CARDIOVASCULAR AND RENAL PHARMACOLOGY Flashcards
Abciximab
1 - a MAB against the glycoprotein 2b/3 receptor, inhibits the fibrinogen bridging necessary for platelet aggregation.
2 - also binds the vitronectin receptor on platelets, endothelial cells and VSMCs - involved in cell adhesion and haemostasis.
3 - used with coronary angioplasty to prevent coronary artery thrombosis.
Acetazolamide
1 - Carbonic anhydrase inhibitor diuretic
2 - largely obsolete as a class
3 - inhibit reabsorption of NaHCO3 in PCT and DCT (80%) in PCT
4 - exchange utilises Na/H exchanger on the apical membrane driven by the Na pump
5 - urine pH rises
6 - weak diuretics, >99% of the enzyme must be inhibited for an appreciable effect
7 - main clinical use is in glaucoma, suppresses HCO3- secretion which is an important part of aqueous humour formation
8 - can help acclimatisation and reduce mountain sickness and alleviate sleep apnoea at high altitudes.
Alteplase
1 - single chain recombinant human tissue plasminogen activators
2 - greater action of plasminogen bound to fibrin in clots therefore localised action
Amiloride
1 - a potassium sparing diuretic
2 - blocks apical Na channels in the late distal tubule, less Na driven out basement membrane hence less K into cell hence less K out channel into lumen. diuresis is weak but spares K.
Aminocaproic Acid
1 - chemically similar to lysine
2 - competitively inhibts plasminogen activation
3 - prevents excessive clots lysis which would cause severe bleeding
Amiodarone
1 - class 3 antidysrhytmic 2 - prolongs the cardiac AP (complex mech) and thus also the refractory period. amiodarone is the best known example. 3 - can be used for ventricular dysrhythmias and reentrants that dont respond to class 1. 4 - prolongs phase 3 (repolarisation but also has beta blocker and K channel blocker like effects at the SA and AV nodes.
Amrinone
Fill
Anistreplase
combined plasminogen and anisoylated streptokinase
2 - streptokinase is inactive until the anisoyl group is removed, this hapens slowly in the blood
2 - the result is more prolonged activity (4-6hrs) than streptokinase alone.
Aspirin
1 - reduces thrombosis
2 - low dose often combined with clopidogrel to improve morbidity and mortility in patients with a wide range of heart disease
3 - prophylaxis is approx a quarter of a tablet a day but only suitable due to the side effects for elderly people or those who’ve had a CV incident.
4 - inhibits production of thromboxane which helps aggregate platelets.
Atenolol
1 - selective β1 antagonist 2 - its selectivity reduces risk of bronchorestriction 3 - class 2 antidysrhythmic 4 - can be used with phenoxybenzamine to block the effects of a large release of catecholamines when a phaeochromocytoma is removed 5 - The mainstay of treatment for LQTS, unless there is an identifiable reversible cause, is lifestyle modification and beta-blocker therapy with the implantation of a cardioverter-defibrillator (ICD) in patients who have had a previous cardiac arrest and in those continuing to have symptoms despite beta-blockade. LQTS is the principle cause of SADS.
Bisoprolol
1 - a “3rd generation” β1 blocker.
2 - currently in clinical use in the UK for stable heart failure
3 - danger of over-inhibition so doses have to be carefully titrated whilst cardiac function is monitored.
Bosentan
1 - new, non-specific endothelin receptor antagonist. used for pulmonary arterial hypertension. endothelin-1 (of 3) is a potent vasoconstrictor but as ETb receptor mediates both constriction of VSMCs and dilation of endothelial cells (via NO) the use of the class of drugs is disputed.
Caffeine
1 - A1 (acts via Gi/o) antagonist (hence diuresis via decreased renin?) (also an A2 antagonist)
2 - nonselectively inhibits PDEs so potentiates cAMP signalling and hence rate and force of cardiac contraction along with more disposed to dysrhythmias.
3 - adenosine acts via A1 Rs in the brain to presynaptically inhibits glutamate releasing neurons causing decreased motor activity, respiration, anxiety and to induce sleep. Caffeine inhibits this.
a methylxanthine.
CNS effects due to adenosine antagonism
Captopril
1 - an ACE inhibitor
2 - decreases pre and afterload on the heart, the aim is to reduce vascular resistance in heart failure.
3 - almost always combined with diuretics
4 - reduction in aldosterone should, in principle, help avoid hypokalaemia.
5 - ACE also known as kininase 2 which breaks down bradykinin. inhibiting it raises bradykinin levels which acts as an irritant and causes a dry cough (ie not caused by secretions) which can be intolerable to some patients. captopril is especially bad.
6 - hypotension is a dangerous with any ACE inhibitor as risk of renal failure is increased by the block of angiotensin 2 which normally mediates glomerular efferent arteriolar constriction.
Carvedilol
1 - a “3rd generation” β1 blocker.
2 - currently in clinical use in the UK for stable heart failure
3 - danger of over-inhibition so doses have to be carefully titrated whilst cardiac function is monitored.
Clonidine
1 - α2 (and α1) agonist
2 - antihypertensive but can cause rebound hypertension if a dose is missed. acts via hindbrain receptors
Clopidogrel
1 - inhibits platelet aggregation by inhibiting the binding of ADP to its platelet receptor
2 - given with a low dose of aspirin
Digoxin
1 - a caridac glycoside that inhibits the sodium pump
2 - commonly used as an antidysrhytmic, but not alone. can also be used in heart failure.
3 - like ouabain but ouabain is too potent for clinical use
4 - dont use with thiazide diuretics as the significant drop in plasma K conc will compound the effect of cardiac glycosides in reducing the activity of the Na pump.
Diltiazem
1 - blocks L type Ca channel but distinct site to DHP. enhances their binding.
2 - greater use dependence and more prolonged than DHPs.
3 - preferential to cardiac hence antidysrhytmic (type 4), Acts preferentially at the nodes where the AP depends upon the L and T type current hence slowing conduction.
4 - a benzothiazepine.
5 - more effect on S.M. than verapamil.
6 - well absorbed by GI, extensively metabolised.
7 - side effects - flushing and headache,
Dipyridamole
PDE5 (cGMP specific) inhibitor like sildenafil.
an inodilator.
Dobutamine
1 - analogue of dopamine
2 - β1 agonist. greater ionotroph than chronotroph.
3 - used in acute cardiogenic shock to raise HR and CO, given IV.
4 - increases HR and O2 demand so arrhythmogenic
5 - can be used to treat heart failure in the absence of hypertension, and improve CO after open heart surgery.
Duteplase
1 - double chain recombinant human tissue plasminogen activator
2 - greater action on plasminogen bound to fibrin in clots therefore localised action. plasminogen being the precursor for the serum protease plasmin which breaks down both fibrinogen and fibrin.
Enalapril
1 - an ACE inhibitor
2 - the inactive form. converted to the active enalaprilat in the liver
3 - decreases pre and afterload on the heart
4 - almost always combined with a diuretic but the reduction in aldosterone should, in principle, help avoid hypokalaemia.
5 - ACE also known as kininase 2 which breaks down bradykinin. inhibiting it raises bradykinin levels which acts as an irritant and causes a dry cough (ie not caused by secretions) which can be intolerable to some patients. captopril is especially bad.
6 - hypotension is a dangerous with any ACE inhibitor as risk of renal failure is increased by the block of angiotensin 2 which normally mediates glomerular efferent arteriolar constriction.
Eptifibatide
1 - a cyclic heptapeptide that binds to and inhibits the glycoprotein 2b/3a receptor. a receptor key to fibrinogen bridging and platelet aggregation.
Furosemide
1 - a sulphonamide loop diuretic like bumetanide, causes a v.high rate of diuresis.
2 - blocks the NKCC in the apical membrane of the thick ascending limb.
3 - actively secreted into the proximal tubule hence PCT conc is 10-30 times that of the plasma.
4 - acts on heart failure within 10 mins if given IV as it causes venodilation and hence a drop to AFP before the diuresis. large reduction in fluid vol makes them useful in acute heart failure.
5 - weakly inhibits carbonic anhydrase
6 - can cause hypokalaemia due to increased DCT Na load, and metabolic alkalosis due to increased Na/H exchange and stimulated renal synth of NH3.
7 - also increases Ca and Mg loss
8 - decreases uric acid excretion and hence can cause gout
9 - IV = 10mins, oral = 1-1.5hrs
Heparin
1 - a naturally occuring anticoagulant produced by basophils and mast cells.
2 - binds antithrombin 3 causing a conformational change to expose the active site. this activates thrombin and other clotting proteases including factor Xa.
3 - used to treat unstable angina, after myocardial infarcts, to treat DVT and as a prophylactic following surgery.
4 - given IV (hence not very good prophylactic)
Hydrochlorothiazide
1 - a thiazide diuretic like bendroflumethiazide.
2 - weakly inhibits carbonic anhydrase
3 - primary action is to block the Na/Cl cotransporter in the early distal tubule
4 - some vasodilator effects
5 - side effects of metabolic alkalosis and hypokalaemia
6 - causes an average fall in plams K of 0.7mM which is significant and hence must not be used with cardiac glycosides
Isobutylmethylxanthine (IBMX)
1 - a methylxanthine like caffeine and theophylline.
2 - both a nonselective inhibitor of PDEs (competitive) and Adenosine receptors.
Levosimendan
1 - one of the calcium sensitising inodilators
2 - only drug of this particular type that has an significant use in human clinical practice. for heart failure but not licensed in the UK.
Lidocaine
1 - local anaesthetic, pd gated Na channels.
2 - pKa 8-9
3 - stabilises inactivated state by blocking channel
4 - an amineester
5 - neutral crosses membrane, protonated form blocks.
6 - inhibits C and Aδ fibres first
7 - use dependent for high rates of stimulation. class 1b antidysrhythmic w/ v.fast association/dissociation.
8 - neuropathic pain.
9 - amides metabolised in the liver.
10 - increases proportion of inactive channels at any pd.
Losartan
1 - and non-peptide angiotensin 2 antagonist
2 - acts on AT1 not AT2 receptors
3 - AT1 involved in thirst, aldosterone secretion and vasoconstriction, but AT2 involved more in vasodilation via NO generation and subsequent rise in cGMP. A2 binding AT2 actually inhibits, in certain cells, proliferation but will mediate neural tissue differentiation and can induce apoptosis.
Mannitol
1 - an osmotic diuretic
2 - filtered but not reabsorbed hence increases the osmotic gradient and urine volume. also decreases Na reabsorption by lowering its conc in the filtrate
3 - useful for maintaining urine flow and preventing kidney damage by low flow rates
4 - doesnt cross the BBB so useful to rapidly reduce intracranial and intraocular pressure in cerebral oedema
α-methylNA
Fill
Milrinone
1 - PDE3 (cGMP inhibited) inhibitor. this raises cAMP which in cardiac M makes it an inotroph (ino-).
2 - an inodilator most often used in heart failure. limited use as can cause dysrhythmias so confined to short term treatment of severe heart failure unresponsive to other therapy.
3 - the rise in cAMP in S.M. causes vasodilation and decreases after load on the heart. (-Dilator)
4 - the inodilator most often used in heart failure.
Minoxidil
1 - pd gated K channel opener.
2 - vasodilate hence hypertension.
3 - side effect of hirsutism, hence treat alopecia.
Ouabain
1 - a cadiac glycoside like digoxin and digitoxin that inhibits the sodium pump
2 - too potent to be used clinically but used experimentally.
Nicotine
1 - NACHR antagonist
Nifedipine
1 - DHP L type antagonist.
2 - aromatic, highly lipid soluble, accesses channel via lipid phase.
3 - favours mode 0, closed.
4 - Causes peripheral and coronary vasodilation hence treats hypertension and angina.
5 - causes reflex tachycardia.
6 - more active on vascular Ca channels as inactive channels dominate due to the less negative resting pd.
7 - usually combined with a β blocker to combat reflex tachycardia.
Pimobendan
1 - an inodilator
2 - a calcium sensitiser, improving binding of Ca2+ to troponin in cardiac muscle without a requirement of more energy.
3 - peripheral vasodilation via PDE3 (cGMP inhibited) inhibition.
4 - used in dogs to treat canine dilated cardiomyopathy and advanced canine mitral valve regurgitation
Propranolol
1 - non specific β antagonist. replaced by atenolol. 2 - class 2 antidysrhythmic 3 - non-selective so can cause bronchoconstriction 4 - β1 is linked to Gs causing a rise of cAMP, increases likelihood of opening of L types and T types hence ionotrophic and chronotrophic.
Reserpine
1 - blocks NA and DA transport into vesicle by tightly binding amine binding site of VMAT-2 (vesicular monoamine transporter). also causes long term NA (and 5HT in brain) depletion as they leak out of vesicles and are metabolised by MAO.
2 - acts in periphery and brain.
3 - used as antihypertensive but discontinued due to profound psychological depression
4 - recovery requires synthesis of new vesicles
Saralasin
1 - an angiotensin 2 partial agonist
2 - a peptide so cant be given orally and hence not competitive with other antihypertensives.
Sildenafil
1 - an inodilator that inhibits PDE5 (cGMP specific). increased cAMP in SM caues dilation.
Spironolactone
1 - an aldosterone antagonist and hence K sparing diuretic
2 - competes for the cytoplasmic steroid receptor
3 - metabolised to canerone which, along with its K salt potassium canrenoate acts as a K sparing diuretic
4 - effect is only significant when distal tubule cells are under the influence of aldosterone. As the mech depends on channel turnover the rate of onset is slow.
5 - can be used with loop or thiazide diruetics to counteract hypokalaemia.
Streptokinase
1 - from haemolytic streptococci
2 - binds plasminogen activator to cause plasmin generation. plasmin being a protease that hydrolyses arg-lys bonds.
3- leads to the degredation of fibrin in clots (and clotting factors 2, 5 and 7)
4 - 47kDa.
Tirofiban
1 - a non-peptide inhibitor of the glycoprotein 2b/3 receptor. blocks the fibrinogen bridging that causes platelet aggregation in clot formation.
2 - used to prevent myocardial infarcts in patients with unstable angina or in those who’ve recently had certain types of myocardial infarc.
Tranexamic Acid
1 - an analogue of aminocaproic acid.
2 - chemically similar to lysine
3 - competitively inhibts plasminogen activation
4 - prevents excessive clots lysis which would cause severe bleeding
Triamterene
1 - a K sparing diuretic
2 - blocks apical Na channels in the late distal tubule, less Na driven out basement membrane hence less K into cell hence less K out channel into lumen.
3 - diuresis is weak but spares K.
Warfarin
1 - given orally
2 - an anticoagulant as it inhibits the synthesis of clotting factors 2, 7, 9 and 10 as well as regulatory factors prteins c, s and z.
3 - similar uses as heparin but also used to prevent clotting on prosthetic heart valves or reoccurance of clots.
4 - dosing is complicated as it interacts with many other drugs and foodstuffs.
5 - can be used as a rodenticide but resistance is appearing.
Probenecid
1 - inhibits uric acid reabsorption by competing for the same carrier in the PCT
2 - used to treat gout which results from the deposition of sodium urate crystals in the synovial tissue of joints.
procainamide
1 - class 1A antidysrhythmic 2 - increases AP duration by blocking pd gated Na channel with intermediate rate of association/dissociation.
Flecainide
1 - class 1C antidysrhythmic
2 - no affect on AP but v slow association/dissociation
3 - only used for unusual conditons such as Paroxysmal Supraventricular Tachycardia
(PSVT)
Rolipram
1 - an inodilator that blocks PDE4 (cAMP specific)
Dabigatran
1 - a thrombin inhibitor.
2 - approved by NICE in October 2012 for patients with atrial fibrillation and one other risk factor for stroke.
3 - evidence that it can reduce risk by up to 40% vs warfarin
4 - the issue is it’s far more expensive - £2.30 a day rather than 3 pence for warfarin.
Aliskiren
1 - new renin inhibitor hence blocks angiotensinogen to angiotensin 1
