- treatment and/or prevention of bleeding: 

- resulting from use of oral anticoagulant drugs (e.g. warfarin)

- babies:  to prevent haemorrhagic disease of the newborn.

for vitamin K deficiencies in adults:

- sprue, coeliac disease, steatorrhoea.

- lack of bile (e.g. with obstructive jaundice)

heparin is not absorbed from the gut due to its charge and size.  Can be given IV or subcut.

Heparin acts immediately following IV administration, however following SC administration - onset is delayed by up to 60 minutes.

half life is approximately 40-90minutes.  LMWHs have a longer half life - dose independent.

elimination - by renal excretion.

heparin activates antithrombin III which proteolyses factors including thrombin and factor Xa.

LMW heparin increase the action of AT III on xa but not on thrombin.

Clinical use:

For immediate effect – DVT, PE, AMI Used in conjunction with thrombolytics for revascularization and with glycoprotein Iib/IIIa inhibitors during angioplasty. Does not cross placenta so safe in pregnancy

1.  haemorrhage - treated by giving protamine.

2.  thrombosis - thrombocytopenia secondary to IgM or IgG antibodies against complexes of heparin and platelet factor 4.  Circulating immune complexes bind to Fc receptors on circulating platelets - activating them and antibody binds to platelet factor 4 complexed with glycoaminoglycans on the surface of endothelial cells, leading to immune injury of the vessel wall, thrombosis and DIC.

3.  osteoperosis with spontaneous fractures with long term treatment (usually during pregnancy).

4.  hypoaldosteronism 

5.  hypersensitivity reactions - rare with heparin, but more common with protamine.

- small, lipid soluble molecules.

- readily absorbed after oral administration.

- highly bound to plasma proteins - albumin (>99%).

- effect on prothrombin time (PT) of a single dose does not start for 12-16 hours and lasts 4-5 days.  expressed as INR.

- elimination dependent on metabolism by cytochrome P450.

- crosses the placenta, teratogenic and risk of intracranial haemorrhage.

- interferes with Vitamin K dependent modification of clotting factors II, VII, IX and X.

- these clotting factors have long half life (8-60hours) - therefore warfarin takes days to take effect.

- reversal with vitamin K takes 6-24hours for more factors to be synthesized; reversal with FFP is faster because it contains pre-formed factors.

- effects of warfarin measured by PT or INR.

- liver disease 

- conditions that increase metabolic rate - fever, thyrotoxicosis, increase the effects of the anticoagulants by degradation of clotting factors.

drugs:  agents that inhibit hepatic drug metabolism e.g. cimetidine, imipramine, co-trimoxazole, chloramphenicol, ciprofloxacin, metronidazole and many antifungal azoles.

drugs that inibit platelet function - NSAIDs.

drugs that displace warfarin from biding sites on plasma result in increase in the concentration of free warfarin.

drugs that inhibit reduction of Vitamin K - cephalosporins.

drugs that decrease the availability of Vitamin K - broad spectrum anti-biotics and some sulfonamides.

- physiological states such as pregnancy where there is increased coagulation factor synthesis.  Hypothyroidism which is associated with reduced degradation of coagulation factors.

- drugs - Vitamin K.

- drugs that induce hepatic P450 enzymes - such induction will increase the degradation of warfarin.

- carbamazepine, barbituates - induction may wane only slowly after the inducing agent is discontinued.

drugs that reduce absorption - colestyramine.

- aspirin and other NSAIDs.

- glycoprotein IIa/IIIb receptor inhibitors (abciximab, tirofiban and epitifibatide).

- antagonists of ADP receptors ( clopidogrel and ticlopidine).

- inhibitors of phosphodiesterase 3 (dypyridamole and cilostazole).

- the reduced form of Vitamin K is a cofactor in the post translational gamma-carboxylation of a cluster of glutamic acid (glu) residues in each of factors II, VII, IX and X; vitamin K is oxidised during the reaction.

the gamma-carboxylated glutamic acid (gla) residues are essential for the interaction of these factors with Ca2 and negatively charged phospholipid.

dual mechanism of action:

- inhibit phosphodiesterase 3 --> reduced degradation of cAMP --> inhibit aggregation.

- inhibit uptake of adenosine by EC and RBC --> increased plasma adenosine --> increase platelet cAMP --> decreased aggregation

clinical use:  intermittent claudication and PVD.

toxicity:  headaches and palpitations.

- haemorrhage.

- tetratogenic

- hepatotoxicity

necrosis of soft tissue owing to thrombosis in venules due to inhibition of biosynthesis of protein C -> resulting in procoagulant state.

- main drug is aspirin.  Other drugs can be additive in their effects.  Uses mainly relate to arterial thrombosis and include:

- AMI

- high risk of myocardial infarction, including:  patients who have recovered from myocardial infarction and patients with symptoms from atherosclerosis, including angina, transient cerebral ischemic attacks, intermittent claudication.

- following coronary artery bypass grafting.

- unstable coronary syndromes.

- following coronary artery angioplasty and stenting.  

- TIA or thrombotic stroke to prevent recurrence.

AF if oral anticoagulation is contraindicated.

aspirin inhibits cyclooxygenase irreversibly.  The balance between prostaglandin I2 (an inhibitor of aggregation generated by vascular endothelium)) and thromboxane (a stimulant of aggregation generated by platelets) is thus altered, since the endothelium can synthesize more enzymes but platelets cannot.  Synthesis of the latter only recovers when new platelets are formed (7-10days later).

other nsaids effects are only a few hours.

clinical use:  prevents further infarcts and reduce the incidence of first infarct, prevent TIAs and embolic CVAs.

toxicity:  GI bleeding

antagonists of glycoprotein (GP) IIb/IIIa receptors include a monoclonal antibody (abciximab) and several oliopeptides (e.g. tirofiban).  They inhibit diverse agonists (e.g. ADP, TXA2 etc).  since different pathways of activation converage at GP IIb/IIIa receptors.  they are used IV for short term treatment.

clinical use:  prevention of restenosis after PTCA and in ACS.

toxicity:  can also cause thrombocytopenia.

2 main drugs are streptokinase and tissue pasminogen activators (tPA)

- main use is in acute MI, within 12 hours of onset.

other uses:  acute thrombotic stroke within 3 hours of onset (tPA) in selected patients, clearing thrombosed shunts and cannulae, acute arterial thromboembolism.

agonist - bind to and activate the receptor in some fashion which directly or indirectly brings about the effect.

directly - e.g. ion channel opening.

indirectly - coupling to seperate effector molecules.

antagonists:  bind to but compete with and prevent binding by other molecules.  

a) diffuse passively through aqueous channels in the intracellular junctions.

b) or through lipid membranes.

c) durgs with the appropriate characteristics may be transported by carriers into or out of the cells.

d)  bind to cell surface receptors, be engulfed by cell membrane (endocytosis) and then released inside the cell or expelled via the membrane limited vesicles out of the cell into the extracellular space (exocytosis).

1)  lipid soluble ligand that crosses the membrane and acts on intracellular receptor.

2) a transmembrane protein receptor whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the proteins extracellular domain.

3) a transmembrane receptor that binds and stimulates a protein tyrosine kinase.

4) ligand gated transmembrane ion channel that can be induced to open or close by the binding of a ligand.

5) a transmembrane receptor protein that stimulates a GTP binding signal transducer protein which then modulates production of an intracellular second messanger.

cross the plasma membrane and act on intracellular receptors (steroids) - binding stimulates the transcription of genes by binding to a specific DNA sequences near the gene whose expression is to be regulated.

1.  all hormones produce their effects after a characteristic lag period for the synthesis of new proteins.

2.  effects can persist for hours to days after the agonist concentration has been reduced to zero. - due to slow turnover of most enzymes and proteins.

receptor tyrosine kinase signalling begins with binding of ligand, to a receptor's extracellular domain - resulting in change in receptor conformation causes receptor molecules to bind to one another which in turn brings together the tyrosine kinase domains which become enzymatically active and phosphylate one another.

activated receptors catalyze phosphorylation of tyrosine residues on different target signalling proteins.  (e.g. insulin)

potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drugs maximal effect.  

Depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug receptor interaction is coupled to response.

- rate limiting step in cholesterol synthesis in the liver is conversion of hydroxymethylgutaryl coenzyme A (HMG-coA) -> mevalonate by HMG-coA reductase.

- statins are structural analogues of HMG-CoA that competitively inhibit this enzyme.

- lovastatin and simvastatin are prodrugs, the others are active as given.

- greatest affect of statins is reduction in the hepatic pool of cholesterol by increasing number of high affinity LDL receptors -> clears LDL and VLDL from blood.

- also have direct antiatherosclerotic effects and prevent bone loss.

a) alteration in the concentration of drug that reaches the receptor.  Due to age, weight, sex, disease state and liver and kidney function.  MDR genes.

b) variation in concentration of an endogenous receptor ligand.  e.g. marathon runners.

c) alterations in number or function of receptors. (e.g. withdrawal)

d)  changes in components of response distal to the receptor.

measure of the ability of the body to elminiate the drug.

may occur in the kidney, the lung, the liver and other organs.

kidney - renal clearance.

liver - drug elimination occurs via biotransofrmation of parent drug to one or more metabolites, or excretion of unchanged drug into the bille, or both.

the measure of the apparent space in the body available to contain the drug.

Vd relates the amount of drug in the body to the concentration of the drug in blood or plasma.

- 1st order:  drugs with constant clearance over the concentration range encountered in the clinical setting.  Elimination is not saturable, and the rate of drug elimination is directly proportional to concentration.

capacity limited:  clearance will vary depending on concentration of drug that is achieved.  Important for 3 drugs - ethanol, phenytoin and aspirin.

defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route.  (ie for IV drugs - bio availability - 100%) less for oral as:

a) after administration drug may be incompletely absorbed from gut/lipophilic or hydrophilic.

b)  first pass elimination 

c) rate of absorption.

- reduce LDL cholesterol -> reduce risk of coronary events.

- rosuvasttin, atorvastatin and simvastatin have greater maximal efficacy and also reduce TG and increase HDL.

- mild serum elevations of aminotransferases not associated with hepatic damage (up to 3 times normal).

- increase in CK from (10% of patients), with occasional rhabdomyolysis and severe muscle pain.

- metabolized by cytochrome P450 -> increased levels with P450 inhibitors (grapefuits).

- teratogenic - avoid in pregnancy.

- vit B3.

- reduces LDL, VLDL and TG and increases HDL.

- reduces VLDL synthesis in the liver -> reduces LDL stores.

- in adipose tissue -> activates signalling pathway -> reduces lipase activity -> decreases plasma fatty acid and TG levels reduction in LDL formation.

- increases HDL levels by increasing plasma levels of apoA1-I (major lipoprotin in HDL).

- deceases circulating fibrinogen and increases t-PA.

clinical use:  - decreasing VLDL, LDL and TG and increasing HDL.

doses: 2-6g daily for heterozygous familial HC; 1.5g-3.5 g for other forms of HC.

tox:  cutaneous flushing from vasodilatation is a common side effect.  can be mitigated by pretreatment of aspirin or NSAID - prostaglandin mediated.

- dose dependent abdomina pain and nausea.

- pruritis.

- elevation of liver enzymes and hepatotoxicity.

- hyperuricaemia (20% of patients).

- ligands for peroxisome proliferator - activated receptor alpha (PPAR-alpha) which regulates transcription genes for lipid metabolism.

- interaction of PPAR - alpha -> increases synthesis of lipoprotein lipase -> enhances clearance of TG rich lipoproteins.

- stimulates fatty acid oxidation in liver -> limits supply of TG and reduces synthesis of VLDL.

- LDL not usually affected, but may increase in patients with familial combined hyperlipoproteinaemia (^ LDL and VLDL).

use: treatment of hypertriglyceridaemia.

- combined with other LDL lower drugs because minimal effects on LDL (may increase levels).

tox:

- nausea most common adverse effect.

- skin rashes common with gemifibrozil.

- mild decrease in WCC

- may potentiate anticoagulants.

- increased cholesterol gallstones.

- increases statin-associated myopathy.

moa:  

- bind bile acid (normally 90%) is reabsorbed in the GIT and returned to the liver to reuse) > hepatic cholesterol is used to produce new bile acid > reduced pool.

- also > compensatory increase in LDL receptors in liver > reduced circulating LDL.

- but in combined familial Hchol -> may increase VLDLs and TG in blood.

use:  hypercholesterolaemia, reduce pruritis in patients with cholestasis and bile salt accumulation.

tox: 

-bloating, constipation and gritty taste.

-impairment of absorption of vitamins (vit K, folates) and drugs (digitalis, thiazides, warfarin, pravastatin, fluvastatin).

moa:  prodrug > converted in liver to active glucuronide form.

- inhibits transporter that mediates GI uptake of cholesterol and phytosterols (plant sterols) > reduced absorption of dietary cholesterol that is excreted in bile > reduced hepatic pool > compensatory increase in LDL receptrs.

- most effective when combines with HMG-CoA reductase inhibitors.

use: 

-treatment of hypercholesterolaemia and phytosterolaemia.

tox:

- well tolerated, 

- may increase risk of hepatotoxicity of statins.

- serum concentrations are increased by fibrr\ates and reduced by resins.