S2: Heart - Cardiac Drugs Flashcards
What are cardiac drugs?
Drugs that affect:
- HR
- Contractility/Ionotropic effect
- Afterload
- Coronary blood flow
- Common cardiovascular disease (CVD)
Why lower heart rate?
High heart rate is a predictor of morbidity and mortality from CVD
- Resting rate of >70 bpm is considered to show greater risk
High HR is ..
- Linked to atherosclerosis/ coronary artery plaque distruption
- Increases myocardial O2 consumption so heart must work harder
- Reduces coronary circulation perfusion time which only occurs during diastole
- Increases risk of arrhythmias
Drugs that reduce heart rate are central to treating CVD e.g. angina, heart failure, post-MI treatment, arrhythmias
How can you regulate heart rate?
Changing sino-atrial pacemaker potential frequency by decreasing initiation and frequency of pacemaker potentials.
It does this by:
- Inhibiting voltage gated Ca2+ channels: Reduce phase 0, slower upstroke
- Inhibiting If channels: Increase phase 4, slower to activate Ca2+ channels
- Changing autonomic control of SAN
What are Ca2+ channel blockers?
Drugs that sit in pore of channel and block Ca2+ entry into sino-atrial cells reducing HR
What are the concerns when using Ca2+ channel blockers?
Ca2+ channels are also found in cardiac myocytes (phase 2, plateau phase) and VSM where they provide Ca2+ influx needed for contraction.
Therefore there is a need to selectively target Ca2+ channels in SAN.
Non-selective blocking actions on Ca2+ channels in cardiac myocytes (needed for contractility) and AV node needed for atria-ventricle conduction could make heart failure worst, cause heart block
What are the 3 subtypes of Ca2+ channel blockers?
· Dihydropyridines (vascular selective) in vascular smooth muscles, often used for hypetension – amlodipine
·
Diphenylalkyamines (cardiac selective) – Verapamil
Benzothiazepines (vascular+cardiac) – Diltiazem
As cardiac and vascular smooth muscle have slightly different Ca2+ channel structures use Verapamil, diltiazem
Describe If channel blockers and give an example
Ivrabradine
- Selective inhibitor of If channel in the sino-atrial node
- Decreases pacemaker potential frequency
- Decreases HR to reduce myocardial O2 demand
- Used to lower HR in heart failure, angina
Mechanism of changing autonomic control of SAN
-Increase in B1 activity –> Sympathetic (GaS)
This increases If channel activity increasing HR
- Increase M2 –> Parasympathetic (Gai)
This decreases If channel activity which decreases HR
What do B1-adrenoreceptor blockers do?
Give an example
They reduce action of sympathetic nervous system (NA/A) on sino-atrial node
- Prevent HR from increasing too much reducing work/O2 demands on the heart
- B1-adrenoreceptor blockers are central drugs in the treatment of angina
Example: Atenolol
Concerns of B1-adrenoreceptor blockers
- Not perfectly selective so it could have effects on B2 receptor (though not as much as B1). In the lungs of asthmatic patients, B2 would cause bronchoconstriction
- Could make heart failure work
- Don’t use in combination with calcium channel blocker - can reduce contractility and produce bradycardia
- Fatigue because inability to increase HR during excersize
Describe Muscarinic receptor blockers
Give an example
- Will reduce activity of parasympathetic nervous system (vagus, Ach) on sino-atrial node
- Removal of inhibitory influence on heart rate - vagal
- Muscarinic blockers increase heart rate creating a more stable CO during sinus bradycardia e.g. following MI
Example: Atropine
Concerns with muscarinic receptor blockers
- Muscarinic blockers are used to treat many conditions e.g. COPD, IBS, overactive bladder so tachycardia may be a side effect
- As tachycardia increases O2 demands on the heart it is important in patients with co-morbidities e.g. COPD and angina
Why increase contractility (ionotropic effect)?
During heart failure where:
- CO is not properly maintained
- End organs are poorly perfused
This can be corrected by:
- Increase in contractiltiy
- Increase ejective force
- Increase in stroke volume : CO = HR x SV
What are the two types of heart failure?
Acute heart failure – cardiac arrest, sepsis
Chronic heart failure – cardiomyopathy, chronic hypertension, valve disease
List the types of drugs that increase contractility (ionotropic agents)
- Gs coupled receptor agonist and pathways
- PDE inhibitors
- Other Ca2+ rising processes
Example of other Gs-couples 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 in this situation)
Gs agonists not used in chronic heart failure – increase heart rate (proarrhythmic), increase myocardial work + O2 demand
Describe PDE inhibitors
Give an Example
e.g. Amrinone – phosphodiesterase III inhibitor (IIIPDE is heart specific)
If PDE is blocked, less cAMP is broken down which increases PKA levels and therefore contractility as there is an increase in VGCCs and Ca2+ influx
Only used in severe and chronic cases – those waiting for heart transplants
What does PDE(phosphodiesterase) do?
It an enzyme that breaks down cAMP to AMP
Explain the mechanism of cardiac glycosides
Give an example
Cardiac glycosides e.g. digoxin increases contractility by reducing Ca2+ extrusion
-It has a high toxicity due to narrow therapeutic window
Mechanism:
- Digoxin inhibits Na+/K+ ATPase
- There is a build up of intracellular Na+. This reduces the gradient for the Na+/Ca2+ exchanger to work
- Less Ca2+ extrusion by Na+/Ca2+ exchanger (NCX)
More Ca2+ uptake into stores and greater CICR - greater contraction
Explain the mechanism of Ca2+ sensitisers
Give 2 main examples
- Drugs have no effect on Ca2+ levels
- They increase the contractile apparatus sensitivity (e.g. troponin) to Ca2+ so contraction works better at lower Ca2+ levels
- These drugs do not increase O2 consumption or be proarrhythmogenic
Problems with Gs-coupled agonist induced rise in Ca2+
Solutions??
- Increased need for Ca2+-ATPase to reuptake more Ca2+ into SR stores
- More O2 consumption, stresses the heart
- Also increases heart rate
Solution: Calcium sensitisers
2 examples of calcium sensitisers
When are they used?
· Levosidan - Bind to troponin C, increase binding of Ca2+ to Trop C (move more tropomyosin, more binding sites exposed and greater contraction)
Omecamtiv – Increases actin-myosin interactions (in absence of rise in Ca2+)
Drugs used in decompensated heart failure – associated with poor outcome
Why is B blockers used in chronic heart failure?
It may seem like a paradox to use B blockers e.g. during chronic heart failure with poor CO which needs better contractility and it might seem to make more sense to promote B-adrenoreceptor activity.
We use B blockers:
- Prevent overworking of a failing heart by slowing HR to increase diastolic time increasing coronary perfusion
- Reduces cotnractility reduces O2 demand making failing heart work more efficiently
- Prevent down regulation of B-adrenoreceptors due to excess sympathetic nerve activity - more B receptors available for contractility
- Prevent B-adrenoreceptor associated arryhythmias
What 2 drugs reduce afterload?
Diuretics e.g. loop diuretics, thiazide, K+ sparing
ACEi, ARB, e.g. ramipril, losartan
Why is reducing afterload important?
It promotes an increase in CO and SV
BP = CO (e.g. blood volume) x TPR (e.g. blood vessel constriction)
What do diuretics do?
- Reduce blood volume
- Reduced central venous pressure and stroke volume (via Starling’s law)
- Reduce cardiac output and therefore blood pressure
What do Ace inhibitors and ARb do?
· Reduce Ang II-induced vasoconstriction – reduces TPR
Reduce Ang II-induced aldosterone – reduce blood volume – reduce CO
Why is increasing coronary artery blood flow during angina important?
· In angina, cardiac pain is produced by poor blood flow to heart often due to occlusion of coronary arteries
Need coronary arteries to dilate more to increase blood flow and relieve symptoms
What drug increases coronary artery blood flow?
Use Nitrate donor – e.g. GNT
Often administered as a spray under tongue
