2.2 CVS Pharmacology (1 + 2) Flashcards
What are the aims of CVS drug therapy? (5)
- Enhance systolic function
- Enhance diastolic function
- Ensure optimal cardiac rate and rhythm
- Optimise distribution of fluid within the circulation
- Counteract effects of detrimental neurohormonal activities
What cardiac functions can be manipulated pharmacologically?
Heart rate
Heart rhythm
Cardiac muscle contractility
What is the effect of noradrenalin on cardiac muscle cells?
Inhibits phosphodiesterase
cAMP not broken down
Increased action of protein kinase A
Increased [Ca2+]i
Describe ion handling in cardiac myocytes
- Ca2+ influx balanced by efflux via Ca2+/Na+ exchange
- Na+ extruded in exchange for K+ by the Na+/K+/ATPase
- Changes in [Na+]i affect [Ca2+]i
List the targets for drugs acting on cardiac muscle
1) Receptors (e.g. M2, B1 adrenoreceptors)
2) Ion channels (e.g. fast Na+ channels, slow Ca2+ channels, K+ channels)
3)Cardiac muscle cell enzymes (e.g. Na+/K+ ATPase, PDE)
What are the effects of a sustained increase in HR?
- Increased myocardial O2 consumption
- Reduced time for ventricular filling
- Reduced time for coronary blood flow
List the drugs that slow HR (negative chronotropes)
- Muscarinic (M) receptor agonist
- Drugs that act centrally to increase vagal tone - cardiac glycosides
- π adrenoceptors antagonists
List the drugs that increase HR (positive chronotropes)
- Muscarinic receptor antagonists
- π adrenoceptor agonists
Describe the use of B adrenoceptor antagonists as drugs that slow heart rate
Particularly effective in hearts driven by high sympathetic tone
Also reduces the force of contraction of ventricular muscle (which may have negative effects)
Describe when B adrenoceptor agonists may be used as drugs that increase heart rate
Non-selective agonists increase heart rate more than B1-selective drugs
Causes vasodilation (particularly in skeletal muscle) B2 effect
Used in emergency of complete (3rd degree) cardiac block
Describe when muscarinic receptor antagonists as drugs that increase heart rate might be used
Premedication for anaesthesia and surgery, particularly when vagal stimulationn and slowing of the heart is a potential problem
Treatment of bradycardia (incomplete heart block)
What are the actions of the 4 classes of commonly used antidysrhythmic drugs?
Class I: Block voltage-dependant Na+ channels
Class II: Antangonise π adrenoceptors
Class III: Unknown mechanism
Class IV: Inhibits Ca2+ channels
Describe class I antidysrhythmic drugs
Block voltage-dependant Na+ channels
-Decreased rate and magnitude of depolarisation
-Reduced conduction in non-nodal tissues (e.g. purkinje fibres)
Describe class II antidysrhythmic drugs
Antagonise π adrenoceptors
-Reduce excessive sympathetic tone that may cause arrhythmias
Describe Class III antidysrhythmic drugs
Mechanism not yet understood
-Involves blockade of K+ channels involved in cardiac repolarisation
-Emergency use in vet med
Describe class IV antidysrhythmic drugs
Reduce plateau current, shorten action potential, negative isotropic effect
List the types of drugs that increase cardiac muscle contractility (positive isotropes)
Cardiac glycosides
Phsophodiesterase (PDE) inhibitors
Benzimidazole derivatives
Sympathomimetric drugs
Explain how cardiac glycosides increase muscle contractility
Glycoside inhibits Na+/K+ exchange
Increased [Na+]i
Decreased Na+/Ca2+ exchange
Increased [Ca2+]i
Increased force of contraction
Explain how PDE inhibitors increase muscle contractility
PDE inhibited
Increased cAMP
Increased force of contraction
Explain how benzimidazole derivatives increase mucle contractility
Increases Ca2+ sensitivity of cardiac myofibrils
Inhibits types III cAMP-phosphodiesterase
What is vascular tone maintained by?
Balance between opposing actions of neurotransmitters, hormones, and mediators that have vasoconstrictor and vasodilator properties
Which mediators have vasoconstrictor properties?
Noradrenaline / Adrenaline (π adrenoceptors)
Prostacyclin (PGl2)
NO
Atrial natriuretic peptide (ANP)
Which mediators have vasoconstrictor properties?
Noradrenaline / Adrenaline (π adrenoceptors)
ATP
Angiotensin II
Vasopressin (ADH)
Endohelin
TxA2
ADP
What mediators have vasodilator properties?
Noradrenaline / Adrenaline (π adrenoceptors)
Prostacyclin (PGl2)
NO
Atrial natriuretic peptide (ANP)
Adenosine
Why is the sympathetic system important in the vasculature?
Can control contraction/dilation of blood vessels
Helps contribute to arterial BP control
What targets for drugs acting on the vasculature are there?
Membrane receptors
Cell membrane ion channels
Smooth muscle cell enzymes
Enzymes generating or inactivating vasoconstrictors/dilators
What do arterial dilators act on? How do these work?
Arterioles
Reduce afterload
Cause an increase in SV
Decreases myocardial O2 consumption
Eventually decreases preload
What do venodilators act on? How do these work?
Veins
Reduce preload by βtrappingβ blood in the venous circulation
What are the three targets for drugs which interfere with natural vasoconstrictors?
Sympathetic nervous system
RAAS
Endothelin-I
What vasodilator drugs act on the symapthetic system?
Ξ±1-selective agrenoreceptor agonists
How do Ξ±1-selective agrenoreceptor agonists work?
Act on venous and arteriole circulation
Best response where sympathetic tone to blood vessels is high
Fall in vascular tone is usually short lived
What is renin?
Proteolytic enzyme
Secreted by specialised cells in the kidney
What is the stimulus for renin release?
Renal sympathetic nerve stimulation
Reduced pressure in afferent arteriole
Reduced [NaCl] in distal tubules
What is ACE?
Angiotensin Converting Enzyme
Non-specific carboxypeptidase that also breaks down bradykinin
Where is ACE found?
Endothelial cells of lung capillaries
What is angiotensin II?
One of the most potent vasoconstrictor agent known
How does angiotensin II work?
- Enhances salt and water retention (acts via aldosterone)
- Acts on cardiac muscle to cause hypertrophy (promotes protein synthesis to make heart grow)
- Increases release of norepinephrine from sympathetic nerves
At what points can RAAS be influenced by drugs?
Renin release
ACE
AT1 receptors
What drugs affect renin release?
π-antagonists block renin secretion
What is the RAAS
Angiotensinogen -(Renin)-> Angiotensin I -(ACE)-> Angiotensin II
How is angiotensin production controlled?
By controlling renin release:
- reduced glomerular filtration
- Reduced [Na] in distal tube
- π antagonist
- π agonist
ACE inhibitors
AT1 antagonists
