A nti A nginal A gents

1. Anti AnginalAgents 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 tachyphylaxisas 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‘slaw - 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 • Epicardialarterial 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 6 - 8 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 dihydropyridinesbind 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

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-anginalagents • 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