What is an oral anticoagulant used? Describe its properties/MoA.
WARFARIN
- main oral AC in UK
- prevents the reduction of vitamin K (i.e. Vitamin K antagonist)
- takes many hours to act because of time taken for degradation of factors already formed
- main side effect = haemorrhage
- need to monitor pts (PT/INR)
What factors (i) increase the effectiveness (ii) decrease the effectiveness of oral coagulants?
(i) Decrease the availabiliity of vit K
broad spectrum Ab
Liver disease
Drugs that impair liver func, displace warfarin from their binding sites on plasma albumin, agents which inhibit microsomal enzymes in the liver
(ii) Drugs which increase drug metabolism
Oral contraceptives
What are the 2 types of injectable anticoagulants? Describe them.
HEPARIN (e.g. Dalteparin) - family of sulphated-glycosaminoglycans - naturally occurring - found in mast cells, plasma & in endothelial cells - starts acting almost immediately HEPARAN SULPHATE - a related glycosaminoglycan - occurs EC in many tissues - an important endogenous anticoagulant
What is the MoA of heparin?
Acts mainly on FIBRIN formation
- acts on ATIII (naturally occurrign inhibitor of thrombin) & other serine proteases in the coag cascade (XIIa, XIa, IXa & Xa)
- AT forms a 1:1 complex with thrombin by binding to active site
=> Heparin accelerates the rate of this inhibition
What are 2 direct Xa inhibitors?
RIVAROXABAN APIXABAN - both orally active - doesn't require PT/INR monitoring - takes few hrs to act - effects last 8-12 hrs (factor Xa activity takes about 24hrs to return to normal BUT there's no antidote
What is the function of antiplatelet drugs? Give 2 examples and what they target.
Decrease platelet aggregation
Inhibit thrombus formation
ASPIRIN: inhibits COX
CLOPIDOGREL: inhibits P2Y12 purinergic receptors & inhibits ADP-induced platelet aggregation
Name a fibrinolytic agent & its function.
STREPTOKINASE
- non enzymatic protein
- acts indirectly
- forms a stable complex with plasminogen (activates enzymatic activity of plasminogen by inducing a conformational change
Name a tissue plasminogen activator & its function.
ALTEPLASE
- synthesised in vivo by endothelial cells
- can be made by recombinant technology
- enzymatic activity is enhanced more in the presence of fibrin-bound plasminogen than plasma plasminogen (=> said to be ‘clot selective’)
What 3 sources is cholesterol derived from?
De novo synthesis in the liver
Uptake from circualting LDLs
Uptake of chylomicron remnants
What is the function of colestyramine?
Is a basic anion exchange resin
- sequesters bile acids in the intestine to prevent enterohepatic recirculation
- decreases the absorption of exogenous cholesterol
- increase the metabolism of endogenous cholesterol into bile acids
- inceases LDL receptor no. in liver resulting in the removal of LDLs from the blood.
NOTE: Bile-sequestering + statins can lower blood cholesterol by 50%
What is the function of ezetimibe?
Inhibit transport protein for cholesterol in the brush border of enterocytes in the duodenum
What is the function of fibrates? Give some named examples.
ALTER PLASMA LIPOPROTEIN LEVELS
- decrease plasma TG’s & to a lesser extent, cholesterol
- particularly decreases elevated conc. of VLDL
- MAIN ACTION: stimulation of lipoprotein lipase which decreases the TG content of VLDL
- Clearance of LDL by the liver is also stimulated
- increase in HDL production & reverse cholesterol transport
What are the clinical uses of fibrates?
Mixed dyslipidaemia (i.e. raised serum TG as well as cholesterol) In pts with low HDL & high risk of atheromatous disease (e.g. type 2 diabetes) Combined w.other lipid lowering drugs in pts with severe treatment resistant dyslipidaemia
What is the function of nicotinic acid?
It is a vitamin with lipid lowering properties
- decreases VLDL production which leads to a decrease in LDL
- also activates lipoprotein lipase
What is the function of statins? Give some named examples.
HMG-CoA reductase inhibitors
HMG-CoA reductase = major RLS in cholesterol synthesis. It converts HMG-CoA to mevalonic acid
Simvastatin, pravastatin, atorvastatin, rosuvastatin
What are the clinical uses of statins?
- Secondary prevention of MI
& stroke in those who have atherosclerotic diseases - Primary prevention of arterial disease in patients w. high serum cholesterol
- Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia
Below are drugs that affect noradrenergic neurons. Describe the function of them.
(i) Methyldopa
(ii) Amphetamines, clonidine
(iii) Cocaine, tricylic antidepressants
(iv) Monoamine oxidase inhibs
(i) Affects catecholamine synthesis
(ii) Affects catecholamine release. The former by indirectly acting sympathomimetrics. The latter by acting on alpha2 adrenoreceptors
(iii) Inhibs catecholamine uptake, NET inhibitors
(iv) inhibits catecholamine metabolic degradation.
For alpha 1 what is the (i) main ANS location (ii) cellular response (iii) functional ANS response?
(i) CV, GI tract, GU
(ii) increase IP3 & DAG
(iii) vasoconstriction, smooth muscle contraction (GI sphincters & GU)
For alpha 2 what is the (i) main ANS location (ii) cellular response (iii) functional ANS response?
(i) Neuronal
(ii) Decreases cAMP
(iii) Decreases transmitter release
For beta 1 what is the (i) main ANS location (ii) cellular response (iii) functional ANS response?
(i) Heart, Kidneys
(ii) Increases cAMP
(iii) Increases cardiac rate & force
Renin release
For beta 2 what is the (i) main ANS location (ii) cellular response (iii) functional ANS response?
(i) Lungs, Smooth muscle, Skeletal muscle
(ii) Increase cAMP
(iii) Bronchodilation, relaxation of visceral smooth muscle
vasodilation (sk. muscle) tremor
What is the two main mechanisms of NSAIDs?
All inhibit COX but do so by 2 main mechanisms:
(1) An irreversible, time-dependent inhibition of the enzyme
(2) A rapid, reversible competitive inhibition of the enzyme
Describe aspirin as an NSAID.
Part of the salicylates family, is a pro drug.
Inactivates COX
- aspirin acetylates the alpha-amino group of the terminal serine of the enzyme forming a covalent bond
- further synthesis of PG requires synthesis of a new enzyme
- found in plasma w/in 30mins
- peak conc w/in 1-2hrs
Can be metabolised to the active compound salicylic acid by plasma & tissue esterases (approx 70%)
Describe ibuprofen as an NSAID. What group of molecules does it come from? Name another NSAID from this family.
Binds reversibly to COX & competes with arachidonic acid
NAPROXEN
- are both well-absorbed
- last for 4-6hrs (longer than aspirin)
