Drugs Affecting Control of Blood Pressure Flashcards
How does vascular smooth muscle contract?
Depends on the conc. of Ca2+ in the cell:
By the activated of a G-protein coupled receptor to Gq/11
OR
By depolarisation - opening of L-type Ca2+ channels
Increased Ca2+ binding to CaM (Calmodulin) to form Ca2+-CaM
This activates Myosin Light Chain Kinase, which phosphorylates a Myosin Light Chain (results in contraction)
How does vascular smooth muscle relax?
cGMP (cyclic guanosine monophosphate) activates myosin light chain phosphatase
This dephosphorylates myosin light chain (results in relaxation)
Functions of the endothelium?
- Generate locally acting substances - vasoconstrictors and dilators which act on adjacent smooth muscle cells, e.g: nitric oxide and exogenous organic nitrates
- Suppress platelet aggregation
Production of nitric oxide in endothelial cells?
NO can be produced by the endothelium in response to any influence that increases Ca2+ conc. in endothelial cells, e.g: vasodilators do this
If increased Ca2+ conc. there is increased Ca2+-CaM and this activates eNOS
eNOS utilised L-arginine and oxygen to produce nitric oxide (diffuses into adjacent smooth muscle cells - highly soluble but has a short half-life)
Mechanism of action of NO in smooth muscle cells?
NO activates guanylate cyclase - converts GTP into cGMP (activates protein kinase G and dephosphorylation of Myosin Light Chain)
This results in RELAXATION (NO is a vasodilator) and also HYPERPOLARISATION - NO from the endothelial cell opens Ca2+-dependent K+ channels
Hyperpolarisation inhibits Ca2+ influx, as there is no depolarising influence on the channels, and also increases uptake of Ca2+ by the SR - net result is relaxation
Mechanism of action of organic nitrates, e.g GTN spray?
Enzymes/tissue thiol cause liberation of NO from the compound
NO activates guanylate cyclase - convertes GTP into cGMP (activates protein kinase G and dephosphorylation of Myosin Light Chain)
Results in RELAXATION and HYPERPOLARISATION - NO from the endothelial cell opens Ca2+ dependent K+ channels
Hyperpolarisation inhibits Ca2+ influx, as there is no depolarising influence on the channels, and also increases uptake of Ca2+ by the SR - net result is relaxation
Effects are more prolonged than those of endogenous NO
Examples of vasodilating substances?
Bradykinin
ADP
5-HT
Clinical doses of organic nitrates cause?
Venorelaxation - in SMALL doses, cause decreased capacitance vessel pressure (preload) and so reduces SV. But CO is maintained due to an increase in HR so there is no change in arterial pressure
Arteriolar dilatation - HIGHER doses decrease arterial pressure and so reduce afterload:
Large arteries are more sensitive so there is decreased pulse wave pressure from arterial branches (only need to know that this decreases work of the heart by reducing afterload)
Benefits of organic nitrate use in angina?
Increase coronary blood flow (in NORMAL subjects) - in ANGINA, there is no overall increase, but blood is REDIRECTED towards the ischaemic zone
In angina, the benefits are due to decreased myocardial oxygen requirement, so:
Decreased preload
Decreased afterload
Improved perfusion of the ischaemic zone
How do organic nitrates redirect blood flow to ischaemic zones?
Prolonged occlusion of a vessel by an atheromatous plaque will result in collateral formation (branches from healthy vessel going to an area below the obstruction on another vessel that supplies a now ischaemic zone) - blood is shunted from normally perfused area to ischaemic zone
Organic nitrates dilate both the blood vessel and the collaterals
Clinical uses of organic nitrates?
Used in STABLE angina and ACUTE coronary syndrome
Examples of organic nitrates?
Glyceryltrinitrate (GTN) - administered shublingually for rapid effect before exertion (stable angina) or by IV infusion (with aspirin) in acute coronary syndrome; short-acting drug that undergoes first-pass metabolism. Longer acting if given by transdermal patch
Isosorbide mononitrate - longer-acting and is resistant to first-pass metabolism; administered orally for prophylaxis of angina and more sustained effect (available in immediate and slow release formulations)
Tolerance to organic nitrates?
Repeated administration may be associated with a diminished effect (can be minimised by nitrate low periods, e.g: not taking in the evening until next morning)
Unwanted effects of organic nitrates?
Postural hypotension
Headaches (initially)
Rarely, formation of methaemoglobin (non-oxygen carrying)
Production of endothelin by endothelial cells?
Released by endothelial cells, as endothelin-1, in response to vasoconstrictors, like adrenaline, Ang. II and ADH
Endothelin production is reduced by vasodilators, like NO, natriuretic peptides and shear stress
These factors all alter gene expression in order to increase/decrease production of endothelin precursors - which are converted to endothelin-1
Mechanism of action of endothelin-1 in vascular smooth muscle cells?
Endothelin-1 binds to ETA receptors on vascular smooth muscle cells
Via numerous signalling pathways, inc. Gq/11, they increase intracellular Ca2+ and so cause CONTRACTION
Therapeutic methods utilising endothelin-1 pathway?
Can block ETA receptor, using antagonists, e.g: bosentan and ambrisentan
Used in the treatment of PULMONARY HYPERTENSION
RAAS system regulates?
Sodium excretion
Vascular tone
Factors causing renin release from the kidney?
Increase in renal sympathetic nerve activity
Decrease in renal perfusion pressure
Decrease in glomerular filtration
Briefly describe the RAAS system?
Renin released from the juxtaglomerular apparatus (kidney) causes conversion of angiotensinogen, from the liver, to Ang. I
Ang. I is converted to Ang. II by Angiotensin Converting Enzyme (ACE)
Effects of Ang. II?
Binds to and activates smooth muscle AT1 receptors to increase noradrenaline release from sympathetic nerves - VASOCONSTRICTION (increased MABP)
Cell growth in heart and arteries
Ang. II stimulates aldosterone secretion from adrenal cortex, which causes tubular Na+ reabsorption and salt retention - INCREASED BLOOD VOLUME and MABP
Functions of ACE?
Membrane-bound enzyme on endothelial cell surfaces:
- Converts inactive Ang. I to Ang. II (vasoconstrictor)
- Inactivates bradykinin (vasodilator)
Function of ACE inhibitors?
E.g: Lisinopril - block conversion of Ang. I to to Ang. II and so:
1. Cause venous dilatation (decrease preload) and arteriolar dilatation (decreased afterload and TPR), decreasing MABP and cardiac load
- Reduce direct growth action of Ang. II upon the heart and vasculature
- Prevents ACE from inactivating bradykinin - so, retains vasodilator effect
- Reduce, but do not abolish, release of aldosterone (decrease promotes Na+ and H2O loss)
- Cause a small fall in MAPB in normal subjects and a much larger effect in hypertensive patients (esp. if renin secretion is enhanced - due to diuretic therapy)
Have no effect on cardiac contractility
Cautions with ACE inhibitor use?
Should not be used with angiotensin receptor blockers - would decrease BP too much
Contraindicated in pregnancy due to foetal toxicity
Should not be used in bilateral renal artery stenosis (although ACEIs are used in diabetic neuropathy)
What are the Angiotensin sensitive tissues in the body?
ACE inhibitors have greatest effect her:
Vascular beds of brain, heart and kidney - important as may help maintain perfusion of critical organs
Adverse effects of ACE inhibitors?
May initially cause hypotension - esp. in those treated with diuretics
Dry cough - if too irritating, patient can be switched to Angiotensin 1 (AT1) receptor blocker
Function of AT1 receptor antagonists (ARBs/’sartans’)?
Block the agonist action of Ang. II at AT1 receptors, in a competitive manner
Do not inhibit metabolism of bradykinin
Examples of angiotensin receptor blockers?
SARTANS, e.g: Losartan
Contraindications of AT1 receptor blockers?
Contraindicated in pregnancy due to foetal toxicity (try to avoid use in anybody of CHILD-BEARING AGE - any possibility you could be pregnant?)
Should not be used in bilateral renal artery stenosis
Clinical uses of ACE inhibitors and AT1 receptor antagonists?
Hypertension - benefit from:
- Reduced TPR and MABP
- Possible suppression of smooth muscle cell proliferation in media of resistance vessels
Cardiac failure (associated with inappropriate activation of RAAS system) - benefit:
- Decrease vascular resistance, improving perfusion
- Increased Na+ and H2O excretion
- Cause regression of left ventricular hypertrophy
Following MI - as for cardiac failure
What are adrenoceptors?
G-protein coupled receptors (GPCRs) activated by noradrenaline (sympathetic neurotransmitter) and the hormone adrenaline
Functions of α1, β1 and β2 receptors?
α1 - constrict blood vessels
β1 - increase HR, increase force, increase AV node conduction velocity
β2 - cause relaxation vascular and pulmonary smooth muscle
Clinical used of β-adrenoceptor antagonists (β-blockers)?
Treatment of:
Angina pectoris (NOT VARIANT ANGINA - due to periodic spasm of smooth muscle, not occlusion)
Hypertension (no longer 1st line)
Heart failure
Why are β-blockers used in angina pectoric treatment?
β-blockers (part. β1-selective agents) are used as:
- Decreased myocardial oxygen requirement, as decreased HR and SV lead to decreased myocardial work and less oxygen requirements
- Counter elevated sympathetic activity, associated with ischaemic pain
- Increase amount of time spent in diastole (decreased HR), improving left ventricle perfusion (increased in window for coronary blood flow?)
Why are β-blockers used in hypertension treatment?
Help restore normal BP by:
- Reducing CO, but CO returns to normal over time but MABP remains depressed by “resetting” of TPR at a lower level - mechanism uncertain)
- Reducing renin release from kidney
- CNS action that reduced sympathetic activity
Why are β-blockers used in heart failure treatment?
Combo with other drugs to suppress adverse effects associated with elevated effects of the sympathetic NS and RAAS
However, must START LOW AND GO SLOW
What do calcium antagonists do?
Prevent opening of L-type channels in excitable tissues, in response to depolarisation and hence they limit the intracellular Ca2+ conc.
Clinically useful Ca2+ antagonists interact preferentially, or solely, with L-type Ca2+ channels found:
- In the heart
- In smooth muscle
L-type channels mediate what and how do Ca2+ antagonists affect this?
Activated by depolarisation and provide a pathway for Ca2+ into the cell causing:
- Upstroke of the action potential in the SA and AV nodes - Ca2+ antagonists can REDUCE HR and conduction through the AV node
- Phase 2 of the ventricular action potential - Ca2+ antagonists can reduce force of contraction
Mechanism of action of Ca2+ antagonists?
Prevent opening of L-type Ca2+ channels and so prevent Ca2+ influx
Thus, contraction is prevented
Three main types of calcium antagonist exemplified by?
Verapamil - relatively selective for cardiac L-type channels
Amlodipine (dihydropyridine compound) - relatively selective for smooth muscle L-type channels
Diltiazem - intermediate selectivity
Clinical uses of calcium antagonists?
Hypertension:
Reduced Ca2+ entry to vascular smooth muscle cells causes generalised arteriolar dilatation, reducing TPR and MABP - major effect is on the arteries/arterioles with little effect on veins
Cause coronary vasodilatation and are part. useful in patients suffering from both angina and hypertension - also indicated for isolated systolic hypertension
Angina - prophylactic treatment, often in combo with GTN, part. if β-blockers are contraindicated
Which Ca2+ antagonists are preferred?
Those with SELECTIVITY for smooth muscle L-type channels, e.g: amlodipine, to minimise unwanted effects upon cardiac muscle
This is part. important in patients with hypertension and heart failure, or heart block
Adverse effects of Ca2+ antagonists?
Mostly result from excessive vasodilatation and inc. hypotension, dizziness, flushing and ankle oedema
Why are Ca2+ antagonists uses in angina?
Cause peripheral arteriolar dilatation, decreasing afterload and myocardial oxygen requirement - preload is not significantly changed
Produce coronary vasodilatation - esp. useful in patients with VARIANT ANGINA
Why are Ca2+ antagonists uses in dysrhythmias?
Ventricular rate in rapid AF is reduced by suppression of conduction through the AV node
Usually, VERAPAMIL is used but AVOID IN HEART FAILURE, PART. IN COMBINATION WITH A β-BLOCKER
Describe amlodipine
Relatively little effect upon heart and is LONG-ACTING
Describe diltiazem and verapamil
Produce negative inotropic effects but latter offset by activation of the baroreceptor reflex, in response to vasodilatation and increased sympathetic activity
Mechanism of action of POTASSIUM CHANNEL OPENERS?
Open ATP-modulated K+ channel (KATP) in vascular smooth muscle
Act by antagonising intracellular ATP (which closes the KATP channel)
Causes hyperpolarisation, switching off L-type Ca2+ channels and thus reducing intracellular Ca2+ conc.
Thus, there is RELAXATION and they act potently and primarily upon arterial smooth muscle
Examples of K+ channel openers and when they are used?
Minoxidil - drug of last reost in severe hypertension but causes reflex tachycardia (prevented by a β-blocker) and salt and water retention (alleviated by a diuretic)
Nicorandil (also has NO donor activity) - used in angina, refractory to other treatments
Clinical uses of α1-adrenoceptor receptor antagonists?
Cause vasodilatation by blocking vascular α1-adrenoceptor; reduced sympathetic transmission results in decreased MABP
Also provide symptomatic relief in benign prostatic hyperplasia and are part. indicated for hypertensive patients with this condition
Examples of α1-adrenoceptor receptor antagonists?
Prazosin
Doxazosin
Both are competitive antagonists and both are the most frequently used compounds
Adverse effects of α1-adrenoceptor receptor antagonists?
Main effect is postural hypotension
What do diuretics do?
Act of kidneys to increase excretion of Na, Cl and H2O and exert addition, indirect, relaxant effects upon the vasculature
Major classes of diuretic?
Thiazide diuretics, e.g: bendroflumethiazide
Loop diuretics, e.g: furosemide
Mechanism of action of thiazide diuretics?
Inhibit NaCl reabsorption in the DISTAL TUBULE by blocking the Na+/Cl- co-transporter
Cause up to 5% of filtered Na+ to be excreted along with H2O, producing a moderate diuresis
Mechanism of action of loop diuretics?
Inhibit NaCl reabsorption in the thick ascending limb of the LOOP OF HENLE by blocking the Na+/K+/2Cl- co-transporter
Cause up to 15-25% of filtered Na+ to be excreted with accompanying H2O producing a strong diuresis
Undesirable effect of thiazides and loop diuretics?
Loss of K+ (occurs through Na+/K+ exchange in the late distal tubule) - corrected by co-administration of a “potassium sparing diuretic) or K+ supplements
Clinical uses of thiazide diuretics?
Mild heart failure
Hypertension - loss of Na+ and H2O reduces blood volume and initially reduces CO. Subsequently, CO returns to normal, but MABP remains depressed through lowering of peripheral resistance (mechanism uncertain)
Severe resistant oedema (with a loop agent)
Clinical uses of loop diuretics?
Used to reduce salt and water overload associated with:
Acute pulmonary oedema (IV)
Chronic heart failure
Benefit occurs due to absorption of extracellular fluid, that is contributing to the oedema, into the capillaries as a consequence of diuretic-induced reduction of blood volume
