Drugs and the heart Flashcards
How are heart rate and contractility regulated?
SERCA2a is responsible for the removal of >70% myoplasmic Ca
Tf SERCA2a determines:
- Rate of Ca removal - tf rate of cardiac muscle relaxation
- Size of Ca store - tf cardiac contractility in subsequent beat
SERCA2a activity is regulated by interaction with phospholamban (PLN):
- Dephosphorylated PLN INHIBITS SERCA2a
- Phosphorylated by PKA, PLN dissociates from SERCA2a activating Ca pump –> increases rate of cardiac relaxation –> increases contractility in proportion to elevation in size of SR Ca store and the resulting increase in Ca release from SR
- PLN is dephosphorylated by protein phosphatase (PP1) - terminates stimulation phase
Which drugs impact heart rate and contractility and how?
- Beta blockers - If + Ica - impact both
- Calcium channel antagonists - Ica - impact both
- Ivabradine - If - impacts HR
Beta blockers:
Block beta receptors –> less cAMP produced –> less downstream signalling to promote cardiac contractility
CCAs:
Block Ica in plasma membrane –> reduced influx of external Ca –> reduced Ca release from SR
Which drugs impact myocardial oxygen supply?
- Organic nitrates
2. Potassium channel openers
What are the different classes of calcium channel antagonists?
Rate slowing
- Phenylalkylamines, e.g. verapamil
- Benzothiazpeines, e.g. diltizaem
Non-rate slowing
- Dihydropyridines, e.g. amplodipine
What are the side effects of beta blockers?
Despite being cardioselective, most drugs have some b2 effects as well:
- Worsening of cardiac failure
- Bradycardia (heart block) - due to less conduction thr AVN
- Bronchoconstriction - b2 blockade in airways
- Hypoglycaemia - in diabetics on insulin, decreased glycogenolysis/gluconeogenesis
- Cold extremities + worsening of peripheral arterial disease - b2 blockade in skeletal muscle vessels
Possible - fatigue, impotence, depression
How is myocardial oxygen supply regulated?
Coronary vessels deliver O2 and nutrients to heart muscle depending on how hard heart is working, which depends on:
HR, preload, afterload, contractility
Increased venous return –> increased preload –> increased contractility
Increased TPR –> increased afterload –> heart must work harder against increased TPR
All associated with increased myocardial work and myocardial O2 demand
What is the Vaughan Williams classification?
Classifies anti-arrhythmic drugs by mechanism of action
I - Na channel blockade
II - Beta adrenergic blockade
III - Prolongation of repolarisation (membrane stabilisation, mainly due to K channel blockade)
IV - Ca channel blockade
What is the major side effects of non-rate slowing CCAs (DHPs)?
Reflex tachycardia
Bc they have no effect on the heart
What effect do rate slowing CCAs have on the CVS?
Reduce HR
Vasodilation
How do drugs affect myocardial oxygen supply and demand?
Vasodilation reduces TPR tf reduces afterload
Heart has to work less hard against resistance
Venodilation –> reduces venous return –> reduces preload + contractility
Reduced afterload + preload –> reduced myocardial oxygen demand
Improves balance between supply and demand
How do K channel openers work to reduce myocardial oxygen demand?
- Promote K efflux to hyperpolarise the smooth muscle
- Reduce ability to contract
- Promotes smooth muscle relaxation
How do organic nitrates work to reduce myocardial oxygen demand?
Promote NO production in endothelial cells
NO diffuses into VSM
Vasodilation of coronary vessels and relaxation by activating guanylate cyclase
Promote smooth muscle relaxation
What drugs are used to treat angina?
- Beta blocker
- Organic nitrates
- K+ channel openers
- CCAs
What are the side effects of CCAs?
CCAs that target heart (rate-limiting) have similar side effects to beta blockers - verapamil
- Bradycardia, AV block, HF (Ca channel block)
- Constipation (gut Ca channels)
DHPs
- Fluid accumulation - ankle oedema
- Headache/flushing - vasodilation
- Palpitations
- Reflex tachycardia
What are the limitations of the Vaughn Williams classification?
Too many drugs cross classes
Limited clinical significance
How do CCAs treat angina?
- Bind to and inhibit opening of L-type calcium channels
- Rate-slowing CCAs (verapamil, diltiazem) have effects on heart + BVs
- Non-RS CCAs (DHPs, e.g. amlodipine)
act mainly on BVs - All CCAs cause arterial vasodilation and reduce cardiac workload by this mechanism
- Verapamil also has negative inotropic and chronotropic actions as a result of reducing Ca2+ entry into cardiac myocytes
What are the side effects of organic nitrates?
- Hypotension
- Headache
What agents are used to treat arrhythmias?
- Adenosine
- Rate-slowing CCA (verapamil)
- Amiodarone
- Digoxin and cardiac glycosides
Why is amiodarone used in the treatment of arrhythmias?
- Prolongs repolarisation by multiple ion channel blockade (mainly K)
- Prolongs time during which heart cannot depolarise, thus restoring normal rhythm
- Reduces re-entry
What are the adverse effects of amiodarone?
- Long-lasting effects and long half-life tf accumulates in the body
- Important adverse effects on the skin, lungs and thyroid
Why is adenosine used in the treatment of arrhythmias?
- Endogenous mediator produced by the metabolism of ATP
- Acts on a1 receptors to hyperpolarize cardiac tissue and slow conduction through AVN
- i.v. to terminate superventricular tachyarrhythmias (SVT)
Why are digoxin and cardiac glycosides used in the treatment of arrhythmias?
- Inhibitors of Na-K ATPase (Na/K pump)
- Cardiac slowing and reduced rate of conduction through AVN (largely as a result of central vagal stimulation)
- Increased force of contraction
What drugs can be used to treat acute HF after cardiac surgery or in cardiogenic or septic shock and why?
- b1 adrenoceptor agonist (dobutamine)
- Stimulates cardiac contraction
- Doesn’t have too marked an effect on HR - Glucagon - endogenous peptide hormone
What are the side effects of digoxin?
Dysrrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
