Pharmacology 11 - Drugs and the Heart Flashcards
List the mechanisms regulating heart rate
- Sinoatrial node
- Generation of regular spontaneous action potentials
- If channels (hyperpolarisation activated cyclic nucleotide gated, drive sodium entry to initiate depolarisation)
- Ica channels (T-type transient or L-type long lasting calcium channels)
- Ik channels (potassium)
- If first, then Ica (T-type then L-type). Ik channels initiate repolarisation
List the mechanisms regulating contractility
- Action potential depolarises cardiac muscle tissue
- VGCC open, Ca2+ in (25%)
- Opens ryanodine receptors (calcium induced calcium release from sarcoplasmic reticulum) (75%)
- Ca2+ binds to troponin to initiate contraction
- Relaxation when Ca2+ unbinds, Ca2+ pumped back into the SR and out of the cell via sodium/calcium exchanger
How is myocardial oxygen supply and demand regulated?
- Myocardial oxygen supply by coronary blood supply and increased arterial oxygen content
- Work is the oxygen demand, increased alongside heart rate, preload, afterload and contractility
List the drugs decreasing heart rate, and how they act
- B blockers decrease If and Ica (via B1)
- Calcium antagonists decrease Ica
- Ivabradine decreases If (hyperpolarisation-activated cyclic nucleotide-gated channel blocker)
List the drugs decreasing contractility and how they work
- B-blockers decrease contractility (reduce calcium entry)
- Calcium antagonists decrease Ica
What are the classes of calcium antagonists?
- Rate slowing (cardiac and smooth muscle actions - phenylalkylamines and benzothiazepines)
- Non rate slowing (smooth muscle actions, more potent - dihydropyridines)
List the drugs influencing myocardial oxygen supply and demand
- Organic nitrates (promotes relaxation via increased cGMP, and potassium channel opening)
- Potassium channel openers (eg. nicorandil)
- These work by increasing coronary blood flow
List the beta blocker side effects
- Worsening heart failure (due to cardiac output reduction and increased vascular resistance via vasoconstriction)
- Bradycardia (heart block - decreased conduction through AV node)
- Need to know if patients are asthmatic or diabetic (interfere with liver control of glucose by masking hypoglycaemia)
- Cold extremities (loss of B2 receptor mediated vasodilation in extremities)
- Fatigue, impotence, depression, CNS effects (eg.nightmares)??
List the side effects of verapamil
- Calcium channel blocker (rate slowing)
- Bradycardia, AV block via Ca2+ block
- Constipation (25% - gut Ca2+ channels)
List the side effects of dihydropiridines
- Calcium channel blocker (non-rate slowing)
- Ankle oedema (vasodilation increases pressure on capillary vessels)
- Headache/flushing (vasodilation)
- Palpitations (reflex tachycardia)
How many people in the UK are affected by abnormalities of cardiac rhythm?
700,000`
List the aims of treatment of rhythm disturbances
- Reduce sudden death
- Prevent stroke
- Alleviate symptoms
How are rhythm disturbances managed?
- Cardioversion
- Pacemakers
- Catheter ablation therapy
- Implantable defibrillators
How can arrhythmias be classified based on origin? Which drugs are used for each type?
- Supraventricular arrhythmias (e.g. amiodarone, verapamil)
- Ventricular arrhythmias (e.g. flecainide, lidocaine).
- Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).
How do the SNS and PNS affect the heart rate?
- Sympathetic increases cAMP, If and Ica
- Parasympathetic decreases cAMP and promotes Ik opening
How does afterload increase myocardial oxygen demand?
The heart has to contract more forcefully when resistance of the cardiovascular system increases
How does preload increase myocardial oxygen demand?
- Lots of blood returning to the heart means the heart has to work harder to pump this through the heart
- Stroke volume increases as preload increases
How do non-rate slowing calcium antagonists affect the heart?
- No direct effect
- Profound vasodilation can lead to reflex tachycardia
How do nitrates/potassium channel openers influence preload and afterload?
- Also cause vasodilation
- Therefore the afterload will decrease due to decreased resistance in the system
- Reduced preload due to vasodilation of the veins
- Therefore reduced myocardial oxygen demand
List the treatments for stable angina
- Beta blocker or calcium channel blocker is first line
- If not tolerated, switch to the other option
- Then consider combination if this doesnt work
- If not able to use B blockers or calcium channel blockers, consider either a long acting nitrate, ivabradine or nicorandil
How can B-blocker side effects be avoided?
In heart failure:
- Use of pindolol which has intrinsic sympathetic activity (positive effect on the heart), as well as acting as a B-blocker during exercise
- Carvedilol is a mixed B blocker with a1 blockade, which will have vasodilator properties
What is the vaughn williams classification?
- Classification of anti-arrhythmic drugs
- An old method
- Class I sodium channel blockade
- Class II beta adrenergic blockade
- Class III prolongation of repolarisation (mainly potassium channel effects)
- Class IV calcium channel blockade
ISSUE: many drugs have multiple mechanisms
How are supraventricular arryhthmias treated?
- Adenosine (short lived 20-30s, used in hospital settings as its safer than verapamil)
- Verapamil
- Amiodarone (also ventricular arrythmias)
- Digoxin (cardiac glycoside)
How does adenosine work in supraventricular arrhythmias?
- Binds to a1 receptors and in the SA node that inhibits adenosine cyclase
- Decreases cAMP
- This decreases the funny (If) current to reduce depolarisation through the SA node
- Also increases cAMP in smooth muscle to promote relaxation and therefore vasodilate, reducing preload and afterload
How does verapamil work in supraventricular arrhythmias?
- Nodal effect, blocks calcium channels to decrease ability to depolarise
- Decreases the time of depolarisation to increase the chance of normal contraction
- Reduces ventricular responsiveness to atrial arrythmias
How does amiodarone work?
- In normal tissue a purkinje fiber forms two branches, a signal travels down each branch and they will cancel each other out
- When there is dead tissue there can be reentry rhythm which will depolarise tissue
- Amiodarone prevents this from gappening, predominantly via potassium channel blockade to increase the length of the repolarised state and decrease reentry rhythms
List the adverse effects of amiodarone
- Accumulates in body
- Photosensitive skin rashes
- Hypo/hyperthyroidism
- Pulmonary fibrosis
How does digoxin work?
- Inhibits sodium/potassium ATPase to increase intracellular Ca2+ via effects on the sodium/calcium exchange, which slows conduction at the AV node (direct and indirect action)
- Therefore, it has a positive inotropic effect
- Also performs central vagal stimulation (stimulates vagus nerve) increases refractory period, and reduces the rate of conduction through the AV node
- Ventricular rate falls, increases strength of contraction
List the uses of digoxin
Atrial fibrillation and flutter, which lead to a rapid ventricular rate that impair ventricular filling and reduce cardiac output
List the adverse effects of digoxin
- Dysrhythmias (AV conduction block, ectopic pacemaker activity)
- Affects are worsened by hypokalaemia, as the digoxin binding site is the potassium ion binding site
