drugs and the heart Flashcards
what are If channels?
hyperpolarisation-activated cyclic nucleotide gated channels
“funny channels”
predominantly Na channel
what are Ica (t or l) channels
transient T-type Ca channel or long-lasting L-type
mediate fast calcium influx
what does the SNS do in terms of these channels?
inc. cAMP
this inc. If and Ica
what does PNS do in terms of these channels?
dec. cAMP
this inc. If
what do beta-1 adrenergic stimulation activate?
- activated adenylate cyclase
- creates cAMP
- this activated PKA
- PKA then has 2 actions
what are the 2 actions of PKA then?
- phosphorylates proteins in myofibril
- induces CICR in SR by stimulating Ca influx into SR
- most Ca is from CICR
what mediates removal of Ca from cells?
- PMCA (ATPase Ca channel)
- NCX (Na/Ca exchanger)
what is the primary determinant of myocardial oxygen?
myocyte contraction
what influences contraction?
- inc. HR = inc. contractions
- inc. afterload/contractility = inc. force of contractions
- inc. preload = small inc. force of contractions
what 3 classes of drugs have an effect on the HR?
- beta blcokers: dec. If and Ica
- Ca antagonists: dec. Ica
- Icabradine: dec. If
how do these drugs reduce the HR?
by prolonging the extent of the depolarisation
dec. SNS drive
what are the 2 classes of drugs that have an effect on contractility?
- beta blockers: dec. contractility - reduce phosphorylation and cross bridge formation
- Ca antagonists: dec. Ica - stops further entry of Ca into myofibrils
what are the 2 classes of Ca antagonists?
- rate slowing - cardiac and VSM: phenylalkylamines (Verapamil) and benzothiazepines (Diltazem)
- non rate slowing - VSM (more potent): dihydropyridines (Amlodipine)
even though non-rate slowing have no effect on the heart, how do they cause tachycardia?
they cause a lot of vasodilation and can lead to a reflex tachycardia
what are the classes of drugs that have an effect on myocardial oxygen supply/demand?
- organic nitrates (directly supply NO, inc. cGMP which stimulates K+ channel opening and relaxation directly)
- potassium channel openers (stimulates hyperpolarisation)
what does these drugs do?
stimulates hyperpolarisation (ability of coronary arteries to contract is impaired)
what effect do these drugs have on preload and afterload? How?
drugs dec. preload and afterload (demand) and inc. oxygen supply (inc. blood flow)
- vasodilation = dec, afterload as less TPR
- venodilation = dec. preload
what is angina caused by?
- angina is classic mismatch b/ myocardial supply and demand
what classes of drugs are used in angina treatment?
- beta blocker or CCA: background treatment
- nitrate: symptomatic treatment (i.e. exercise)
- K channel openers
what are the side effects of beta blockers?
- cardiac failure worsening (beta 1)
- bradycardia (beta 1)
- bronchoconstriction (beta 2)
- hypoglycaemia (beta 2)
- cold extremities
what are the side effects of rate limiting calcium channel blockers? e.g. Verapmil
- bradycardia and AV block (heart Ca channels blocked)
- constipation (gut Ca channels blocked)
what are the side effects of non-rate limiting calcium channel blockers? e.g. Dihydropyridines
- ankle oedema (vasodilation so more capillary pressure in extremities)
- headache/flushing (vasodilation)
- palpitations (reflex SNS adrenergic activation due to vasodilation)
what are the side effects of potassium channel openers and nitrates?
- ankle oedema (vasodilation, capillary pressure in extremeities)
- headache/flushing (vasodilation)
what are the aims of treatment in rhythm disturbances?
- reduce sudden death
- alleviate symptoms
what is the simple classification of rhythm disturbances?
based on site of origin
- supraventricular e.g. amiodarone, verapmil
- ventricular e.g. flecainide, lidocaine
- comples (supra and ventricular) e.g. disopyramide
Describe the Vaughan Williams Classification of antiarrhythmic drugs
Class 1: Na+ channel blockers
Class 2: beta blockers
Class 3: K channel blockade (prolong repolarisation)
Class 4: Ca channel blockade
why is this classification of limited significance?
due to significance of cross overs in rhythm disturbances
what is the MoA of adenosine (selective anti-arrhythmics)?
- activates A1 receptors in SA and AV nodes
- Gi protein activation to reduce AC conversion of ATP to cAMP
- dec. cAMO
- dec. ionotropic and chronotropic effect
describe facts of adenosine
- IV given
- targets SVT
- short action so safer than Verapmil
- class V anti-arrhythmic
what are the uses of verapamil?
reduces ventricular responsiveness to atrial arrhythmias
what is the MoA of verapamil?
- blocks VGCC and so depresses SA firing and subsequent AV node conduction
- Class 4 anti-arrhythmic
what are the uses of amiodarone?
- SVT and VT
what is the MoA of amiodarone?
complex but probably involving multiple ion channel block
prolongs hyperpolarisation which reduces chance of re entry
what are the adverse effects of amiodarone?
- accumulation in body
- skin rashes (photosensitive)
- hypo/hyperthryroidism
- pulmonary fibrosis
what is the MoA of digoxin?
- inhibits Na/K ATPase
- inc. intraceullar Na
- reversal of Na/Ca exchanger
- Na effluxed and Ca influx
- inc. intraceullar Ca
- this lengthens class IV are of ventricular muscle graph so lower chronicity
- but inc. ionotropic effect as more Ca inside cell
what is the other MoA of digoxin?
central vagal stimulation –> inc. refractory period and reduced rate of conduction through AVN
what are the uses of digoxin?
- atrial fibrillation and flutter lead to rapid ventricular rate
- this impairs ventricular filling and reduces CO
- digoxin via vagal stimulation reduces conduction within AVM so fewer impulses get to ventricles
- slows down ventricular tachyarrhyth,ia
what are the side effects of digoxin?
dysrhythmias e.g. AV conduction block
what happens if digoxin is co-administered with diuretics?
- get hypokalaemia
- can lower threshold for digoxin toxicity
- digoxin is a K receptor antagonist
- low blood potassium means less competition, so effects of digoxin are enhanced
