PK3 by KGS by akashyap

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									Bioavailability

Destroyed in gut

Not absorbed

Destroyed Destroyed by gut wall by liver

Dose

systemic circulation

• Definition- as per US FDA “ the rate at which the active concentration of the drug is available at the desired site of action” • Designated as “ F ” • In other words….. It is the fraction of the drug that reaches the systemic circulation from a given dose in an unchanged form

• Intravenous route of drug administration gives 100% bioavailability as it directly enters the circulation. “ F ” is equal to 1 • Non i.v - ranges from 0 to 100%; value of “ F ” is equal or less than 1 e.g. lidocaine bioavailability - 35% → due to destruction in gastric acid and liver metabolism, hence not given orally • The term bioavailability is used commonly for drugs given by oral route.

How is bioavailability measured?
• To measure bioavailability, drug plasma levels are measured at different time points following various routes of administration • Plasma levels are plotted against time

• Area under the curve (AUC) is measured
• If oral and iv doses are the same, then F = AUCoral/ AUCiv

70 60
Plasma concentration

Bioavailability

= (AUC)o (AUC)iv

50 40 30 20 10 0 0 2

i.v. route

AUC
oral route

4 6 Time (hours)

8

10

Why less Bioavaililbity for drugs given other than IV route?

• Because they undergo …..

FIRST PASS METABOLISM

Hepatic „First-Pass‟ Metabolism
• Metabolism of drug in gut (liver) before drug reaches systemic circulation • Drug absorbed into portal circulation, must pass through liver to reach systemic circulation • Reduce the bioavailability of drug • Orally administered drugs will have high FIRST PASS METABOLISM • Parenteraly administered drugs will bypass the FIRST PASS METABOLISM to the major extent

Bioequivalence…Refer graph in next slide
• Two different formulations or two different brands (brand A and B) of a same drug give orally to the

same person
• If they differ in bioavailibility and rate of absorption …both brand A and B are said to be Bioinequivalent…..this is common • If they have same bioavailibility and rate of

absorption …both brand A and B are said to be
Bioequivalent…..this is uncommon

Factors influencing bioavailability
Physicochemical properties of the drug. • Physical state • Lipid soluble and unionized form - better absorbed • Particle size: smaller particle size absorbed better than larger ones

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•

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Disintegration time: Time taken for the formulation (tablet or capsule) to break up into small particles. Dissolution time: Time taken for the particles to go into solution. Shorter the time better is the absorption. Formulations

• Route of drug administration • pH and ionization: Strongly acidic and strongly basic drugs usually remain ionized at all pH - are poorly absorbed • Food: milk + tetracyclin = compound that canoot be absorbed • Presence of other drugs: • Gastrointestinal and other diseases: • Area of the absorbing surface: • Pharmacogenetic factors: In pernicious anemia, vitamin B12 is not absorbed from the gut due to lack of intrinsic factor.

DRUG DISTRIBUTION
• Distribution is defined as the reversible transfer of drugs between body fluid compartments
• Various body fluid compartments are (for a 70 kg person)

• Apparent volume of distribution (aVd) is the hypothetical volume of body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma, assuming the body to be a single compartment.

Clinical importance of Vd : • Aspirin Vd = 0.1571 L/Kg ; Pethidine Vd = 280 L/Kg • Hemodialysis is useful only for drugs with small volume of distribution eg. Aspirin • Drugs with low volume of distribution would be found in the intravascular compartment

Factors affecting drug distribution / Vd
Physicochemical properties of the drug: Lipid soluble and unionized form of drugs readily cross the cell membrane and are widely distributed e.g.. lignocaine, propranolol, tricyclic antidepressants etc. Drugs like heparin (strongest acid in the body) is confined only to intravascular compartment as it exists in ionized form.

• Degree of plasma protein binding: Drugs highly bound to plasma proteins have a low volume of distribution. • Tissue storage: Certain drugs can get sequestrated in some tissues. Such drugs have a large Vd eg. digoxin is sequestrated in heart, muscle, liver etc. and has a Vd of 66L/kg.

• Disease states: Eg: In CHF, the Vd of some drugs can increase due to increase in ECF volume or it could decrease due to reduced perfusion of tissues. • Fat: lean body mass ratio: If the ratio is high, fat acts as a reservoir for certain drugs

Redistribution • Highly lipid soluble thiopentone → IV administration immediately gets distributed to areas of high blood flow - brain → general anaesthesia. • In few minutes, it re crosses the BBB gets distributed to less perfused tissues such as muscle, adipose tissue → termination of action Thiopentone • Has a very short duration of action (5-10 min) and is used for induction of general anaesthesia.

Drug reservoirs or tissue storage • Tetracyclines : bones, teeth • Thiopentone, DDT : adipose tissue • Chloroquine : liver, retina • Digoxin : heart • Clinical importance of drug storage: Because of such storage, repeated exposure to some chemicals like DDT in small quantities may lead to chronic toxicity

Blood Brain Barrier (BBB) • The capillary boundary that is present between the blood and brain is called BBB • Barbiturates, diazepam, volatile anesthetics, amphetamine etc – cross BBB

• Meningitis, encephalitis - increase the permeability of the BBB eg. penicillin in normal conditions has poor penetration through BBB, but its penetrability increases during meningitis and encephalitis.

Placental Barrier : • The lipid membrane between the mother and fetus is called placental barrier. • Unionized and lipid soluble drugs can freely cross the placental barrier. e.g.. anesthetics, alcohol, morphine etc. • Quaternary ammonium compounds eg. dTC and substances with high molecular weight eg. insulin cannot cross the placental barrier.

Plasma protein binding: • Acidic drugs bind to albumin, Basic drugs bind to 1 acid glycoprotein etc Clinical importance of Plasma protein binding: • Free form Bound form Free form – Pharmacologically active Bound form - Pharmacologically inactive, acts as a “temporary store” of the drug

• Plasma protein binding favours drug absorption. • Drugs which are highly bound to plasma proteins have a low volume of distribution. • Plasma protein binding delays the metabolism of drugs. • Bound form is not available for filtration at the glomeruli, hence delays its excretion.

• Highly protein bound drugs have a longer duration of action. • In cases of poisoning, highly plasma protein bound drugs are difficult to be removed by Hemodialysis. • Disease states like anemia, renal failure, chronic liver diseases etc have low plasma albumin levels. So there will be an increase in the free form of the drug which can lead to drug toxicity.

• Plasma protein binding can cause displacement interactions • More than one drug can bind to the same site on albumin. The drug with higher affinity will displace the one having lower affinity and may result in a sudden increase in the free concentration of the drug


								
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