A nti A nginal A gents - PowerPoint Presentation

Slide1

Anti Anginal Agents

Pharmacology Week 10

Angina

Angina pectoris - chest pain caused by accumulation of metabolites resulting from myocardial ischemia

Nitrates are the main stay of treatment

Calcium channel blockers are also important for treatment, especially for prophylaxis

Beta blockers also play a role

Most common pathophysiology is atheromatous disease of the coronary arteries - transient spasm of these vesseles in localised areas can cause ischemia and pain

Primary mechanism is an imbalance between myocardial oxygen supply and oxygen demand

This imbalance can be treated by either increasing supply or decreasing demand

Angina continuedMajor determinants of myocardial oxygen needs:

Wall stress: a relationship between intraventricular pressure, ventricular radius, wall thickness

Heart rate

Contractility

Determinants of coronary blood flow

Coronary perfusion is directly related to aortic perfusion pressure and the duration of diastole

Blood flow is inversely proportional to resistance

Determinants of vascular tone - arterial pressure determines systolic tone, venous pressure determines diastolic tone

Vascular smooth muscle tone

Increasing cGMP - facilitates dephosphorylation of myosin light chains and prevents interaction between actin and myosin

Nitric oxide

Decreasing intracellular calcium - intereferes with actin and myosin interaction

Stabilising or preventing smooth muscle cell depolarisation

K channel openers - Minoxidil

Increasing cAMP in vascular smooth muscle cells

Increases the rate of inactivation of myosin light chain kinase which is responsible for actin and myosin interaction - beta 2 agonists act in this way but are NOT used in angina

Viva Questions

What is the mechanism of GTN

What are its clinical effects

What are the indications for GTN use in the ED

What is meant by the

term

tachyphylaxis

as it related to GTN

When should GTN be used with caution

Nitrites and Nitrates

Mechanism of action: Nitroglycerin is

denitrated

by Glutathione - S - Transferase and a free nitrogen ion is released - this is then converted to nitric oxide

Nitric oxide causes activation of cellular cGMP which has muscle specific effects

Tolerance develops rapidly

(

tachyphylaxis

)

Pharmacokinetics:

A: Oral

bioavailibility

is 10% - liver contains a large amount of organic nitrate reductase that removes nitrate groups in a stepwise fashion - hence SL administration to bypass first pass metabolism

D: Low

Vd

3L/kg

M: Hepatic

E: Renal

Nitrates

Organ system

effects

Vascular

smooth muscle:

Veins are effected at lower concentrations and arteries at higher concentration - arterioles and pre capillary

sphinters

are the last ones effected

Primary direct effects are to increase venous capacitance and decrease preload - pulmonary vascular pressures and heart size are reduced

Cardiac output is decreased

Because venous capacitance is

increased

- postural hypotension may be an issue

Compensatory

effects:

Tachycardia common

Increased myocardial contractility

Salt and water retention especially with long standing

nitrates

Throbbing

headache is a result of meningeal artery dilation

Other smooth muscle:

Relaxation of bronchi and GIT

Platlets

- decreases aggregation - no benefit in survival

Nitrates

Organ effects continued

Nitrate ions react with hemoglobin to form meth-hemoglobin which has low affinity for oxygen

Toxicity and tolerance

Acute adverse effects are direct extensions of therapeutic effect (vasodilation) -

Orthostatic hypotension

Tachycardia

Throbbing headache

Carcinogenic

potential -

oesophageal

and gastric Ca, poorly understood

mechanism

Tolerance

- isolated smooth muscle may develop complete tolerance - mechanism is poorly understood

Nitrates

Mechanism of clinical effect:

Effect in Angina that is

exertion

al

Decreased venous return, decrease in intra cardiac volume are the two primary effects

Laplace

‘s

law - decreased intraventricular pressure is associated with a decrease in wall tension and thus decrease oxygen requirement

Increases the

caliber

of

epicardial

arteries

Effects in unstable angina

E

picardial

arterial dilation

NitratesClinical use:

SL preparation used most commonly

IV preparation reserved for angina at rest

and for resistant hypertension

Transdermal patches may provide 24 hours of levels, but effect only persists for 6 - 8

hours

due to

tachyphylaxis

- thus you need a nitrate free time of 8 hours between doses

Nicorandil

Vasodilating effects in normal coronary arteries but more complex effects in people with angina

Reduces both preload and after load - May be a role in myocardial protection via activation of K channels

causing hyperpolarization leading to relaxation of SM

Significant reduction in RR of fatal

and

non fatal cardiac events

A: Rapidly and completely absorbed. ~75% oral

bioavailablity

D: Low

Vd

M: Highly

metabolised

by liver

E: Parent drug poorly excreted. The metabolite is the major

excretant

.

Viva QuestionsDescribe the mechanism of action of verapamil.What are the toxic effects of verapamil?

What antidotes can be used to treat verapamil toxicity?

Calcium channel blockers

Successful therapeutic blockers have been L-type channel blockers

Pharmacokinetics:

A: Well absorbed orally

D: Low

Vd

M: High first pass metabolism and high plasma protein binding

E:

Renally

Pharmacodynamcis

:

MOA: L type channel is the most common in cardiac and smooth muscle cells

Nifedipine

and

dihydropyridine

s

bind to one site whilst verapamil and

diltizem

bind to

one

closely related but not identical receptor in another region

Blockade by these drugs reduces the frequency of opening in response to action potentials - causing a marked decrease in transmembrane calcium current

SM relaxation (long term)

Decreased cardiac contractility

Decreased SA node PM and AV node conduction

Calcium channel blockers

Dihydropyridines

bind to one site on a

L

subunit of Ca channels, verapamil, and diltiazem bind at another site on the

subunit

Dihydropyridines

have a higher

ratio

of vascular smooth muscle effects relative to cardiac effects compared to verapamil and

diltiazem

Cardiac selectivity: Verapamil > Diltiazem >

Dihydropyridine

Dihydrropyridine

Drug

Nifedipine

Amlopipine

Felodipine

Verapamil

PO bioavailibility

47 - 70%

65 - 90%

15 - 20%

20 - 35%

Half life

4

30 - 50

11 - 16

6

Indication

Angina, HTN

Angina, HTN

HTN

Angina, HTN, Arrythmia

Calcium channel blockers

Toxicity

Direct extension of therapeutic actions

CVS

Arrest

Bradycardia

AV block

Heart

failure

Hypotension

Minor

Peripheral

odema

Flushing

Constipation

Mechanism of clinical effects

Decreased myocardial contractile force —> reduced O2 requirement

Decreased SVR —> Decreased arterial and intra ventricular pressure, LV wall stress declines and decreased myocardial O2 demands

Decreased HR —> Decreased oxygen demand

Decreased coronary artery spasm

Calcium channel blockers

Well documented efficacy in HTN and SVT

All can cause a worsening of heart failure due to their negative inotropic effects

Amlodipine

is considered safe

Other anti-anginal agents

Beta blockers - useful for

exertional

angina

Related primarily to their H

R

effects

Increased in diastolic perfusion time

Decreased HR, Contractility and BP all decrease O2 demand

Undesirable

effects include an increase in EDV and increased ejection time

Hence

concomitant

use of nitrates