Basic ion exchange resins, supplied in chloride form. They are neither digested nor absorbed and basically decrease LDL levels. This reduction is around 20-25%.
Have little effects on TGs and HDL. Effect is apparent within 3-5 days. Peak effect is visible in 2 weeks.
Normally bile acids are absorbed in jejunum, where they exert negative feedback and prevent conversion of cholesterol into bile acids.
When bile acid binding resins are used, they bind bile acids and increase excretion of bile acids. No negative feedback occurs, and more conversion of cholesterol into bile acids takes place.
There is compensatory increase in LDL receptors in liver.
There is more extraction of LDL from plasma.
Clearance of IDL, LDL & indirectly VLDL is raised.
Rationale of combining resins and statins
When resins are administered, compensatory increase in cholesterol synthesis occurs (due to decreased cholesterol stores), increasing HMG CoA reductase activity, leading to increased cholesterol synthesis. So HMG CoA reductase inhibitors are also administered.
1. GIT –abdominal discomfort and constipation (due to increased water intake)
Bloating and dyspepsia (heart burns). Remedy is refrigeration of drug and suspending the drug in liquid medium (evening drug should be suspended in morning)
2. Can aggravate hemorrhoids, relieved by taking dietary fibers
3. Can produce hypochloremic acidosis as bind chloride ions
4. Can produce hypoprothrombonemia (increased bleeding tendency) due to malabsorption of vitamin K.
5. Interfere with absorption of fat soluble vitamins.
6. Can interfere with absorption of lipids, producing steatorrhoea. Common in patients of cholestais and inflammatory bowel disease
7. Interfere with absorption of various drugs like Digoxin, thyroxine, thiazide diuretics, tetracycylines, warfarin and aspirin.
8. Interfere with absorption of folic acid
9. Cholelithiasis –increased cholesterol content of bile.
1. Primary hypercholesterolemias
2. Pruritis –due to choliestasis or due to bile salts accumulation
3. Digitalis toxicity as bind Digitalis
2. Patients of hemorrhoids
Available in form of powders, in packets. Dose is 16-36 g/day. Should not be taken in dry form. Taken with meal.
Clofibrate is the 1st drug discovered, but rarely used because of toxic effects. Better drugs with less toxicity and more effects are available.
It acts by:
Stimulating activity of lipoprotein lipase enzyme involved in breakdown of TGs. In this way, TGs are decreased.
Acting as an agonist at PPAR alpha receptor (peroxisome proliferated activated receptor alpha), involved in fatty acid metabolism.
Fibric acid derivatives also cause up and down regulation of genes involved in fatty acid metabolism
Upregulation of apolipoprotein alpha 1 gene.
Down regulation of apolipoprotein C2 gene.
So produce hypolipidemic effects. Also increase:
LDL receptor expression in liver under effect of PPAR alpha. More extraction of LDL from plasma occurs.
Also decrease TGs synthesis by liver.
Decrease TGs by 40-60%
Decrease LDL, but to a lesser extent 10-15%
Increase HDL by 10-25%
Different kinds of hyperlipidemias (type III)
Regression of xanthomas
Mobilize cholesterol from storage sites
Decrease incidence of coronary heart diseases by 50% when used for prolonged time.
Absorbed after oral administration. Bioavailability is increased with food.
Plasma peak concentration is achieved in 3-4 hours
Extensively bound to plasma proteins
Metabolized in liver and predominantly eliminated in urine.
Half life of Bezafibrate and Gemfibrozil is 2 hours.
Half life of Fenofibrate is 20 hours.
a. GIT disturbances
b. Allergic reactions
c. Myopathies esp. when combined with HMG CoA reductase inhibitors (muscle weakness, tenderness and cramps), less frequently with Fenofibrates. (Rosuvastin amongst statins has lesser incidence of myopathies.
d. Can produce hypokalemias
e. Clofibrate produces blood dyscrasias and cardiac arrhythmias
f. In experimental animals, are found to be teratogenic
g. Liver injuries
h. Can displace oral anticoagulants from protein binding sites
i. Can enhance toxicity of warfarin
j. Increase the incidence of gall stones as increase the secretion of cholesterol in bile.
k. Decrease the conversion of cholesterol into bile acids, so chances of gall stones are more.
m. Anemias, decrease WBC count
n. Hair loss
2. Liver disease
3. Gall stones
4. Renal failure
300 mg, which may be increased up to 600 mg, twice or thrice daily, depending upon the severity of disease. Usually taken with meals.
Lovastatin and Mevastatin are obtained from natural source, from micro-organisms, penicillin and micromonosporas.
Pravastatin and Simvastatin are semi-synthetic drugs.
Rosuvastatin, Atorvastatin and Fluvastatin are fluorine containing compounds.
Site of action
Main site of action is liver. In liver, they decrease the synthesis of TGs that in turn lead to decrease in VLDL as well as LDL.
Active forms of these drugs are structural analogs of enzyme hydroxyl methyl glutaryl CoA reductase. This enzyme is involved in the synthesis of sterols, and is responsible for the 1st step in that synthesis.
Mechanism of Action:
1. Competitive Inhibition
These drugs by competitive inhibition interfere with the synthesis of sterols.
2. Up regulation of LDL receptors
They can cause compensatory upregulation of LDL receptors in liver, which can cause increase extraction of LDL from plasma, so LDL levels are again decreased. Thus affect mainly LDL levels.
Can also enhance catabolism of LDL. Thus cause:
Reduction in LDL about 20-80%
Reduction in TGs about 25%
However, raised HDL 10-30%
Statins decrease the availability of isoprenyl groups from HMG CoA pathway, leading to:
I. decreased prenylation of Rho proteins, decreasing the activity of Rhokinase, decreasing the incidence of new coronary events.
II. decreased prenylation of Rab proteins, leading to decreased accumulation of Aβ in neurons, decreasing the manifestations of Alzheimer’s disease.
Statins decrease the oxidative stress by LDL and decrease atherosclerosis.
Statins stabilize the plaque, decreasing the chances of embolism.
Statins increase the NO.
Administered at bed time. Since activity of HMG CoA reductase is maximum at night.
Incompletely absorbed after oral administration.
Extensive first pass metabolism
Bioavailability is increased when given with meals, so given with food.
Peak plasma concentration is achieved in 2-4 hours.
These drugs have extensive plasma protein binding.
Mainly excreted in bile. About 10% eliminated in urine.
Most statins have half life of 2 hours, except atorvastatin (14 hours) and Rosuvastatin (19 hours).
1. Familial hypercholesterolemia (due to increased LDL) not used in children
2. Acute coronary syndrome
Remarkably well tolerated except for a few adverse effects.
Drugs that lower lipid and lipoproteins levels in the blood are known as hypolipidemic drugs.
The first measure in controlling hyperlipidemias is dietary restriction. However, if it proves unsatisfactory, hypolipidemic drugs are prescribed.
Hypolipidemic drugs have attracted considerable attention since they prevent cardiovascular diseases by retarding atherosclerosis in hyperlipidemic individuals.
Carried in plasma in form of lipoproteins, after getting associated with several apolipoproteins.
Plasma lipid concentrations are dependent upon the concentration of lipoproteins.
Lipoprotein globules consist of core of triglyceride and cholesterol esters. The outer polar layer has phospholipids, apoproteins and free cholesterol.
Divided into 6 classes depending upon particle size and density. These are:
b. Chylomicron remnants
a) Chylomicrons are the largest lipoproteins containing about 90% triglycerides and about 5% cholesterol.
b) Chylomicron remnants contain more cholesterol than triglycerides.
c) VLDL contains 50-60% triglycerides and 10% cholesterol.
d) IDL, just like chylomicron remnants, contain more cholesterol than triglycerides.
e) LDL contain 50% cholesterol and 5% triglycerides.
f) HDL contain 20% cholesterol and 10% triglycerides.
Dietary lipids are absorbed in the intestine with help of bole acids and chylomicrons are formed.
They are passed into lacteals and reach blood stream.
During passage via capillaries, the endothelial lipases hydrolyze TGs and convert them into fatty acids, which are carried to muscles to be utilized as energy source or are taken up by fat cells, where they are reconverted into fat cells.
Remaining part left is chylomicron remnant, which is engulfed by liver, which has receptors for it.
Free cholesterol liberated is either stored in liver cells or excreted in bile in form of bile acids.
Liver secretes VLDL which contain more TGs than cholesterol esters.
Lipases act and convert it into IDL, which contains more cholesterol than TGs
Half IDL is taken up by liver cells, while remaining half loses TGs and becomes LDL, which contains cholesterol.
LDL circulates in plasma for a long time and uptake into cells is dependent upon the needs of cells for cholesterol.
Cholesterol ester present in LDL is de-esterified and mainly used in cell membrane formation.
The cholesterol released from degradation of membrane is incorporated into HDL. It is then esterified with help of enzyme and transferred back to VLDL or IDL. Thus completing the cycle.
Excess lipoproteins in plasma are phagocytosed by macrophages for disposal.
If too much lipoprotein is to be degraded in this manner, excess of cholesterol is in atheromas i.e. arterial walls and xanthomas i.e. in skin and tendons.
Raised levels of VLDL, IDL, LDL and rarely those of chylomicrons and chylomicron remnants all are atherogenic.
Raised levels of HDL, however, may be protective since HDL facilitates the removal of cholesterol from tissues.
Causes of Hyperlipidemias:
Types of Hyperlipidemias
Type 1 (Familial Hyperchylomicronemias)(mainly increased VLDL levels)
Type 11A (Familial Hypercholesterolemia) (mainly increased LDL levels)
Type 11B (Familial Combined Hyperlipidemias) (mainly increased LDL and VLDL levels)
Type 111 (Familial Dysbetalipoproteinemias) (mainly increased VLDL levels)
Type IV (Familial Hypertriglyceridemia) (mainly increased VLDL levels)
Type V(Familial Mixed Hypertriglyceridemia) (mainly increased LDL and VLDL levels)
HMG CoA Reductase Inhibitors (also known as statins)
Fibric Acids Derivatives (also called fibrates)
Bile Acid Binding Resins
Cholesterol Absorption inhibitors
Omega-3 marine triglycerides
HMG CoA Reductase Inhibitors
Fibric Acid Derivatives
Bile Acid Binding Resins
Probucol and Nicotinamides
Cholesterol Absorption Inhibitors, Fish Oils and Orlistat
Naturally when endothelial injury occurs, after some time clot is formed, and endothelial tissue releases tissue plasminogen activator. This acts on plasminogen converting it into plasmin, when acts on fibrin polymers, breaking them down, leading to thrombus breakdown.
Not only break pathological thrombi but also normal haemostatic plugs in body, which are protective in nature.
There is a generalized lytic state. Increased internal bleeding and hemorrhage might occur, thus patients are carefully selected.
Proteinin nature obtained fromstreptococci. It forms one to one complex with plasminogen, activating it, plasminogen forms and fibrin polymer breakdown takes place.
It is given parentally, having half life of 2 minutes.
Enzyme obtained from fetal kidney cells, grown on tissue culture.
Longer half life than streptokinase of about 15 minutes.
Anisoylated plasminogen streptokinase activator complex (APSAC), a complex of human plasminogen and streptokinase obtained from streptococci. The active site of enzyme is covered with acyl group.
On administration, acyl group is hydrolyzed, the complex and plasminogen is activated.
Drug has more clot selectivity.
Thrombolytic duration of action is 70 minutes.
Tissue plasminogen activator (t-PA)
Naturally present in the body. Also prepared by recombinant DNA technology. Different preparations are available:
1. Alteplase –mutant form of tissue plasminogen activator
2. Reteplase – less fibrin specific than alteplase
3. Tenecteplase – more fibrin specific
1. Acute MI
Main use. Proper patient selection must be done in emergency. Thrombolytic therapy has best outcome when administered as early as possible. Best results are obtained within 6 hours of attack, although administered up to 24 hours, the benefits decrease as time from onset of attack is increased. Administered in patients with ST elevation, indicating patient has complete obstruction of coronary vessel by clot, so needs this treatment.
2. Pulmonary embolism
3. Severe DVT – sup. vena caval syndrome 4. Ascending thrombophlebitis – ileofemoral vein 5. Cerebrovascular ischemia with stroke
1. Bleeding –due to lytic state.
All contraindications of heparin are same here.
2. Micro-emboli –when thrombus breaks 3. Arrhythmias –due to sudden reperfusion after acute MI 4. Allergy –streptokinase is obtained from streptococci, which are antigenic in nature, body may form antibodies, esp. in patients with streptococcal infections.
If suspect infection in the last 2 weeks, then not given.
Similar in structure to Lysine. As the name suggests, its action is opposite to fibrinolytics. It binds plasminogen and inhibits the binding of fibrinogen with plasmin.
Analogue of aminocaproic acid, used orally and parentally.
Bleeding –adverse effect of fibrinolytic therapy
Adjunctive in hemophilia –dental extraction etc. when chances of bleeding
Prophylaxis –intracranial aneurysms to prevent bleeding
Postsurgical bleeding –esp. GIT / prostate
Bladder hemorrhage –due to cystitis, drugs or radiations
Antiplatelet drugs affect the fluidity of blood in thromboembolic conditions.
Normally when endothelial injury occurs, it exposes tissues to platelets, leading to activation and aggregation.
During this activation, different substances are synthesized and released, leading to:
a. platelet aggregation
The important ones are:
– Thromboxane A2
Conformational change occurs in IIb/IIIa receptors present on platelet surface to which fibrinogen binds, leading to anchoring with other platelets and endothelial lining.
Antiplatelet drugs either:
1. act on these receptors or
2. inhibit the release of these substances
1. Thromboxane-A2 inhibitor
2. ADP receptor inhibitors
3. Glycoprotein IIb/IIIa receptor blockers
4. Phosphodiesterase inhibitors
Thromboxane-A2 Inhibitor Aspirin (details with NSAIDS)
Aspirin is normally present in platelets
Arachidonic acid is converted into thromboxane A2 by cyclooxygenase I (COX-I) enzyme.
This enzyme is inhibited by aspirin, acetylating it irreversibly.
Thus, no thromboxane A2 is produced responsible for platelet activation and aggregation.
Vasoconstrictor as well as vasoconstriction is decreased.
75 – 300 mg/day, but in certain patients for prophylaxis of MI, 325 mg are given.
Advantages of low dose
1. Toxic effects (GIT) are less
2. Antiplatelet effects but production of prostacyclines are not affected (vasodilator substances beneficial in cardiac patients).
ADP Receptor Inhibitors
2 drugs acting on purinergic receptors – P2Y1 & P2Y12
Irreversible binding –staying for life of platelets (7-10 days)
When ADP binds, it leads to platelet aggregation, so these drugs prevent ADP binding.
Both drugs are prodrugs, activated after oral administration
Ticlopidine is used along with aspirin producing synergistic effects, as both have different sites of action.
It produces more side effects including:
a. GIT disturbance
c. Thrombotic thrombocytopenic pupura-hemolytic uremic syndrome (TTP-HUS)
Side effects involving while blood cells are visible during the first three months, so repeated counts are taken during this time.
Dose 250 mg twice daily
Once daily dose of 75 mg OD. It has fewer side effects.
Glycoprotein IIb/IIIa Receptor Blockers
Receptors are present on platelet surface to which fibrinogen, fibronectin, vitronectin, von Willebrand factor bind, leading to platelet activation and aggregation with one another and endothelium, leading to clot formation. These drugs inhibit this binding and prevent platelet aggregation.
Individuals lacking these receptors suffer from Glanzmann’s thrombasthenia, leading to bleeding tendency.
Chimeric (part animal part human source). It not only effects IIb/IIIa receptors only but also Vitronectin receptors on other tissues, leading to side effects like:
It is mostly used with heparin, aspirin (anticoagulants) in patients of angioplasty.
Peptide analog having same structure as the terminal part of fibrinogen, so instead of fibrinogen, it binds receptors, blocking them to which fibrinogen cannot bind.
Nonpeptide small molecule having same action as eptifibatide.
During early 20th century, hemorrhagic diseases occurred in cattle that ate spoiled fodder (spoiled sweet clover silage). Chemists at Wisconsin Alumni Research Foundation extracted Bishydroxycoumarin responsible for this disease.
Afterwards warfarin was synthesized as coumarin derivative.
It was first used as Rodenticide
Afterwards during second half of 20th century, it was used as oral anticoagulant.
Mainly two chemical compounds are chosen for oral administration:
Coumarin –commonly used like Warfarin
Administered as racemic preparation, two enantiomers or isoforms exist:
1. S warfarin (levorotatory) 4 times more potent
2. R warfarin (dextrorotatory)
Mechanism of Action
Factor II, VII, IX, X are the glutamic acid residues and need to be carboxylated to alpha carboxy glutamic acid. This is required so that the Ca++ bridge with epithelium is formed.
During carboxylation, vitamin K is converted from reduced to oxidized form.
Oxidized form has to be converted back into reduced form, by vitamin K epoxide reductase for the reaction to continue.
Thus, reduced form is inhibited, and the process is suppressed.
The synthesis of factor II, VII, IX, X, protein C and S is suppressed, as no carboxylation occurs due to non-availability of reduced form of vitamin K.
The action of warfarin is delayed because of two reasons:
a. Delayed onset
Longer half life of about 40 hours, steady state is achieved after 2 days.
b. Anticoagulant effect
Already synthesized clotting factors are available in blood, warfarin effects can only be seen when new factors are synthesized.
As warfarin is given in racemic form, so S warfarin is 3-5 times potent than R warfarin.
Up till now no separate preparation has been prepared, and are given in combination.
Resistance to warfarin
Resistance to warfarin is genetic, due to mutation in epoxide reductase.
Administration & monitoring
Monitored by PTT and INR.
PT (Common and Extrinsic Pathway) – time taken for clotting of citrated plasma after addition of Ca+2 and standardized reference thromboplastin (12-14 s). Role of thromboplastin is not present in this clotting time as it is added from outside, so that only prothrombin is active.
Should be maintained at 2.5-3.5 times normal in warfarin therapy.
Different animal sources are used in different labs, due to differences in kits, various variations in prothrombin time are observed, and thus better method is introduced.
INR – International Normalized Ratio, which is the prothombin time ratio of a patient with reference value(2 – 3.5)
ISI is the international sensitivity index. Each thromboplastin is assigned a specific throboplastin number.
If INR is <1.5 there are more chances of thromboembolic phenomenon.
If INR is >4 there are more chances of bleeding.
Normal medicinal range is 2-3, while that for prosthetic heart valves is up to 3.5
Route of Administration
Most commonly orally, other routes include parenteral and rectal. After oral route, bioavailability is 100%.
Absorbed in GIT
Highly bound to plasma proteins (98-99%)
BBB & Placenta
Can cross BBB and placenta, thus not administered in pregnancy
Half life of S type is less than 25 hours.
Half life of R type is up to 50-60 hours.
On average, half life is 40 hours.
Metabolism is different for S and R types.
S type is metabolized by cytochrome P2C9
R type is metabolized by cytochrome P1A2, P3A4 and P2C19.
Excreted in urine.
1. Anticoagulant action –delayed onset (48hours) because clotting factors already present are not affected)
2. Also decreases synthesis of endogenous anticoagulants (protein C and S)
Prevention of thromboembolism
Not given in emergency, heparin is started, while warfarin is started as well. After 3-4 days, heparin is stopped, and then only warfarin is used.
Differences from heparin
Given in emergency
Not given in emergency
Can be given in surgery
Cannot be given in surgery
Can be given in pregnancy
Cannot be given in pregnancy
If minor and patient is stable, only drug is discontinued, patient is monitored.
a. .Phytonadione (K1)
If INR is greater than 5, vitamin K preparation is given orally or I/V according to the need of patient. Action of this is only after 12-24 hours.
If INR is much higher, fresh frozen plasma is administered.
c. Different preparations of clotting factors are administered.
As inhibits clotting factors and protein C (half life 8 hours) and S (natural anticoagulant).
First natural anticoagulant is affected, and are not formed, but small thrombi are formed, especially patients deficient in protein C and protein S. There are greater chances of skin and tissue necrosis (fatty tissue necrosis).
2. Skin / Tissue necrosis
Occurs early in adults.
As warfarin can cross placental barrier, it is teratogenic and inhibits gamma carboxylation of proteins. In fetus bone and soft tissues are not properly formed. Also hemorrhagic disorders occur in fetus.
4. As it decreases activity of protein C, it leads to cutaneous necrosis and infraction of breast fatty tissue, intestine and extremities (rare)
5. warfarin induced depression of protein C also leads to venous thrombosis
Warfarin Sensitivity – CYP2C9
Polymorphism occurs, less dose is required, as unable to metabolize at the natural rate (rate decreased)
Warfarin Resistance – VKORC1
Polymorphism occurs, leading to change in dose. In certain patients larger dose is required to produce therapeutic effects.
Dosing algorithms are prepared taking genotype, etc. in account, to calculate individualized dose.
Occur in two categories:
Mostly due to:
i. enzyme induction
ii. enzyme inhibition
iii. decreased PPB
1. Pyrazolone, Phenylbutazone and Sulfinpyrazone decrease metabolism of S-warfarin and displace albumin bound warfarin leading to increased warfarin and increased anticoagulant effects (increased risk of bleeding)
i. Augment hypoprothrombinemia
ii. Decrease platelet function
iii. May induce peptic ulcer disease
2. Barbiturates and Rifampicin (enzyme inducers) increase metabolism of warfarin, decreasing its effects.
3. Metronidazole, Trimethoprim-sulfamethoxazole (co-trimoxazole) and Fluconazole decrease metabolism of S-warfarin, increasing its effects.
4. Amiodarone, Disulfiram and Cimetidine decrease metabolism of both S and R warfarin, enhancing the effects.
5. Cholestyramine binds warfarin in intestine and decreases absorption and bioavailability.