Cardiac Pharmacology (Block 3) Flashcards
Coronary vascular control by metabolites/mediators
Adenosine is formed by ATP & ADP hydrolysis during hypoxia and increased oxygen consumption - this leads to vasodilation
Nitric oxide (NO) is also important vasodilator
Coronary vascular control by neural mechanisms
Sympathetic stimulation of the heart results in brief vasoconstriction due to alpha-1 adrenoreceptor activation in coronary vasculature
This is followed by vasodilation due to beta-1 adrenoreceptor stimulation in myocardium, increasing mechanical and metabolic activity of the heart
Effects of autonomic neurotransmitters on cardiomyocytes - Actions of sympathetic system
Positive inotropic effect (increased force of contraction)
Positive chronotropic effect (increased heart rate)
Increased automaticity (spontaneous depolarisation)
Repolarisation (following generalized depolarisation)
Reduced cardiac efficiency (O2 consumption increased more than work rate)
Effects of autonomic neurotransmitters - mediated by beta-adrenoreceptor activation
Increased Ca++ influx causing increased force of contraction
Increased sensitivity of contractile machinery (via troponin C phosphorylation)
Increased slope of pacemaker potential (phase 4) increases heart rate
Delayed after depolarization = increased automaticity
Restoration of function after MI via stimulation of Na+/K+ pump by adrenaline
Parasympathetic system - mediated by acetylcholine activating muscarinic receptors
Cardiac slowing (SA node)
Inhibition of AV conductance
Reduction in adenylate cyclase activity and subsequent reduction in cAMP
- reduces Ca++ influx and shortens plateau
Negative inotropic effect (reduced force of atrial contraction)
Negative chronotropic effect (reduced heart rate)
Cardiac dysrhythmias (also called arrhythmias)
Abnormalities in HR or rhythm
Found in 5% f the population of western countries
Caused by errors in generation or conduction of cardiac action potentials
4 basic types of cardiac dysrhythmias
Delayed after-depolarisation
Re-entry
Ectopic pacemaker activity
Heart block
Delayed after-depolarisation
Caused by excessive intracellular Ca2+ levels after repolarisation stage 3; may be cause by activation of Na+-Ca2+ exchange
Re-entry
Caused by a unidirectional block within a conducting pathway. It is often secondary to ischaemic stress
Block allows recircularization of an action potential (blue arrow) and may cause tachycardia
Timing is crucial, as recircularization may be blocked unexcitable tissue (in ERP).
Drugs can affect ERP timing and may abolish re-entry
Ectopic pacemaker activity
Can occur when the SA node ceases to operate as the dominant pacemaker site
Sympathetic activity can increase ectopic pacemaker activity
Can occur following hypoxia (fast Na+ channels close, phase 0 generated instead by slow inward Ca++ currents)
Heart block
Heart block is the failure of SA node-derived signal to reach the ventricle
This can cause atria and ventricles to beat independently and is most commonly caused by AV node tissue damage
Antiarryhthmic drugs - one example for each class
Class I - Na+ channel blockers
Class II- Sympatholytics (b-blockers)
Class III - K+ channel blockers
Class IV - Ca++ channel blockers
Action of Class I, III, and IV antiarrythmic drugs
Directly block ion channels
Action of Class II antiarrythmic drugs
Indirectly moderate channel activity
Class I - Na+ channel blockers
Block Na+ channels which slows and depresses impulse conduction
There are three sub-classes of class I antiarrhythmics:
1A quinidine, disopyramide, procainamide
1B lignocaine, phenytoin
1C encainide, flecainide
These sub-classes differ in how fast they unbind from the channel (B=fastest, A=intermediate, C= slowest)
Block is use dependent: open and inactivated channels are blocked more tightly than resting channels
Type 1B drugs prevent dysrhythmias because high frequency activation is blocked
Type 1C drugs can prevent re-entrant rhythms because they lengthen the ERP
State-dependent block
sodium channel blockers bind
preferentially to open (activated) or inactivated states
Class II - sympatholytics
• A sympatholytic is any drug that interferes with the action of the sympathetic nervous system on the heart
e.g. beta blockers: propranolol (beta-1/beta-2), sotalol (beta-1/beta-2), atenolol (beta-1)
- Noradrenaline (NA) is released onto beta-1-adrenoceptors on pacemaker cells
- NA increases the slope of the phase 4 diastolic depolarisation (therefore HR increases)
- NA increases Ca2+ entry (increases force of contraction)
- beta-blockers therefore reduce heart rate and force of contraction
• Sympatholytics are used where arrhythmias are due to abnormal pacemaker activity
Class II- K+ channel blockers
• Class III antiarrythmics block delayed rectifier K+ channels, reducing the outward potassium currents that cause repolarisation
• They prolong repolarisation (phase 3 of the cardiac action potential). They therefore prolong ERP
examples include amiodarone, sotalol, dofetilide & bretylium
Class IV - Ca2+ channel blockers
Ca2+ channel blockers will prevent arrhythmias which arise in slow response nodal cells (SA, AV)
They can also be effective in arrhythmias resulting from damaged cells (partial depolarisation), that have become slow response cells
e.g. myocardial ischemia can cause membranes to become “leaky” (partially depolarised).
In this case the Na+ current is inactivated, and the cell depends on Ca2+ for the upstroke of the action potential
Types of Ca2+ channel blockers
Phenyalkylamines
Benzothiazepines
Dihydropyridines
Vascular vs cardio selectivity
All Ca2+ channel blockers can be used to treat hypertension and angina
• Only diltiazem and verapamil-like drugs have antiarrhythmic activity
• These drug groups have mixed cardiac and vascular actions
• All dihydropyridines in contrast (e.g. nifedipine) are “vascular selective”. At doses that block vascular Ca2+ channels they have no effect on cardiac Ca2+ channels
Class I drugs a to on phase
0
Class II drugs act on phase
4
Class III drugs act on phase
3
Class IV drugs act on phase
2
Isachaemic heart disease
Angina
Myocardial infarction
Angina is caused by
Insufficient myocardial perfusion
3 types of angina
Stable
Unstable
Variant
Stable angina
Predictable pain during exertion. Caused by coronary atheroma (aterial deposits)
Unstable angina
Pain comes with less exertion, ultimately resulting in pain at rest.
Caused by thrombus resulting from plaque rupture. Similar to MI without complete vessel occlusion. Risk of MI very high.
Variant angina
Uncommon
Pain at rest due to coronary vasospasm, often associated with atheroma.
Treatment of angina must
Angina treatment must either increase cardiac oxygen supply or reduce oxygen demand (or both)
Treatment of angina - organic nitrates
Organic nitrates (e.g. glyceryl trinitrate, isosorbide mononitrate) cause vasodilation resulting in: reduction in cardiac oxygen consumption, improved blood flow to ischaemic areas (via collaterals), relief of coronary spasm
These effects are mediated by nitric oxide (NO)
Side effects are minimal but include headaches and postural hypotension
Organic nitrates and ischaemia
Can redistribute coronary blood flow to ischaemic myocardial regions by preferential dilation of collateral vessels
Other vasodilators (e.g. dipyridamole) have opposite effect
Treatment of angina - Ca2+ antagonists
Nifedipine (and other vascular-selective dihydropyridines) prevents coronary artery spasm & dilates coronary arteries, thus increasing coronary blood flow (increased oxygen supply)
• Verapamil & diltiazem (non-selective)
- same effect as nifedipine on coronary arteries
- also reduce force of heart contraction
- have additional antiarrhythmic action
• Negative inotropic action of verapamil and diltiazem also reduces oxygen demand
Treatment for angina - beta-blockers
• Can be either selective (e.g. atenolol, 1) or non-selective (e.g. propranolol, 1/2)
• Prevent angina by decreasing heart rate and myocardial contractility
• Decreased heart rate prolongs diastole, allows more time for coronary blood flow
- most coronary blood flow occurs in diastole, as heart compression in systole occludes blood supply
• Decreased force of contraction decreases oxygen demand
Myocardial infarction
• Commonly known as a “heart attack”
• Complete coronary artery blockage by thrombus (common and often fatal)
• Can be caused by dysrhythmia or ventricular failure
• Sustained reduction in perfusion leads to oxygen starvation and cell death by either necrosis or apoptosis
• Apoptosis may be an adaptive process that sacrifices some myocardial cells to avoid potential dysrhythmia
