P: Drugs for Heart Failure and Dysrhythmias - Week 5 Flashcards
Name the 2 locations in the heart that have cels that can generate rhythmic activity. Which site is the principle site?
- sino-atrial Node (SA node): principle site
- atrio-ventricular node (AV node)
Which site in the heart is responsible for setting the heart rate?
SA node
How does the sympathetic division of innervation affect the SA node?
makes the SA node fire faster, because it allows more sodium into the cells, so it’ll get to the threshold for action potential more quickly
How does sympathetic and parasympathetic stimulation affect contractility of the heart?
parasympathetic = little to no effect
sympathetic = increased contractility due to increased calcium. The higher calcium results in a harder/stronger contraction (the muscles squeeze more forcefully)
List the steps on the hypertension continuum
hypertension – endothelial dysfunction – atherosclerosis – CAD – myocardial ischaemia – coronary thrombosis – stroke, myocardial infarction – arrhythmia and loss of muscle – remodelling – ventricular dilation – congestive heart failure – end stage hear disease
For the parasympathetic division of neural control of HR and contractility, describe the following:
A: location
B: receptor and neurotransmitter used
C: mechanism
D: effect on heart rate/contractility
A: SA node and AV node
B: Acetylcholine; Muscarinic (M2) receptors
C: Gi reduces cAMP, opening K+channels
D: decreases heart rate only
For the sympathetic division of neural control of HR and contractility, describe the following:
A: location
B: receptor and neurotransmitter used
C: mechanism
D: effect on heart rate/contractility
A: SA node, conducting tissue and myocardial cells
B: Noradrenaline; Beta-1 receptors (also circulating hormone - adrenaline)
C: Gs increases cAMP, increases Ca2+
D: increases heart rate AND contractility
What can over-stimulation of the sympathetic division of neural control of heart rate and contractility lead to?
dysrhythmia
Describe the SA cells
a group of specialised cells that have an unstable membrane potential
Do excitable cells tend to have higher or lower membrane potential? What does this mean?
Lower membrane potential (around -80 to -90mV). This means that most of the ions aren’t moving and you have ‘electrochemical stability’
Compare the resting membrane potentials of the SA node and Ventricle of the heart (phase 4)
SA node: -60mV; unstable membrane potential
Ventricle: -90mV; stable
Describe the depolarisation process of the SA node, including the phases
spontaneus depolarisation. If (I-funny) occurs and sodium and calcium come in. then:
Phase 0: depolarization, calcium in
Phase 3: repolarization, potassium out
Describe the depolarisation process of the ventricle, including the phases
Phase 0: Rapid depolarisation, Na+ and some CA2+ in
Phase 1: rapid repolarisation, K+ out
Phase 2: plateau Ca2+ in, K+ out
Phase 3: repolarization, K+ out
Describe the 4 major classes of drugs used to control heart rate, their molecular mechanisms and their outcomes:
- Class 1 - Na+ channel block (reduce phase 0 depolarization)
- Class 2 - B-adrenoceptor antagonism (slow the rate)
- Class 3 - K+channel blockade (extended repolarization phase)
- Class 4 - CA2+ channel blockade (affects refractory period)
Name and describe the unclassified drugs that can be used to control heart rate
Atropine: increase HR by blocking ACh
Adenosine: similar to parasymp stimulation
Cardiac glycosides
Electrolyte supplements
Why should you consider the no treatment option for arrhythmia?
Many arrhythmics have proarrhythmic activity and may worsen arhhythmias and cause sudden death
How do Na+ channel blockers target the corresponding Na+ channels
They selectively target the region where Na+ channels are open more frequently
In what state do Na+ channel blocker drugs typically bind Na+ channels?
They bind Na+ channels in their activated (open) state = ‘use-dependent channel block’
How can we further classify Na+ channel blocker drugs?
Based on dissociation time of drug from channel
Class 1a: moderate Na+ channel block
Class 1b: mild
Class 1c: marked Na+ channel block (so i guess blocks it a lot)
How does Lignocaine act as a Na+ channel blocker?
provides a rapid blockade of activated and inactivated Na+ channels
For what purpose is lignocaine typically used?
- often used in px post myocardial infarction. Is also used intravenously in emergency situations
Also used for ventricular dysrhythmias and fibrillation
Describe the outcome/effect of lignocaine
- depresses conduction and excitability in heart (slows it down, allowing cells a chance to recover)
- local anaesthetic actions on all excitable cells
List 5 adverse effects for lignocaine in order of increasing dosage that causes it
4ug/ml: lip and tongue numbness
7ug/ml: visual disturbance
8ug/ml: muscular twitching
15ug/ml: coma
25ug/ml: cardiovascular depression
How can we more safely apply lignocaine as an anaesthetic?
topically. But if it gets into systemic circulation, it’ll affect cardiac exciteability and sensory + motor nerve function
How fast is repolarization if your heart is beating fast?
fast
Describe the effect of K+ channel inhibitors (1 main point and 3 outcomes)
prolongs ventricular action potential
- slowing of phase 3 repolarization
- decrease incidence of re-entry
- increase risk of triggered events
For what type of arrhythmia is reducing the incidence of re-entry especially important for? Explain it
Especially important for the re-entrant arrhythmiaas, where the electrical activity goes to a point, reaches some damaged cells and goes and looks for healthy cells to go and pass its signal
Why are K+ channel inhibitors considered a “double-edged sword”?
Because they increase the risk of triggered events
Amiodarone is a K+ channel inhibitor. But what else does it block?
Also blocks Na+ (at higher concentrations), Ca2+, and B-adrenoceptors
Name 4 side effects for amiodarone
`- reversible photosensitisation
- skin discolouration
- hypothyroidism
- pulmonary fibrosis (with long term use)
What is the danger in extending repolarization?
is that it’s re-exciteable for a longer period
- because even through there’s a refractory period, there’s a relative refractory period where it’s still excitable if a 2nd stimulus comes in
How is bradycardia different from typical arrhythmias?
instead of raising heart rate, bradycardias slow heart rate
Describe the use and mechanism for atropine in relation to the heart?
- used for bradycardias
- inhibits parasympathetic activation
How does the mechanism of adenosine for the heart compare to atropine?
similar. Similar effects to parasympathetic stimulation
In relation to the heart, describe the effects of “Digoxin”
- slow AV conduction, increasing vagal input to the heart (via CNS effect)
- slows ventricular rate, improves filling
- may cause ventricular fibrillation
How big is the threapeutic index of digoxin?
low therapeutic index - therefore small window with which t can be used
How does digoxin effect the heart rate?
slows heart rate. This is uesful for tachycardia (but not bradycardia)
Describe the steps involved in the process of cardiac contraction and relaxation (9)
- The A.P enters from an adjacent cell
- Voltage-gated Ca2+ channels open, Ca2+ enters the cell
- Entry of Ca2+triggers release of Ca2+ from SR
- Most Ca2+ comes from SR
- Ca2+ ions bind the troponin to initiate contraction
- relaxation occurs when Ca2+ unbinds from troponin (and as Ca2+ dissociates, it fills up the SR stores)
- Ca2+ is pumped back into the SR for storage
- Ca2+ is exchanged with Na+
- Na+ gradient is maintained by the Na/K/ATPase
How high is the therapeutic index of glycosides? Why?
low therapeutic index, because it affects all excitable tissues
How do glycosides affect the following tissues?
A: gut
B: CNS
C: cardiac
A: anorexia, nausea, diarrhoea
B: drowsiness, confusion, psychosis
C: ventricular dysrthythmias
In what situations will glycosides have increased toxicity? (3)
- low K+ (reduced competition for binding)
- high Ca2+ (reduced gradient for Ca2+ efflux)
- renal impairment
How are glycosides absorbed and how long is their half life?
orally. around 40 hours
Describe the volume of distribution (Vd) for glycosides and explain why
around 400 L. Due to high affinity binding to muscle
How can PDE inhibitors be useful in contractility?
can help increase cAMP and therefor Ca2+ entry if B-receptors aren’t working or failing
What is used to break down cAMP?
cAMP is broken down by PDE
How do b-adrenoceptor agonists and PDE inhibitors work to treat heart failure?
Intravenous, short term support for acute heart failure, cardiogenic shock. Help with Ca2+ entry and contraction
Name 3 b-adrenoceptor agonists for heart failure
noradrenaline, adrenaline: activate both alpha and beta adrenoceptors
Dobutamine: selective b1-adrenoceptor agonist
List 3 adverse effects of B-adrenoceptor agonists
- increase cardiac work
- increase O2 demand
- risk of dysrhythmias
Can phosphodiesterase inhibitors treat for heart failure? How? Name one
(just like b-adrenoceptor agonist): used as short term support fo racute heart failure and helps Ca2+ entry and contraction
e.g. Milrinone
Describe the effect of Inotropes on heart failure?
- increase contractile force of cardiomyocytes
- symptomatic relief: however they increase work on the heart and only provide a short term beneifit
other strategies are needed as symptoms progress
Define the following:
A: preload
B: rate
C: contractility
D: afterload
A: The input. What comes in to be be pumped out (i.e. venous return)
B: how fast the pump runs
C: how strong is the pump
D: the amount pumped in relation to resistance. More is pumped if less resistance
Name and describe 2 drugs that reduce preload
- Nitrate venodilators
- used in angina
- venous dilation greater than arterial dilation effect
- has 1st pass metabolism and tolerance - Diuretics
- loop
- aldosterone antagonists, K+ sparing
- reduce mortaility in combination with ACEi, b-blockers
Name 2 drugs that reduce afterload (and preload)
- Angiotensin inhibitors: ACE inhibitors, and AT1 receptor antagonists
- b-adrenoceptor antagonists
How does angiotensin II effect cardiovascular system? (3)
- vasoconstrictor (affect on afterload)
- fluid retention due to increased aldosterone release from adrenal cortex (can effect preload, oedema)
- ventricular hypertrophy (can effect remodelling)
How effective are ACE inhibitors in treatment of heart failure?
effective at all grades of heart failure. They improve symptosm and delay progression
Name the 3 contraindications for ACE inhibitors
- bilateral renal stenosis
- angioneurotic oedema
- pregnancy
Name an alternative to ACE inhibitors and describe when you should use it
replace with AT1 receptor blockers if cough is an issue
Name a contra-indication for b-adrenoceptor antagonists for heart failure? When is it not a contraindiction?
hypertension. Generally is a sort-of contra-indication unless the heart problem is sympathetic, where beta blockers can actually be helpful
Describe the effect of b1 blockade (metoprolol) on tachycardia and cardiac work?
reduces them
How does b1 blockade effect renin release and AII effects
inhibits renin release and subsequent AII effects.
What does b1 blockade protect against?
receptor downregulation
Describe the effects of aldosterone receptor antagonists
- reduce plasma volume and preload
- inhibit aldosterone action on cortical distal tubules that promote Na+ retention
- improves survival with combination therapy in severe heart failure
- require close monitoring of hyperkalaemia and renal function
