Drugs affecting control of blood pressure Flashcards
In vascular smooth muscle cell contraction describe how the intracellular concentration of calcium is increased?
Through the opening of L-type Ca channel bu numerous depolarizing mechanisms and GPCR receptor coupled to Gq/11
In vascular smooth muscle cell contraction what does intracellular calcium couple to?
calmodulin to form Ca-CaM
What role does Ca-CaM play in vascular smooth muscle cell contraction ?
It activated Myosin Light Chain Kinase
What does active MLCK do in vascular smooth muscle cell contraction ?
It phosphorylates the myosin light chain and causes contraction
What is the role of cGMP in vascular smooth muscle cell relaxation?
It activates Protein Kinase G
What is the role of PKG in vascular smooth muscle cell relaxation?
Activates myosin-lc phosphatase
What is the role of myosin-lc phosphatase in vascular smooth muscle cell relaxation?
It dephosphorylates the myosin light chain, causing relaxation
What do organic nitrates do to VSM?
Relax it
What organic nitrates do at clinical doses?
Venorelaxation
Increased coronary blood flow
Arteriolar dilatation
What does venorelaxation cause?
Reduced preload, then SV but CO is maintained by increased HR
What is the benefit of organic nitrates to patients with angina?
Decreased myocardial oxygen requirement
1) decreased preload
2) decreased after load
3) improved perfusion of the ischaemic zone
What is the effect of motivate on the coronary circulation?
dilate the collateral vessels, ensuring blood flow to the myocardium is increased
What is the role of endothelin in vascular smooth muscle tone
when endothelin is produced as a result of altered gene expression through adrenaline, angiotensin II, ADH or NO, natriuretic peptides or sheer stress it will agonise the Eta receptor, and through numerous signalling pathways including Gw/11 increase intracellular calcium and cause contraction
What is the clinical use of organic nitrates?
used in stable and ACS
What are the main organic nitrates used in ACS?
GTN and isosorbide mononitrate (occasionally isosorbide dinitrate)
What is the action of GTN?
Short acting- excessive first pass metabolism (this is why it is given as a spray or sublingual)
How is GTN given in unstable angina?
IV infusion with aspirin to prevent a thrombus
What method can GTN be administered for a long lasting effect?
Transdermal patch
What is the action on isosorbide mononitrate like?
Longer acting as it is resistant to first pass metabolism
How is isosorbide mononitrate administered?
Orally for prophylaxis of angina
What is associated with repeated administration of organic nitrates?
Reduced effect- tolerance
Name some unwanted side effects of organic nitrates?
Postural hypotension
Headaches
What is the Eta targeted in?
Pulmonary hypertension by bosentan and ambrisentan
What causes increased renin release?
increased Renal sympathetic nerve activity
decreased Renal perfusion
reduced glomerular filtration
What does the AT1 (GPCR) cause
Increased release of noradrenaline from sympathetic nerves
Growth in the heart and arteries as a result of altered gene expression
aldosterone release from the adrenal cortex
cousin tubular Na reabsorption and salt retention
Where is ACE present?
On endothelial cells particularly the cells of the lung
Where are AT1 receptors present?
Terminal sympathetic neurons which innervate VSM and VSM cells
What do AT1 receptors in the adrenal cortex cause?
synthesis and release of aldosterone which acts to increase salt retention
What does ACE do?
Convertes inactive angiotensin I to angiotensin II
Inactivates bradykinin (vasodilator)
What do ACE inhibitors do?
block the conversion of angiotensin I to angiotensin II
What do AT1 receptor antagonists do?
Block the action of angiotensin II at AT1 receptors in a competitive manner
What do ACEI do do MABP?
Decrease it venous dilatation (decreased preload) and arteriolar dilatation (decreased afterload and decreased TPR) decreasing arterial blood pressure and cardiac load
What affect do ACEI have on cardiac contractility?
none
What do ACEI do to aldosterone release?
Reduce (not abolish) the release of aldosterone (decrease in circulating levels of aldosterone promotes loss of Na+ and H2O)
Where do they have the greatest effect and on whom?
much larger effect in hypertensive patients (especially if renin secretion is enhanced – e.g. as a consequence of diuretic therapy)
angiotensin-sensitive vascular beds (brain, heart, kidney)
What is the additional effect of angiotensin II on the heart and vasculature?
Causes growth
What are the adverse effects of ACEI?
hypotension
dry cough
What is an essential difference between ARBs and ACEi?
ARBs do not inhibit the metabolism of bradykinin
When are ACEI and ARBs contraindicated?
Pregnancy
bilateral renal artery stenosis
What are the clinical uses of ARBs and ACEi?
hypertension
cardiac failure
post MI
What is the mechanism by which ACEi and ARBs are used in the treatment of hypertension?
benefit derives from
1) reduced TPR and MABP
2) possible suppression of proliferation of smooth muscle cells in the media of resistance vessels
What is the mechanism by which ACEi and ARBs are used in the treatment of cardiac failure?
is associated with inappropriate activation of the RAAS.
ACEIs
1) decrease vascular resistance improving perfusion
2) increase excretion of Na+ and H20
3) cause regression of left ventricular hypertrophy
What is the function of alpha1 adrenoreceptors?
constrict
What is the function of B1 adrenoreceptors?
increase HR
increase force of contraction
increase AV node conduction velocity
What is the role of B2 adrenoreceptors?
bronchorelaxation
vasodilatation
Why are B blockers useful in the treatment of angina pectoris?
decrease myocardial O2 requirement (decreased HR & decreased SV = decreased work = decreased O2)
counter elevated sympathetic activity associated with ischaemic pain
increase the amount of time spent in diastole (decreased HR), improving perfusion of the left ventricle
Why are B blockers useful in the treatment of hypertension?
No longer first line
BUT
reducing cardiac output (MABP = CO x TPR) (However, CO returns to normal over time but MABP remains depressed by ‘resetting’ of TPR at a lower level – mechanism uncertain)
reducing renin release from the kidney
a CNS action that reduces sympathetic activity
Why are B blockers useful in the treatment of heart failure?
In combination with other drugs to suppress adverse effects associated with elevated activity of the sympathetic nervous system and RAAS (Start low, go slow)
What do calcium antagonists do?
prevent the opening of L-type channels in excitable tissues in response to depolarization and hence limit intracellular calcium
What are L type channels responsible for?
upstroke in the AP in the SA and AV nodes- Ca2+ antagonists can reduce rate and conduction through the AVN
phase 2 of the ventricular AP- Ca2+ antagonists can reduce the force of contraction
How do a1 adrenoreceptors function in VSM cells?
a1-adrenoreceptors couple to Gq/11 and open the cation selective channels (Na channel) which allows calcium entry into the cell
what are the three main types of calcium antagonists?
“verapamil: selective for cardiac L-type channels
o physically blocks the L-type channel
amlodipine: selective for L-type channels in VSM
diltiazem: intermediate selectivity from cardiac and VSM cells
o act allosterically
What are the clinical uses of calcium antagonists?
Hypertension
angina
dysrythmias
What is the mechanism whereby calcium antagonists work in hypertension?
reduced Ca entry= arteriolar dilatation= reduce TPR & MABP
What is the mechanism whereby calcium antagonists work in angina?
prophylactic treatment used with GTN (particularly if B blockers are contraindicated)
peripheral arteriolar dilatation- decreasing afterload and myocardial oxygen requirement
coronary vasodilatation
amlodipine: little effect on cardiac muscle
diltiazem and verapamil: negative inotropic effects. some of reduction in cardiac force is compensated by sympathetic system
What is the mechanism whereby calcium antagonists work in dysrythmias?
Ventricular rate in rapid atrial fibrillation reduced by suppression of conduction through the AV node
Verapamil is usually used, but avoid in heart failure, particularly in combination with a b-block
How do potassium channel openers function?
ATP closes the ATP type potassium channels, potassium channel openers have the opposite effect (opens K-ATP channels in VSM- causing the cell to hyperpolarise, moves membrane potential away from threshold- supressing the opening of voltage activated calcium channels- causing relaxation)
What is minoxidil used for?
last resort in severe hypertension (causes reflex tachycardia- can be prevented by administration of a B-blocker) causes salt and water retention (alleviated by a diuretic). restores hair in balding men when applied topically.
What is nicorandil used for?
opens ATP type potassium channels
How do a-1 adrenoreceptor antagonists work?
Cause vasodilatation by blocking vascular a1-adrenoceptors. Reduced sympathetic transmission results in decreased MABP
What are the most commonly used a-1 adrenoreceptor antagonists?
prazosin and doxazosin - both are competitive antagonists
When do a-1 adrenoreceptor antagonists get moved up the prescribing list?
when patient is suffering from benign prostatic hyperplasia, this is because the muscle tone in the prostate is in part modified by -1 adrenoreceptor and noradrenaline and therefore blockers may relieve some of the effects
Adverse effect of a-1 adrenoreceptor antagonists?
postural hypotension
