myocardial infarction or
tachycardia has been reported when beta-blockers are suddenly withdrawn. Reduce dose over
24–48 hours if beta blockers are being withdrawn in such patients.
Clinical use;
They reduce oxygen requirements by reducing increase in heart rate and force which occurs on
exercise thus used in angina and hypertension.
c/I The only absolute contraindication for a beta-blocker is asthma.
Propranolol =management of patients whose angina attacks are frequent and unpredictable
despite the use of organic nitrates. May be combined with the use of nitroglycerin, latter drug
being used to control acute attacks of angina. The combined use of propranolol and organic
nitrates theoretically should enhance the therapeutic effects of each and minimize their
adverse effects
Doses
Propranolol (Inderal; 40–80mg /day in two divided doses
Atenolol: 50–200 mg daily in two divided doses. Not recommended for children
Metoprolol: 100–400 mg daily in two or three divided doses.
Bisoprolol: 5–20 mg once daily.
nadolol (Corgard) 40mg-80mg once daily
Carvedilol 25–50 mg in two divided doses.
These drugs must all be given in an individually titrated dose to control symptoms and
attenuate postural and exercise-induced tachycardia.
c)Calcium antagonists
ca++ is useful in intiating smooth muscle and cardiac cell muscle contraction and in propagation
of cardiac impulse. The ca++ blocker drugs inhibit passage of ca++ through the gated

membrane channels of the smooth muscles thus reducing available intracellular ca++  muscle
relaxation. They are also vasodilators as they have a negative cardiac ionotropic and negative
chronotropic effect via the pace maker cells depressing conducting tissue.
There are two major groups:
1 Dihydropyridines including nifedipine, nicardipine (Cardene, nitrendipine, felodipine and
amlodipine
2 Heart rate limiting ones including verapamil and diltiazem
Their principal action is inhibition of the slow calcium-ion channel component of the smooth muscle
action potential leading to:
Reduction in afterload.
Decreased tone in vascular smooth muscle cells including coronary arteries.
Decreased contractility in myocardial cells.
Depressant effects by verapamil and diltiazem on sinus node and atrioventricular node
function and therefore slow heart rate. These drugs have additional anti-arrhythmic
activity.
Pharmacokinetics
All drugs are well absorbed following oral administration.
They are cleared by liver metabolism.
All undergo extensive first-pass metabolism terminating their action. Active metabolites may
contribute to their effects.
Adverse effects
Headache, nausea, Constipation occurs with verapamil., flushing and ankle swelling with
nifedipine and other dihydropyridines due to vasodialatation. The side effects of nifedipine
appear to be diminished markedly by combination with a beta-blocker.
Short-acting formulations of calcium antagonists, particularly dihydropyridines, should be
avoided, especially in patients not treated with a beta-blocker as there is some evidence that
rapid onset vasodilatation, leading to a fall in blood pressure and reflex tachycardia, can worsen
angina or even precipitate myocardial infarction
Drug interactions
Verapamil or diltiazem should not be given routinely with beta-blockers since the combined
negative inotropic and chronotropic effects can cause bradyarrhythmias and heart block and
can rarely precipitate heart failure. Bradycardia may also follow use of these agents with
digoxin or amiodarone.

Enzyme inducers like rifampicin reduces their effect due to 1st pass metabolism.enzyme
inhibitors like cimetidine increase the effect of ca++ blockers
Clinical use
They are used in stable or unstable angina and hypertension.
Verapamil and diltiazem are alternative first-line agents to a beta-blocker in intolerant patients
in stable or unstable angina. Nifedipine and other dihydropyridines are used to best effect in
combination with beta-blockers in severe angina.
1. Nifedipine (adalat tabs:
Plasma t1/2=2hrs, effectively dilate arteries with little effect on veins , has less negative
ionotropic and chronotropic effects than verapramil. given po 40- 80 mg/ day in two divided
doses or 80mg od as a long-acting preparation. side effects as above and gum hypertrophy.
2. isradipine tabs
t1/2- 8hrs , similar to nofedipine, total dose 2.5mg-10mg/ 24hrs in1-3 divided doses.
3. nicardipine (Cardene)
Preparations nifedipine slow release tabs 20mg, dose 20mg -40mg/day either once or in two
divided doses.
Caps nifedipine 10mg. Dose 60-120mg/24 hrs. In three divided doses
Plasma ½=4hrs.
4. Amlodipine( norvasc); tabs: 5–10 mg once a day.
Onset of action 6-12 hrs after po dose, acting duration24hrs
5. Verapamil (Calan,caveril), tab
pk; t1/2 =4hrs has both arteriol and venous dilatation , marked negative ionotrpic and
cjhronotopic effects. contraindicated in patients with 2nd and 3rd degree heart block and wolff
white parkinsonism syndrome. interactions increases quinidine and amioradone plasma
concentration which may cause hypotension
Dose 40 mg two or three times daily up to 360 mg /daily in divided doses or as a single dose of
120mg-360mg slow-release preparation
6. diltiazem (Cardizem).
t1/2 =5hrs , limits heart rate like verapramil, doses po 60mg -120mg /24hrs in three divided
doses

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