Drugs on heart Flashcards
What does high HR do?
- Increases myocardial O2 consumption
- Reduces coronary circulation perfusion time (only perfuses during diastole)
- Increases arrhythmia risk
- Linked to atherosclerosis/coronary artery plaque disruption
What HR shows greater risk to CVD?
Resting rate > 70 bpm
What’s the central treatment for angina, heart failure, post-MI treatment, arrhythmias?
drugs that lower HR
Why lower HR
High HR is predictor of morbidity + mortality from CVD
How to lower HR?
Decrease initiation + frequency of pacemaker potentials by:
- Inhibit vgcc: reduce phase 0, slower upstroke
- Inhibit If channels: increase Phase 4, slower diastolic depolarisation before reaches threshold, slower to activate vgcc
What are Ca2+ channel blockers (CCB)?
Drugs that site in channel pore blocking Ca2+ entry into SA cells reducing HR
Why do CCB need to selectivity target Ca2+ channels in SAN?
Ca2+ channels also in cardiac myocytes (phase 2, plateau phase) + vascular smooth muscle
providing Ca2+ influx for contraction
Subtypes of CCB?
vascular = Dihydropyridines cardiac = Diphenylalkyamines vascular+cardiac = Benzothiazepines
What’s Amlodipine?
Dihydropyridine
vascular selective CCB
What’s Verapamil?
Diphenylalkyamine
cardiac selective CCB
What’s Diltiazem?
Benzothiazepine
vascular+cardiac selective CCB
How can CCBs cause heart block?
Non-selective blocking actions on:
Ca2+ channels in cardiac myocytes for contractility
AVN for conduction
What’s Ivabradine?
Selective inhibitor of If channel in SAN
Decreases pacemaker potential frequency
Decreases HR to reduce myocardial O2 demand
Used in heart failure, angina
Describe how If channel blockers work?
- inhibits If
- inhibits diastolic depolarisation
- slows unstable membrane potential from reaching threshold
- slower to activate vgcc
- slower upstroke of phase 0
- reduction in pacemaker frequency potentials
- decrease HR
How sympathetic increases HR?
NA binds to β1 adrenoceptor (Gs) - stimulate adenyl cyclase producing cAMP from ATP which increases If channel activity
How para decreases HR?
Ach binds to M2 (Gi) - inhibit adenyl cyclase so no cAMP from ATP which decreases If channel activity
Affect of β1-adrenoceptor blockers (antagonists)?
reduce sympathetic NA/A on SAN reducing HR
What’s Atenolol?
β1-adrenoceptor blockers (antagonists)
reduce sympathetic NA/A on SAN so increase in HR/contractility subdued which reduces work / O2 demands on heart
Why isn’t β1-adrenoceptor blockers used with CCB?
reduce contractility too much + produce too much bradycardia
Why isn’t β1-adrenoceptor blockers used on asthmatic patients?
can affect β2 on lungs so less bronchial dilation
Why can β1-adrenoceptor blockers cause fatigue?
can’t increase HR enough, less blood flow
Affect of Mus receptor blockers (antagonists)?
reduce para vagus/Ach on SAN so removal of inhibitory influence on HR – vagal tone which increase HR
What treatments are Mus blockers used for?
COPD, IBS, overactive bladder
What’s Atropine?
Mus receptor blockers (antagonists)
increase HR creating stable CO
Adverse effect of Mus blockers?
tachycardia increases O2 demands on heart
Important in patients w co-morbidities (COPD + angina)
What happens during heart failure?
CO unmaintained – poor blood flow so end organs poorly perfused
How to maintain CO in heart failure?
Increase: contractility, ejective force, SV - CO = HR x SV
eg of acute heart failure?
cardiac arrest, anaphylaxis, sepsis
eg of chronic heart failure?
cardiomyopathy, chronic hypertension, valve disease
What are drug targets to increase contractility (inotropic agents)?
Gs coupled receptor agonists - bind to receptors linked to Gs (β1, glucagon receptor)
PDE inhibitors - less cAMP -> AMP, build up of cAMP driving PKA
Other Ca2+ rising processes
What’s phosphodiesterase (PDE)?
cause breakdown cAMP -> AMP
What are β1-adrenoceptor agonists + eg?
Gs coupled receptor agonists
A, dobutamine, dopamine
Used in acute heart failure
eg of other Gs coupled agonist?
Glucagon – glucagon receptors in heart muscle
What’s used for acute heart failure when the patient is on β blockers?
Gs coupled agonist GLUCAGON
A, dobutamine, dopamine won’t work
Why isn’t Gs coupled agonists used in chronic heart failure?
increase: HR (proarrhythmic), myocardial work, O2 demand
What are PDE inhibitors + eg?
Gs coupled receptor agonist
Amrinone – phosphodiesterase III inhibitor (PDE3 is heart specific)
Used in severe + chronic cases - waiting for heart transplant
Describe how PDE inhibitor Amrinone work
build up of cAMP, activates PKA, increase vgcc + Ca2+ influx
What are cardiac glycosides + eg?
other Ca2+ rising process : increases contractility
by reducing Ca2+ extrusion - but high toxicity
Digoxin
Describe how cardiac glycosides Digoxin work
- Digoxin inhibits Na+/K+ ATPase on cardiomyocyte surface
- No 3Na+ out , 2K+ in
- build up of Na+
- less Ca2+ out, 3Na2+ in by Na/Ca exchanger (NCX)
- more Ca2+ uptake into stores so greater CICR
- greater contraction
What are Ca2+ sensitizers + eg?
other Ca2+ rising process
used in decompensated heart failure - condition w poor outcome
Levosimedan, Omecamtiv
Disadvantage of Gs coupled agonist + alternative?
induced rise in Ca2 requires Ca2+-ATPase for reuptake into stores so more O2 consumption, stresses heart, increase HR - pro-arrhythmogenic
Ca2+ sensitizers
Describe how Ca2+ sensitizers work
- no effect on Ca2+
- increase contractile sensitivity (troponin) to Ca2+
- contraction at lower Ca2+
- no increase O2 consumption or pro-arrhythmogenic
Describe how Levosimedan works
Ca2+ sensitizer
- bind to troponin C
- increase binding of Ca2+ to TnC
Describe how Omecamtiv works
Ca2+ sensitizer
-increases actin-myosin interactions
Why use β blockers in chronic heart failure?
To prevent:
- overworking by slowing HR increases diastolic time - increases coronary perfusion
- overworking by reducing contractility reduces O2 demand
- desensitization of βadrenoceptors caused by excess compensatory sympathetic in heart failure - so available for contractility
- βadrenoceptor associated arrhythmias
Describe how Diuretics work
-excrete more fluid
-reducing blood volume
-reducing central venous pressure + SV (via Starling’s law)
-reduces CO
-reduces BP
BP=CO (blood volume) x TPR (blood vessel constriction)
What are Diuretics + eg?
reduces afterload
loop, thiazide, K+ sparing
What are ACEi, ARB + eg?
reduces afterload
ramipril, losartan
Describe how ACEi, ARB work
- reduce Ang II-induced vasoconstriction : reduces TPR
- reduce Ang II-induced aldosterone : reduces blood volume - reduces CO
What’s the cardiac pain in angina caused by?
occlusion of coronary arteries, poor perfusion of heart, produces acid, stimulates sensory nerves
What’s a nitrate donor + eg?
dilates coronary arteries to increase blood flow, relieves cardiac pain from angina
Glyceryl tri-nitrate (GTN) : spray under tongue
What’s nitric oxide (NO)?
- continually produced/released
- lipophilic, soluble gas, freely diffusible out of endothelium into surrounding VSMCs
