Lec 17- Vasodilators Flashcards
Haemodynamic rationale and effect
- Preload- vasodilation and reduction of intracardiac volume
- After load- reduction in systemic vascular resistance
- Coronary perfusion- Decreases myocardial schema , increase coronary blood flow to reduce O2 demand
Preload revision
- This is the volume of blood in the ventricle before contraction
- This is based on venous pressure (venous return)
- If increase right atrial pressure then get increased ventricle filling
- Increased filling results in increased output
- This is an increase in myocardial work and O2 requirements
After-load
- Afterload is the peripheral BP that ventricular contraction must overcome
- Ventricular contraction and cardiac output will compensate for increased after load
- This is an increase in myocardial work and O2 requirement
- Long term increase in arterial pressure results in ventricular hypertrophy
Coronary blood supply
-Angina- blockage via atherosclerosis, if we increase the diameter of the vessels allows blood to pass
Coronary perfusion ‘The perfusion window’
- Blood flow to the heart muscle only occurs during diastole
- Increase HR means there is less time between beats therefore less time for blood to feed the heart so perfusion is decreases
- An increase in ventricular end diastolic pressure will mean less blood flow to the heart
- Reduced diastolic arterial pressure means less blood will flow to the heart
Clincal use of vasodilators
-Reduce cardiac preload \+Cardiac failure (CHF) \+Angina -Reduce cardiac after load- HTN -Local reductions in vascular resistance \+Prinzmetal's (variant) angina \+Peripheral vascular disease \+Raynauds disease
Pre-load reduction
- Relaxation of veins will decrease cardiac filling pressure (pre-load)
- Therefore use vasodilators with predominant venous action
- Useful in CHF and in angina- sudden reduction in preload and so cardiac work
Afterload reduction
- Relaxation of arterioles will decreased resistance and reduce BP (HTN). Afterload reduction also useful in Angina and HF
- Use vasodilators with predominant arterial action
- The sum forces opposing ventricular emptying. Hypertrophy is a physiological mechanism due to increased afterload
- Useful in cardiac failure to reduce cardiac work
Coronary flow
-Relacation of arteries will increase flow to an Organ if arteries are narrowed (angina) and decrease afterload by increasing compliance (Useful in HF)
Vasodilator drugs
Heterogenous Group: 2 major types
1) Directing acting: On vascular smooth muscle (VSM)- affect all constrictor agents
A- Drugs acting at ion channels
B-Drugs acting on NO systems
2) Indirectly acting or anti-vasoconstriction
A-Drugs acting on ion channels
1) Ca2+ channel blockers- inhibit voltage gated Ca2+ channels
2) K+ channel openers: Activates ATP dependant K+ channels
Muscle cell: cardiac or vascular
-Depolarisation, Ca2+ entry = contraction
-
Cardiac APs in general
- Rapid depolarisation
- Partial repolarisation (calcium shoulder, gives prolonged contraction)
- Plateau
- Depolarisation
- Pacemaker potential
Voltage gated calcium channels
- Present in all excitable cells- muscles and nerves
- Activated by cell depolarisation e.g. during cardiac AP
- Different subtypes: L; N; P/Q; T
- Different subtypes have different tissue distributions and functions
- It is L-type channels that mediate voltage dependant Ca2+ entry into the muscle
L-Type channel structure
- The a1C subunit of the L-type Ca2+ channel is the pore-forming unit
- Central function unit with similar structure to Na+ channels
- 4 homologous domains each with 6-a helices membrane spanning segments (S1-6)
- S4 contains +VE charged residues (voltage sensors)
- a1 subunit structure defines subtype and is the target subunit for antagonists and agonists
L-Type blockers act selectively on cardiovascular tissues- important for therapeutic use
-Neurons rely on N and P-type channels
-Skeletal muscle relies primary on [Ca]i
-Cardiac muscle requires Ca2+ influx through L-type Ca2+ channels
+Contraction (e.g. ventricular myocytes)
+Upstroke of AP (pacemaker)
-Vascular smooth muscle requires Ca2+ influx through L-type Ca2+ channels for contraction
CCBs- mechanism of action
- Increase the time that Ca2+ channels are closed
- Relaxation of there arterial smooth muscle but not much effect on venous smooth muscle
- Reduce calcium entry into vascular smooth muscle and so produce vasodilation
- Significant reduction in afterload BUT NOT preload
3 Modes of Ca2+ channel opening
Mode 0 -opening probability 0 -Favoured by DHP antagonists -% of time spent in this mode <1% Mode 1 -Opening probability low -% of time normally spent in this mode= 70% Mode 2 -Opening probability High -Favoured by DHP antagonists -% time open= 30%
-Weather not channel opens affects the binding of the drug
3 classes of calcium channel blocker
- Verapamil (phenylalkyamines)
- Diltiazem (benzodiazepine)
- Nifedipine (1,4-dihydropyridines)
The different drugs have different channel binding region properties
-Use-dependant binding (Target AP conducting cardiac cells)
+Verapamil binds to area of the channel that is only exposed once the channel is open
-Voltage-dependant binding (target smooth muscle)
+Amlodopine needs the channel to be inactive inorder to bind, because of the voltage of the Ca2+ channels (-30mV) the channels are normally closed
