drugs on the heart Flashcards
why lower heart rate?
High heart rate - predictor of morbidity and mortality from CVD
Resting rate of greater than 70 beats/min
considered to show greater risk
Why – what does a high heart rate do? (4)
what does it increase?
what does it reduce?
what does it increase the risk of?
how can it lead to MI?
Increases myocardial O2 consumption – heart must work harder (if CVD, there is poor blood flow to the heart so it must work harder which adds more stress to heart)
Reduces coronary circulation perfusion time – only occurs during diastole
Increases risk of arrhythmias
Linked to atherosclerosis/coronary artery plaque disruption hence can lead to a thrombus formation therefore a blockage/clot which can lead to a MI
How can you regulate heart rate?
Change sino-atrial pacemaker potential frequency
Decrease initiation and frequency of pacemaker potentials hence Reduce heart rate
2 ways to reduce heart rate
1) Inhibit voltage-gated Ca2+ channels: Reduce Phase 0, slower upstroke
2) Inhibit funny channels: Increase Phase 4, slower to activate Ca2+ channels
what are Ca2+ channel blockers (CCB)?
how does it reduce heart rate?
problems with CCB? so what do we need?
Drugs that site in pore of channel - block Ca2+ entry into sino-atrial cells to Reduce heart rate
But - Ca2+ channels also found in cardiac myocytes (phase 2, plateau phase) and vascular smooth muscle
Provide Ca2+ influx involved in contraction
Need to selectivity target Ca2+ channels
what are the 3 subtypes of Ca2+ channel blockers?
why 3 dfferent subtypes?
Dihydropyridines (vascular selective) – Amlodipine
Diphenylalkyamines (cardiac selective) – Verapamil
Benzothiazepines (vascular+cardiac) – Diltiazem
As cardiac and vascular muscle have slightly different Ca2+ channel structures
concerns of Ca2+ channel blockers?
what can this do to the heart?
Non-selective blocking actions on Ca2+ channels in cardiac myocytes (needed for contractility) and at AV node needed for atria-ventricle conduction
So – CCBs can make heart failure worst, and cause heart block
How does funny channel blockers work?
name the drug?
where does it act?
what does it do? effect of this?
when is it used?
Ivabradine
Selective inhibitor of funny channel in the sino-atrial node
Decreases If current – reduces pacemaker potential frequency
Decreases heart rate to reduce myocardial O2 demand
Used to lower heart rate in heart failure, angina as heart has to work less hard due to lower HR
How can you use autonomic system to regulate HR?
sympathetic - what is released and what receptor does it act on? what system does this activate? what does it stimulate and how does this affect HR?
parasympathetic - what is released and what receptor does it act on? what system does this activate? what does it stimulate and how does this affect HR?
Sympathetic system
NA activates B1 adrenoreceptor which activates the GaS system which stimulates adenylate cyclase to convert ATP to cAMP which increases If channel activity hence increase HR
Parasympathetic system
Ach activates M2 receptor which activates the GaI system which inhibits adnylate cyclase hence less ATP is converted to cAMP which decreases If channel activity hence decreases HR
How does B1 adrenoreceptor blockers work?
name a B1 adrenoreceptor blocker
what does it do?
what is it useful for?
β1-adrenoceptor blockers (antagonists) – e.g. atenolol
will reduce action of sympathetic nervous system (noradrenaline/adrenaline)
on sino-atrial node
Reduce heart rate increasing
For example: when walking any distance or climbing stairs etc.
our sympathetic nerve activity is increased to increase heart rate/contractility to enhance cardiac output
In the presence of atenolol – this increase in heart rate/contractility is subdued
This is very useful way of reducing work / O2 demands
on the heart Hence β1-adrenoceptor blockers are central drugs in treatment of angina
concerns of B1 adrenoreceptor blockers
in which partiuclar patients do you avoid this?why?
what other drug do you not want to use this with? why?
what is a side effect of this drug?
Avoid in asthma patients as the blocker will have a small affect on B2 receptors which is essential for asthma patients to stay open
Not used with Ca2+ channel blockers – can reduce contractility too much, and produce too much bradycardia
Fatigue as normal response of increased HR for exercise won’t happen
How does muscarininc blockers work?
name a drug
what do they do? effect of this?
what can happen after MI? what do you use in this situation and why?
Muscarinic receptor blockers (antagonists) – e.g. atropine will reduce action of parasympathetic nervous system (vagus nerve, Ach) on sino-atrial node
Removal of the inhibitory influence of vagal nerve on heart rate
Muscarinic blockers increase heart rate
For example: following MI, heart rate can drop too much (sinus bradycardia) – this may further reduce cardiac output in a heart that is already poorly functioning
Use atropine to increase heart rate to create more stable cardiac output
concerns of muscarininc blockers
slectivity? side effect of this drug? how may this affect people with multiple conditions?
muscarinic blockers are used to treat many conditions
e.g. COPD, IBS, over-active bladder
Increased heart rate (tachycardia) may be adverse side effect of these drugs
Tachycardia increases O2 demands on heart
Important in patients with co-morbidities, e.g. COPD and angina
why use drugs to increase contractility?
what will it aid and effect of this? how does this increase SV?
During heart failure cardiac output is not properly maintained which means end organs are poorly perfused
Hence increased contractility will reduce time in isovolumetric contraction and more energy can be expended for ejection therefore increased ejective force which leads to an INCREASED stroke volume
CO = HR x SV
what are contractility drugs used to treat?
2 groups - what conditions are categorised in those groups?
Acute heart failure – due to cardiac arrest, sepsis
Chronic heart failure – due to cardiomyopathy, chronic hypertension, valve disease
Drug targets to increase contractility (inotropic agents)?
3 main drug targets?
Gs-coupled receptor agonists such as B1 adrenoreceptors and glucagon receptors (linked to heart and Gs pathway)
PDE inhibitors - hence less cAMP is broken down and more PKA is activated
Other Ca2+ rising processes
Gs-coupled receptor agonists + associated pathways
to increase contractility (3)
main Gs coupled agonist?
drugs?
used when?
other Gs coupled agonist?
when are these used?
when are Gs agonists not used? why? what is it only safe for?
name a PDE inhibitor?
what does it do?
when is it ised?
β1-adrenoceptor agonists
e.g. Adrenaline, dobutamine, dopamine
Used in acute heart failure, e.g. cardiac arrest, anaphylaxis, sepsis
Other Gs-coupled agonists
e.g. Glucagon – glucagon receptors expressed in heart muscle. Used in acute heart failure conditions where a patient is taking β-blockers – adrenaline, dobutamine, dopamine etc. would not work - therefore stimulates GS pathway but not the B1 adrenoreceptors
Gs agonists not used in chronic heart failure – increase heart rate (proarrhythmic/basmotropic), increase myocardial work + O2 demand -> heart already has too much work, only safe for acute failure
PDE inhibitors
e.g. Amrinone – phosphodiesterase III inhibitor (PDE3 is heart specific)
Causes build up of cAMP, activation of PKA, increase VGCCs/increased Ca2+ influx
Only used in severe and chronic cases – e.g. waiting for heart transplants
Other Ca2+i rising processes – Cardiac Glycoside
example
what does it do? how?
what is the problem with this?
Cardiac glycosides, e.g. digoxin, increases contractility
by reducing Ca2+ extrusion – but high toxicity
Cardiac Glycosides - mechanism of action
what does it inhibit? effect of this?
how does this increase Ca2+?
what happens to Ca2+? effect of this?
Digoxin inhibits Na+/K+ ATPase (1)
Build up of [Na+]i (2)
Less Ca2+ extrusion by Na/Ca exchanger (NCX) (3) -> less gradient to bring Na+ in due to build up of Na+ from Na+/K+ ATPase blockage
More Ca2+ uptake into stores and greater CICR – greater contraction -> as more in stores, every time heart is stimulated, More Ca2+ released for greater contractions as Ca2+ rise greater in cell
Other Ca2+i rising processes – Ca2+ sensitisers
what is the problem woth Gs-coupled agonist induced rise in ca2+? (2)
solution for this - name the dugs
Problems with Gs-coupled agonist-induced rise in Ca2+
Increase need for Ca2+-ATPase – to reuptake more Ca2+ into SR stores therefore More O2 consumption which stresses the heart
Also, Gs pathways increase heart rate – pro-arrhythmogenic
Potential solution
Ca2+ sensitizers - e.g. Levosimedan, Omecamtiv
Ca2+ sensitisers - mechanism of action
what do these drugs have no effect on?
what do they effect? what does this lead to?
what side effects do these drugs avoid?
what does levosimedan do?
what does omecamtiv do?
when are these drugs used?
These drugs have no effect on Ca2+ levels
But: Increase the contractile apparatus sensitivity (e.g. troponin) to Ca2+
Now: Contraction works better at lower Ca2+ levels
These drugs would not increase O2 consumption, or be pro-arrhythmogenic
Levosimedan - Bind to troponin C, increase binding of Ca2+ to Trop C
Omecamtiv – Increases actin-myosin interactions (in absence of rise in Ca2+)
Drugs used in decompensated heart failure – a condition with poor outcome
β-blockers in chronic heart failure
why?
Chronic heart failure – poor cardiac output – need better contractility
BUT: Frontline treatment for chronic heart failure is β-adrenoceptor blockers – reduce morbidity and increase survival rates
reasons for β-blockers in chronic heart failure
4 reasons
2 ways it prevents overworking of the heart?
how does it make more B adrenoceptors available for contractility?
what does it prevent?
Prevent overworking of a failing heart by slowing heart rate increases diastolic time - increases coronary perfusion hence heart works better
Prevent overworking of a failing heart by reducing contractility reduces O2 demand - makes failing heart work more efficiently
Prevent down-regulation of β-adrenoceptors caused by excess compensatory sympathetic nerve activity in heart failure – so more β-adrenoceptors available for contractility
Prevent β-adrenoceptor-associated arrhythmias
compensatory mechanism heart beta adrenoreceptors
what happens when heart not working well? what drives this process? what will happen over time?
body responds to heart not working well by increased sympathetic nerve activity
this drives B1 adrenoreceptors to work harder to increase HR and increase contractility
over-stimulation of B1 adrenoreceptors will make it down regulated and de-sensitised over time
reducing afterload via drugs
what will you want to reduce to increase SV and CO?
what is the BP equation?
2 different drug types that effect parts of ewaution?
name examples of the drugs
explain what they do
Increased arterial blood pressure reduces stroke volume/cardiac output So reducing arterial blood pressure promotes an increase in SV/CO
BP = CO (e.g. blood volume) x TPR (e.g. blood vessel constriction)
Diuretics, e.g. loop, thiazide, K+ sparing
Excrete more fluid, Reduce blood volume
Reduced central venous pressure and stroke volume (via Starling’s law)
Reduce cardiac output and therefore blood pressure
ACEi, ARB, e.g. ramipril, losartan
Reduce Ang II-induced vasoconstriction – reduces TPR
Reduce Ang II-induced aldosterone – reduce blood volume – reduce CO
