Drugs and the Heart Flashcards
What are If, ICa and IK?
If = hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels – “funny” channels (opened when tissue is hyperpolerised)
* Predominantly a sodium channel
ICa (T or L) = Transient T-type Ca2+ channel or Long-lasting L-type
* Mediates fast calcium influx
IK = Potassium channels
What happens in the SA node (and the AV node)?
largely driven by calcium (not sodium)
- slow “leaking” influx of sodium raises potential towards threshold
- as potential becomes more positive calcium channels open
- initially transient Ca2+ channel opens and eventually L type Ca2+ channel opens
- above 0mV potassium channels open and tissue is hyperpolarised
- Phase 4 is the spontaneous depolarisation (pacemaker potential) that triggers the AP.
** SNS increases cAMP -> increased If and ICa (via B1 receptors)
** PNS decreases cAMP -> increased IK ( via muscarinic receptors)
How is contractility regulated?
driven by calcium
AP -> opening of L type calcium channels -> calcium influx (20/30% of whats needed) -> ryanodine receptor activated -> calcium release from SR -> contraction
calcium driven back into SR via ATP driven process / transported by Na+/Ca2+ transporter -> relaxation
What increases oxygen demand of the heart/
anything that increases work - increased H, preload, afterload, contractility
What is the primary determinant of myocardial oxygen demand?
myocyte contraction
- Increased HR = increased contractions
- Increased afterload/contractility = increased force contractions
- Increased preload = small increase force of contractions
What types of drugs affect heart rate?
B-blockers – decrease If and ICa
Calcium antagonists – decrease ICa
Ivabradine – decrease If.
- The drugs reduce the HR by prolonging the extend of the depolarisation
- If or ICa – i.e. decrease the SNS drive
What types of drugs affect contractility?
B-blockers – decrease contractility
- B receptors (via cAMP) drive Ca2+ influx
- Reduces phosphorylation and cross-bridge formation
Calcium antagonists – decrease ICa
- Stops further entry of calcium into myofibrils (direct)
What are the classes of calcium antagonists?
Rate-slowing - cardiac + VSM:
- Phenylalkylamines - Verapamil
- Benzothiazepines - Diltiazem
Non-rate slowing - VSM (more potent):
- Dihydropyridines - Amlodipine
- Non-rate slowing calcium antagonists (Dihydropyridines) have no effect on the heart (just VSM) but the profound vasodilation produced in response can lead to a REFLEX TACHYCARDIA
Which drugs influence myocardial oxygen supply/demand?
Organic nitrates – directly supply NO
- Increase cGMP which stimulates K+ channel opening and relaxation directly
Potassium channel openers
- Stimulates hyperpolarisation (ability of coronary arteries to contract is impaired)
These drugs decrease preload/afterload (demand) and increase oxygen supply (increase blood flow):
- Vasodilation = decreased afterload (less TPR)
- Venodilation = decreased preload
How can you use B blockers, CCB, nitrates, K+ channel openers and Ivabradine?
Angina treatment – angina is a classic mismatch between myocardial supply and demand:
B-blocker or CCA – background treatment
Ivabradine – new more specific treatment
Nitrate – symptomatic treatment (i.e. exercise)
Other – e.g. K-channel openers if intolerant to other drugs
What are the common side effects of beta blockers?
mainly due to actions on B1 (sometimes on B2):
- Cardiac failure worsening (CO reduction and increased vascula resistance) - B1 [give carvediol - blocks a1 receptors -> decreased vascular resistance]
- Bradycardia - B1
- Bronchoconstriction (exacerbates asthma) - B2
- Hypoglycaemia (watch in diabetics on insulin) - B2 glycogenolysis/gluconeogenesis
- Cold extremities and peripheral artery disease worsening (loss of B2 receptor mediated cutaneous vasodilation in extremities -> no peripheral vessel dilation)
- fatigue, impotence, depression and CNS effects (e.g. nightmares) – studies question validity
What are the side effects of CCBs?
Verapamil (rate-limiting):
- Bradycardia & AV-block – heart Ca2+ channels blocked
- Constipation – gut Ca2+ channels blocked
Dihydropyridines (non-rate-limiting):
- Ankle oedema – vasodilation means more capillary pressure in extremities
- Headache/ facial flushing – vasodilation
- Palpitations – reflex SNS adrenergic activation due to vasodilation
What are the aims of treatment of rhythmic disturbances?
reduce sudden death
alleviate symptoms
prevent stroke
How do you classify arrhythmias?
The simple classification bases the arrhythmia from site of origin:
- Supraventricular – e.g. amiodarone, verapamil
- Ventricular – e.g. flecainide, lidocaine
- Complex (supra- and ventricular) – e.g. disopyramide
What is the Vaughan Williams Classification?
classification of anti-arrhythmic drugs
Class 1 – Na+-channel blockade
Class 2 - B-blockers
Class 3 – K+-channel blockade – prolong repolarisation
Class 4 – Ca2+-channel blockade
This classification is of LIMITED clinical significance due to the significance of cross-overs in rhythm disturbances
What is the method of action of adenosine?
action of smooth muscle and SAN and AVN
stimulated adenylate cyclase in SM -> inceased cAMP -> relaxation
activates A1 receptors in the SA and AV nodes -> GI protein activation to reduce AC conversion of ATP to cAMP -> decreased cAMP -> decreased ionotropic and chronotropic effect
- IV-given, targets SVT and has a short action (thus is safer than Verapamil)
Outline the method of action of verapamil
blocks VGCC and thus depresses SA firing and subsequent AV node conduction - Class IV anti-arrhythmic drug
- Uses – reduces ventricular responsiveness to atrial arrhythmias
Outline the method of action of amiodarone?
What are some sdverse effects?
Uses – SVT and VT (often due to RE-ENTRY)
complex but probably involving multiple ion-channel block - most likely prolongs hyperpolarisation which reduces change of re-entry
Class 1, 2, 3 and 4 – hence limited clinical importance
Adverse effects:
- Accumulation in body
- Skin rashes (photosensitive)
- Hypo- or hyper-thyroidism
- Pulmonary fibrosis
What is the method of action of digoxin (digitalis)?
inhibits Na+/K+ ATPase -> increased intracellular sodium -> reversal of Na+/Ca2+ exchanger -> sodium effluxed and calcium influx -> increased intracellular calcium
Increased intracellular calcium lengthens the class IV area of the ventricular muscle graph so lower chronicity
However, increased ionotropic (contractility) effect as more calcium inside the cells
- potentially improvEs CO
central vagal stimulation -> increased refractory period + reduced rate of conduction through AV-node
What are he uses and side effects of digtalis?
Uses – atrial fibrillation and flutter lead to rapid ventricular rate which impairs ventricular filling and reduce CO -> digoxin via vagal stimulation reduces conduction within AV node and so fewer impulses get to ventricles, slowing down ventricular tachyarrhythmia.
Side effects – dysrhythmias – e.g. AV-conduction block
- if co-administered with diuretics (maybe to reduce BP), hypokalaemia may be present and can LOWER the threshold for digoxin toxicity – digoxin is a K+-receptor competitive antagonist and so low blood potassium means less competition and so the effects of digoxin are enhanced
