Vasodilators Flashcards
Therapeutic uses
Treatment of hypertension (dilation or arteries and veins).
Treatment of angina pectoralis.
Angina pectoralis
Chest pain due to myocardial ischemia. Build up of metabolites (adenosine, CO2, potassium, lactate) activates sensory nerves. Not a disease itself. Ischemia due to increased myocardial O2 demand not being met, and decreased coronary blood flow. 3 types of angina 1. Stable angina - most common 2. Unstable angina 3. Varient angina - least common.
Stable angina
Most common
Attacks predictable - exercise, stress.
Myocardial O2 demand not met.
Involvement of chronic occlusive coronary artery disease - use of cholesterol lowering drugs and statins for secondary prevention.
Unstable angina
Attacks unpredictable
Coronary artery occlusion due to platelet adhesion to atherosclerotic plaque
Low dose aspirin and other anti-platelet drugs used as secondary treatment.
Varient angina
Least common
Attacks unpredictable
Coronary artery occlusion by vasospasm.
Dilatation of coronary arteries
May be valuble to prevent vasospasm in varient angina, but not other forms as may cause coronary steal.
Badly named - dilation takes place in normal vessels, delivering even more blood to already well perfused areas but dilation cannot occur in diseased vessels, so even less blood is delivered to the poorly perfused areas they serve due to a drop in flow pressure.
Major strategy in all forms of angina is to reduce myocardial oxygen demand.
Acheived by drugs acting directly on the heart (beta blockers, calcium channel blockers, If channel blockers).
Achieved indirectly by vasodilators - dilation of arteries (decreases TPR and afterload), dilation of veins (defreases preload and ventricular strech, therefore decreases force of contraction)
Nitrovasodilators
Most commonly used anti-anginals. Glycerol trinitrate Amyl nitrate Isosorbide dinitrate/mononitrate Sodium nitroprusside
Act by -
Venous dilation primarily, arterial dilation at high concentrations.
Venous dilation decreases preload (venous return) therefore decreasing myocardial work and thus myocardial oxygen demand falls.
Used in all forms and angjna, no risk of coronary artery dilation.
All nitrovasodilators are prodrugs.
The active agent is NO
All nitrovasodilators are lipophillic therefore readily enter smooth muscle cells.
NO is released from parent molecule by reductive processes - reduction by enzymes (CYP450, aldehyde dehydrogenase,glutathione-5-transferase) and thiols (L-cysteine,glutathione)
Glycerol trinitrate
Rapid onset, short duration of action.
Sublingual, not orally active.
Used for prophylaxis in stable angina (ie taken before exercise), and relief of ongoing anginal attack.
Common siee effect of headaches due to dilatation of cerebral arteries.
Amyl nitrate
Poppers
Volitile liquid, vials opened and inhaled.
Treatment for cyanide poisoning
Rapid onset, short duration of action.
Isosorbide dinitrate/mononitrate
Taken orally
Slower onset, more prolonged duration of action.
Used for sustained prophylaxis in all forms of angina.
Sodium nitroprusside
Not orally active
Notused in angina.
Given IV in severe hypertensive emergency.
Tolerance of nitrovasodilators
Become ineffective on continuous use.
Tolerance can be reversed by drug free wash-out period.
Tolerance is related to limited capacity to metabolise parent drug into NO or destruction of NO by superoxide anion.
NO activates soluble guanylate cyclase
Soluble guanylate cyclase is a cytoplasmic enzyme.
The receptor on GC contains a ferrous haem moiety, analogous to oxygen binding site of haemoglobin.
NO binds to haem receptor causing enzyme activation, this increases conversion of GTP to cGMP.
Endogenous stimulation of GC
Endothelium derived relaxing factor (EDRF) is NO.
Neurotransmitter of NANC nerves is NO.
NO is present in GI, reproductive and respiratory tracts.
It is also responsible for neurogenic vasodilator innervation of cerebral and penile arteries.
Natriuretic peptide family
ANP - atrial natriuretic peptide, produced in atria.
BNP - brain natriuretic peptide, produced in ventricles
CNP - c-type natriuretic peptide, produced in vascular endothelium.
Structural homology, similar actions.
All stored in secretory vesicles, released by exocytosis and have an endocrine role in regulation of blood volume.
Increase in atrial/ventricular pressure (due to increased blood volume) leads to aftivation of twhe strech receptors in cardiac myocytes, leading to the release of ANP/BNP.
Natriuretic peptides reduce hlood volume and pressure by…
Vasodilation - arterial dilation (renal in particular), increases renal bloodflow, increases glomerular filtration.
Natriuretic action - increased renal secretion of sodium and water. This is achieved by increasing renal blood flow, leading to decreased renin secretion. There is also direct action on JG cels to decrease renin release and direct action on the adrenal medulla to decrease aldosterone secretion.
I.e. Natriuretic peptides oppose the RAAS
Receptors of natriuretic peptides
3 major membrane receptors
NPR1 (NPR-A) - potency: ANP=BNP>CNP.
NPR2 (NPR-B) - potency: CNP>ANP=BNP.
NPR3 (NPR-C) - all natriuretic peptides have equal potency here.
NPR1 and NPR2
Have intrinsic particulate-guanylate-cyclase activity.
Responsible for vasodilator and natriuretic actions.
Different gene products from soluble guanylate cyclase, no haemnin receptors.
Not activated by NO.
NPR3
Most adundant receptor present on cells.
Second messenger unknown,not cGMP.
Clearance receptor - removes natriuretic peptides from circulation.
Acts together with neutral endopeptidases (which digest natriuretic peptides) to limit natriuretic peptide activity.
Potential therapeutic roles of natriuretic peptides
Potential for role in -
Heart failure where RAAS is overactive.
Hypertension.
Not currently used clinically due to short half-life in plasma but possibility to potentiate their endogenoaus actions by -
- Inhibiting neutal endopeptidases (candoxatril)
- Inhibiting NPR3 to prevent scavenging effect (removal of NPs from blood).
Mechanisms of decreasing intracellular calcium concentration
- Inhibition of calcium release from SR (by inhibition of phospholipase c and decreased IP3) (note SR is sparse in smooth muscle)
- Inhibition of calcium entry via store operated calcium channels in a major mechanism.
- Inhibition of calcium entry via L-type voltage channels by phosphorylation.
- Activation of calcium ATPases, causjng jncreased extrusion of calcium from cell, and increased uptake of calcium into SR via SERCA.
Decreasing intracellular calcium concentration leads to decreased calcium-calmodulin complex, so less to activate myosin light chain kinase, leading to decreased phosphorylation of myosin and decreased interaction with actin, therefore relaxation.
Evidence supporting the role of cGMP in smooth muscle relaxation
A rise in cGMP (induced by NO, natriuretic peptides) precedes relaxation.
8-bromo cGMP causes relaxation.
PDE5 inhibitors potentiate relaxation (selectively inhibit hydrolysis of cGMP).
Inhibitors of soluble guanylate cyclase inhibit relaxation induced by nitrovasodilators, NO and nitrergic nerves but not natriuretic peptides (as they use particulate guanylate cyclase), a few exa,ples of these are methylene blue, OQD and Hb.
Inhibitors of particulate GC or NPRs are not yet available.
Phosphodiesterase inhibitors
Prolong life expectancy
Inhibit enzymes that hydrolyse cAMP/cGMP
Actions of cAMP/cGMP are potentiated and prolonged.
Note, hnlike in cardiac muscle, cAMP causes relaxation in vascular smooth muscle beta2 stimulation of cAMP)
3 gene families of PDE are preseng in vascular smooth muscle -
PDE1 - cGMP hydrolysis
PDE4 - cAMP hydrolysis
PDE5 -cGMP hydrolysis
3 classes of PDE inhibitors active in vascular smooth muscle
- Non selective - inhibit most PDEs, cause vasodilation and increased HR and force of contraction in the heart.
- Selective PDE4 inbibitors - I.e rolipram, not used clinically ,can cross BBB.
- Selective PDE5 inhibitors - sildenifil, produces vasodilation and potentiation of NO in smooth muscle. Used to treat impotency but also hypertension in animals.
Calcium channel blocking agents as vasodilators
Classes of voltage gated calcium channels -
- L-type (long lasting current) - present I. Smooth muscle, cardiac muscle and pacemaker Cells.
- T-type (transient) - in cardiac muscle and pacemaker Cells.
- N channle - present in neurones
- P/Q (positive potentials) - in neurones
All channels open on membrane depolarisation
Drugs exist to block alk these channels but only those blocking L/T tupes are used clinically.
L-type channel block
3 classes of drugs do this -
Phenylalkylamines (verapamil)
Benzothiazepines (diltiazem)
Dihydropyridines (nifedipine)
Mechanisms -
- Open channel block (cork in a bottle) phenylakylamines and benzothiazepines work this way.
- Allosteric modulation - binding at allosteric site to reduce the probability of channel opening at given voltage. Dihydropyridines work this way. (some dihydropyridines are VOC agonists and increase probability of channel opening, these are not used clinically).
Tissue selectivity -
Smooth muscle - nifedipine>diltiazem>verapamil
Cardiac muscle - verapamil>diltiazem>nifedipine
Vascular action and uses of L-type channel blockers
Dilate arteries (little effect on veins) , dedrease TPR.
Uses -
Anti-hypertensive
Anti-anginal (nifedipine causes coronary steal in 10%)
Anti-dysrhythmic
Advrse actions - headache, constipation, cardiac failure.
Blockade of T-type channel
Only CV drugcinically used of this type is mibefradil.
Causes arterial dilation
Slows HR (SA/AV node action) without decreasing force of contraction (few t channels in ventricular muscle)
Has adverse effects on metabolism of other drugs.
Ivabradine
Recently introduced to treat angina
Blocks If current that contributes to SA node depolarisation towards threshold.
Decreases HR but not force of contraction, decreases myocardial O2 demand by delaying diastolic depolarisation in the SA node.
