PHARMACOKINETICS

Pharmacokinetics

• Pharmacokinetics is derived from two words: Pharmaco- meaning drug and -kinesis meaning movement.

• In short, it is ‘what the body does to the drug’. It includes absorption (A), distribution (D), metabolism (M) and excretion (E) of a drug.

1. Drug Absorption• The movement of a drug from the site of

administration into the blood stream.• Factors Influencing Drug Absorption :1. Physicochemical properties of the drug:a. Physical state: – Liquid form of the drug is better absorbed than solid

formulations.b. Lipid-soluble and unionized form of the drug:– is better absorbed than the water-soluble and ionized

form.c. Particle size:– Drugs with smaller particle size are absorbed better than

larger ones.

Factors Influencing Drug Absorption

d. Disintegration time:– It is the time taken for the formulation (tablet or

capsule) to break up into small particlese. Dissolution time: – It is the time taken for the particles to go into

solution. Shorter the time, better is the absorption.f. Formulations:– Pharmacologically inert substances like lactose,

starch, calcium sulphate, gum, etc. are added to formulations as binding agents.

Factors Influencing Drug Absorption

2. Route of drug administration: – Drugs like insulin are

administered parenterally because they are degraded in the GI tract on oral administration.

3. pH and ionization: – Strongly acidic (heparin) and

strongly basic (gentamycin) drugs usually remain ionized at all pH; hence they are poorly absorbed.

Factors Influencing Drug Absorption

4. Food: – Fatty meal increases the absorption of some drugs.– some drugs should be taken on an empty stomach.

5. Presence of other drugs:– Concurrent administration of two or more drugs may

affect their absorption,– e.g. ascorbic acid increases the absorption of oral iron.

Antacids reduce the absorption of thyroxine.6. Pharmacogenetic factors: – In pernicious anaemia, vitamin B12 is not absorbed from

the gut due to lack of intrinsic factor.

Factors Influencing Drug Absorption

7. Area of the absorbing surface: – Normally, drugs are better absorbed in the small

intestine because of a larger surface area.– Resection of the gut decreases absorption of

drugs due to a reduced surface area.8. Gastrointestinal diseases: – In gastroenteritis, there is increased bowel

movement that reduces the drug absorption.

Bioavailability• It is the fraction of a drug that reaches the

systemic circulation from a given dose.• Intravenous route of drug administration gives

100% bioavailability, as it directly enters the circulation.

• The term bioavailability is used commonly for drugs given by oral route.

• If two formulations of the same drug produce equal bioavailability, they are said to be bioequivalent.

Factors Affecting Bioavailability

• Factors that affect drug absorption also affect bioavailability of a drug. With other factors:

1. First-pass metabolism:– The net result is a decreased

bioavailability of the drug and diminished therapeutic response.

– certain drugs get metabolized and are removed or inactivated before they reach the systemic circulation.

Factors Aff ecting Bioavailability

• 2. Hepatic diseases: – They result in a decrease in drug metabolism; thus

increasing the bioavailability of drugs that undergo first-pass metabolism, e.g. lignocaine.

2. Drug Distribution• Distribution is defined as the reversible transfer of

drugs between body fluid compartments.• Drug Reservoirs or Tissue Storage– Some drugs are concentrated or accumulated in tissues

or some organs of the body, which can lead to toxicity on chronic use. For example, tetracyclines—bones and teeth.

• Blood–Brain Barrier– The capillary boundary that is present between the blood

and brain.– Only the lipid-soluble and unionized form of drugs can

pass through BBB and reach the brain, e.g. diazepam.• Placental Barrier– The lipid membrane between mother and fetus

Plasma Protein Binding

• Many drugs bind to plasma proteins like albumin, α1 – glycoprotein.

Plasma Protein Binding

• Plasma protein binding delays the metabolism of drugs.

• Bound form is not filtered by kidney; so, excretion of highly plasma protein- bound drugs is delayed.

Highly protein-bound drugs have a longer duration of action

Low plasma protein. there will be an increase in the free form of the drug, which can lead

to drug toxicity.

3. Drug Metabolism• The metabolism of a drug usually converts the

lipid-soluble and unionized compounds into water-soluble and ionized compounds to be excreted.

• Sites: Liver is the main site for drug metabolism; other sites are GI tract, kidney, lungs, blood, skin and placenta.

1. Active drug to inactive metabolite:Phenytoin p-Hydroxyphenytoin

2. Active drug to active metabolite:Diazepam Oxazepam

3. Inactive drug to active metabolite:Levodopa Dopamine

Prodrug

• It is an inactive form of a drug that is converted to an active form after metabolism.

Uses of prodrug (advantages):1. To improve the bioavailability.2. To prolong the duration of action.3. To improve the taste.4. For site-specifi c drug delivery

4. Drug Excretion

• Removal of the drug and its metabolite from the body.

• The main channel of excretion of drugs is the kidney; others include lungs, bile, faeces, sweat, saliva, tears, milk