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 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

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 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

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

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 Questions Describe 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 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

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 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 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