10. Drugs and the heart Flashcards
Name the channels that open during an AP in the SA node and what they do
- If - Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels (opens at -60mV => Ca2+ enters cell)
- Ica - Transient T-type Ca2+ channel (propagates depolarisation)
- Ica - Long Lasting L-type Ca2+ channel (main upstroke of AP)
- Ik Potassium K+ channels (opens once above 0mV for repolarisation)
How does the sympathetic pathway affect the SA node?
- Increase cAMP
- Increased activity of If + Ica
- Promotes depolarisation
- Shorter phase 4 (triggering of AP - spontaneous depolarisation)
How does the parasympathetic pathway affect the SA node?
- Decreased cAMP
- Increased Ik
- Prolonged repolarisation (phase 3)
Describe how Ca2+ causes depolarisation/contraction in the heart?
• APs from the SAN promotes gating of Ca2+ channels
• Small amount of Ca2+ enters cytoplasm from outside
- through L-type channels (Ica)
• This Ca2+ induces release of Ca2+ from SR (Ca-induced Ca-release)
- RyR2 (ryanodine receptors)
- 75-80% of Ca2+
• Intracellular calcium allows formation of actin-myosin cross-bridges
• Beta receptors: Increased cAMP => increased PKA => promotion of contractile machinery + reduction of Ca2+ re-entry back into SR
What is the primary determinant of myocardial oxygen demand and why?
Myocyte contraction
• Higher HR - more contractions
• Higher afterload/contractility - greater force of contraction
• Higher preload - small increase in force of contraction
• Therefore the greater the contraction, the greater the demand for oxygen
How do beta blockers affect the AP in the SAN?
- Beta blockers block the effect of SNS
- Therefore, they affect If and Ica
- Start of depolarisation is prolonged
- Decreased HR
How do calcium antagonists affect the AP in the SAN?
- Blocks Ica
* Dissuades depolarisation
How does Ivabradine affect the AP in the SAN?
- Specifically targets If
- Impacts spontaneous generation of APs
- Prolongs the distance between successive APs
How do beta blockers and calcium antagonists influence contractility and how?
- Beta blockers - decreases contractility (indirectly decreases Ca2+ influx)
- Calcium antagonists - decreases contractility (directly decreases Ca2+ influx)
Which of the following do beta blockers and calcium antagonists influence:
• heart rate
• contractility
Both types of drugs affect both heart rate and contractility
Describe the 2 classes of calcium antagonists
• Rate slowing - cardiac and smooth muscle actions - more powerful on cardiac e.g. benzothiazepines • Non-rate slowing - smooth muscle actions only - more potent - no effect on the heart (profound vasodilation => reflex tachycardia) e.g. dihydropyridines
How do ‘potassium channel openers’ affect the heart?
- Potassium efflux
- Prolonged hyperpolarisation
- Inhibition of VGCCs
- Tissue relaxed for longer
- More dilated (coronary) blood vessels supplying the heart
How do organic nitrates affect the heart?
- Promote NO production in endothelial cells
- NO causes VSMC relaxation by activating guanylate cylase
- Decreased afterload (vasodilation)
- Decreased preload (venodilation)
- Short acting symptomatic treatment for angina (similar effects to potassium channel openers)
How do you treat angina?
- Beta blockers or calcium antagonists permanently
- If you get angina - intervene acutely by giving nitrate to improve myocardial oxygen sypply
- Nitrates may need to be taken before exercise
What are the unwanted effects of beta blockers?
• Worsening cardiac failure (beta blockers reduce work heart has to do - bad CO reduction as heart already has poor output)
• Bradycardia - less AVN conduction
• Bronchoconstriction - blockade of β2
• Hypoglycaemia (in diabetics on insulin) - due to decreased glycogenolysis/gluconeogenesis
• Cold extremities and worsening peripheral arterial disease (β2 blockade in skeletal muscle vessels)
• Fatigue
• Impotence
• Depression
• CNS effects e.g. nightmares
• Increased TPR - worsens HF
- pindolol and carvedilol can stop this and decrease TPR due to ISA and alpha 1 blocking respectively
What is Verapamil, how does it work and what are the unwanted effects?
- Calcium antagonist
- Affects HR (rate limiting) - effects predominantly heart related
- Reduces ventricular responsiveness to atrial arrhythmias
- Decreases depolarisation
- Depresses SA automaticity and subsequent AV node conduction
- Bradycardia and AV block
- Constipation - gut Ca2+ channels affected, less gut contraction
What are the unwanted effects of dihydropyridines (calcium antagonists)?
- Non-rate limiting => concerned about vasodilation
- Ankle oedema - vasodilation => more pressure on capillaries
- Headache/flushing
- Palpitations - baroreceptor reflex response
- Reflex adrenergic activation
(any drugs that act as profound vasodilators e.g. K channel openers, will have the same effects)
Give 3 simple classifications of arrhythmias?
- Supraventricular arrhythmias
- Ventricular arrhythmias
- Complex (both of the above)
(based on the site of origin)
What are the 4 Vaughan-Williams classes of the anti-arrhythmic drugs?
- Class I - sodium channel blockade (depolarisation)
- Class II - beta-adrenergic blockade
- Class III - potassium channel blockade (prolonged repolarisation/membrane stabilisation)
- Class IV - calcium channel blockade (prolonged plateau)
How useful is the Vaughan-Williams classification system?
- Limited clinical significance
- Used to work well when we had limited drugs and their mechanisms weren’t understood well
- Still the major classification
- However, it was discovered there was too much crossover, so many drugs couldn’t be classified
Why is adenosine a popular anti-arrhythmic?
- Short-lived action (20-30s)
- Used acutely
- Safer than verapamil
What is adenosine and how does it work?
• Used to terminate supraventricular tachyarrhythmias (SVT)
• Prescribed IV - very fast effect
• Multiple effects
• Predominantly on nodal tissues (A1):
- inhibit adenylate cyclase => decreased cAMP
- decreased Ca channel opening => prolonged K channel opening
- prolonged depolarisation, slower repolarisation, normalises tachyarrhythmia
• On vascular smooth muscle (A2):
- stimulation of adenylate cyclase
- increased cAMP
- relaxation of smooth muscle
How does amiodarone work as an anti-arrhythmic?
- Some beta-blocking and calcium/potassium channel effects
- ‘Messy’ drug in terms of mechanism
- Major effect - potassium blockade
- Prolonged repolarisation
- Reduces re-entry
- Used for supraventricular and ventricular tachyarrhythmias
What are the adverse effects of amiodarone?
- Accumulates in the body (half life: 10-100 days) - side effects attributed to this
- photosensitive skin rashes
- hypo/hyperthyroidism
- pulmonary fibrosis
What are re-entry rhythms?
- Normally, if APs cross paths and meet anywhere in the tissues, they cancel each other out
- This ensures a unidirectional AP
- If you get damaged bits of tissue where the AP struggles to get through downwards, it is easier for an AP to go back up through it in the opposite direction - ‘re-entry’
- Can get cyclical depolarisation
- This is the basis of arrhythmias
- Prolonging repolarisation can reduce the likelihood of this, as the tissue hasn’t repolarised when the re-entry AP comes to the damaged tissue - AP dies out
What is digoxin and how does it work?
• Treats arrhythmias - commonly AF
• Inhibition of Na-K-ATPase (Na/K pump)
• Increased intracellular Ca2+ - positive inotropic effects
• Central vagal stimulation:
- increased refractory period
- reduced rate of conduction through AVN
• Decreased HR - more time for heart to fill
• Improved ventricular contraction - improved CO
• Normal rhythm is restored
How does digoxin improve contraction?
- Digoxin competes with potassium (Na/K pump)
- Less sodium-potassium exchange
- Build up of sodium inside the cell (K stays outside)
- Therefore, more sodium-calcium exchange
- More calcium comes into the cell
- Therefore, more powerful positive inotropic effect on ventricles
What are the adverse effects of digoxin?
- Dysrhythmias e.g. AV conduction block
* If you have too much vagal stimulation - conduction block
Why is it important to know the plasma potassium levels of a patient before giving digoxin?
- If hypokalaemic (e.g. from diuretics) - less competition between potassium and digoxin
- Digoxin has a more powerful effect - toxic
