1. Anti Anginal Agents
Pharmacology Week 10

2. 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

3. Angina continued Major 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Nitrates Mechanism of clinical effect:
Effect in Angina that is exertional
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
Epicardial arterial dilation

10. Nitrates Clinical 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 hours due to tachyphylaxis - thus you need a nitrate free time of 8 hours between doses

11. 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.

12. Viva Questions Describe the mechanism of action of verapamil.
What are the toxic effects of verapamil?
What antidotes can be used to treat verapamil toxicity?

13. 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 dihydropyridines 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

14. 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

15. Dihydrropyridine Drug Nifedipine Amlopipine Felodipine Verapamil
PO bioavailibility % % % %
Half life 4 6
Indication
Angina, HTN
HTN
Angina, HTN, Arrythmia

16. Calcium channel blockers
Toxicity
Direct extension of therapeutic actions
CVS
Arrest
Bradycardia
AV block
Heart failure
Hypotension
Minor
Peripheral odema
Flushing
Constipation

17. 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

18. 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

19. Other anti-anginal agents
Beta blockers - useful for exertional angina
Related primarily to their HR 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