Pharmacokinetics

 

Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. It involves the examination of the processes involved in the absorption, distribution, metabolism, and elimination of drugs.

All pharmacokinetic processes involve transport of the drug across biological membranes. 

Transfer of drugs across membranes can be by:

1. Passive diffusion:

Aqueous diffusion: through pores.
Lipid diffusion: through lipid membrane (most of drugs).

2. Specialized transport system:

• Active transport.
• Facilitated diffusion 
• Endocytosis and Pinocytosis.

The key pharmacokinetic parameters that are studied include:

1. Absorption: This is the process by which a drug is taken into the body and moves from the site of administration into the bloodstream.
2. Distribution: This is the movement of the drug from the bloodstream to the site of action. The distribution of a drug is influenced by several factors, including its lipid solubility, molecular weight, and binding to plasma proteins.
3. Metabolism: This is the process by which the body modifies the drug molecule to make it more water-soluble, so it can be eliminated from the body. Metabolism occurs primarily in the liver.
4. Elimination: This is the process by which the drug is eliminated from the body. The elimination of a drug can occur through various routes, including the kidneys, liver, and intestines.

Passage of drug through different  compartments:

a) Passing through CNS:  
Drug is lipid soluble  or actively transport because the glial cell surrounding it has a tight capillaries.
N.B: Inflammation (meningitis) increase permeability.
b) Passing through placenta to fetus required higher lipid solubility for drug.

Drug absorption 

Drug absorption is the process by which a drug is taken into the body and moves from the site of administration into the bloodstream. The rate and extent of drug absorption determine the concentration of the drug in the body and thus its pharmacological effect.

The key factors that affect drug absorption include:

1. Route of administration: The route of administration is a major determinant of the rate and extent of drug absorption. Some common routes of administration include oral, intravenous, subcutaneous, intramuscular, and topical.
2. Physical and chemical properties of the drug: The physical and chemical properties of a drug, such as its solubility, ionization, and molecular size, can affect its absorption.
3. Site of administration: The location of the site of administration can also affect drug absorption. For example, drugs that are administered subcutaneously are absorbed more slowly than those that are administered intravenously.
4. Blood flow to the site of administration: The blood flow to the site of administration can also affect the rate of drug absorption. Drugs that are administered to an area with high blood flow will be absorbed more quickly than drugs that are administered to an area with low blood flow.
5. Formulation: The formulation of a drug, such as its dosage form and the presence of excipients, can also affect its absorption.
6. Gastrointestinal transit time: The amount of time a drug spends in the gastrointestinal tract can also affect its absorption. Drugs that are absorbed more quickly will spend less time in the gastrointestinal tract.

Drug Distribution

Drug distribution is the process by which a drug moves from the bloodstream to the site of action in the body. The distribution of a drug is influenced by several factors, including its lipid solubility, molecular weight, and binding to plasma proteins.

The key factors that affect drug Distribution include:

1. Lipid solubility: Lipid-soluble drugs can easily diffuse across cell membranes, allowing them to rapidly distribute throughout the body. On the other hand, water-soluble drugs have difficulty crossing cell membranes, and therefore, their distribution is limited.
2. Molecular weight: The molecular weight of a drug can also affect its distribution. Drugs with a high molecular weight are less likely to diffuse across cell membranes, and therefore, their distribution is limited.
3. Plasma protein binding: Many drugs bind to plasma proteins, such as albumin, in the bloodstream. The extent of plasma protein binding can affect the distribution of a drug. Drugs that are highly bound to plasma proteins will have a limited ability to distribute to tissues, while drugs that are poorly bound to plasma proteins will distribute more freely.
4. Tissue perfusion: The blood flow to a particular tissue can also affect the distribution of a drug. Drugs that are administered to tissues with high blood flow will be distributed more rapidly to those tissues.
5. Tissue binding: Some drugs can bind to specific tissues, such as the liver, where they are metabolized. This tissue binding can affect the distribution of the drug.

Drug Metabolism

Drug metabolism is the process by which the body modifies the chemical structure of a drug to make it more water-soluble, so it can be eliminated from the body. This process is primarily carried out in the liver and is essential for the elimination of many drugs.

Drug metabolism can occur through several pathways, including:

1. Oxidation: This is the process by which the body adds oxygen to the drug molecule to make it more water-soluble. Oxidation can occur through several enzymes, including the cytochrome P450 (CYP450) enzymes.
2. Reduction: This is the process by which the body reduces the drug molecule to make it more water-soluble. Reduction can occur through the action of several enzymes, including the aldehyde dehydrogenase and alcohol dehydrogenase enzymes.
3. Hydrolysis: This is the process by which the body breaks down the drug molecule through the addition of water. Hydrolysis can occur through the action of several enzymes, including the esterases and amidases.
4. Conjugation: This is the process by which the body adds a molecule, such as glucuronide or sulfate, to the drug molecule to make it more water-soluble. Conjugation can occur through the action of several enzymes, including the UDP-glucuronosyltransferases and sulfotransferases.

Note The rate of drug metabolism can be influenced by several factors, including genetics, age, liver function, and concurrent medications. Some drugs can also induce or inhibit the activity of drug-metabolizing enzymes, which can alter the rate of metabolism and elimination of other drugs.

Drug Elimination

Drug elimination is the process by which drugs and their metabolites are removed from the body. The elimination of a drug can occur through several pathways, including the kidneys, liver, and lungs.

The drug eliminated from body either through:

1. Metabolism (biotransformation) in which the drugs undergo a chemical reactions convert them to  a metabolites (some drugs are not..).
2. Excretion in which the metabolites or drugs are expelled outside the body.

• Kidneys: The kidneys play a key role in the elimination of many drugs and their metabolites through the process of renal excretion. Drugs and their metabolites are filtered from the bloodstream by the kidneys and can be eliminated in the urine.

• Liver: The liver also plays a role in the elimination of many drugs and their metabolites through the process of hepatic elimination. Drugs and their metabolites can be eliminated from the liver by secretion into the bile, which is then excreted in the feces.
• Lungs: Some drugs and their metabolites can be eliminated from the body through the lungs through the process of respiratory elimination. This occurs when the drugs are exhaled as volatile compounds.
• The rate of drug elimination can be influenced by several factors, including the rate of drug metabolism, the kidney function, and the blood flow to the elimination organs. Some drugs can also affect the elimination of other drugs by inducing or inhibiting the activity of elimination enzymes or transporters.

In summary, drug elimination is the process by which drugs and their metabolites are removed from the body through various pathways, including the kidneys, liver, and lungs. The rate of drug elimination can be influenced by several factors, including the rate of drug metabolism, the kidney function, and the blood flow to the elimination organs. A thorough understanding of drug elimination is important for optimizing drug therapy and avoiding drug-drug interactions.

Bioavailability (F)

Is the fraction or percentage of unchanged drug reach systemic circulation following administration by any route. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 70 %

For IV route bioavailability= 100%
Products with the same bioavailability is called bioequivalent.

Causes of low oral bioavailability

1. Insufficient absorption

• Large MWT (greater than 400g/mol)
• Highly polar molecule.

2. Competing reaction

• With intestinal enzyme (insulin)
• Acid hydrolysis (penicillin G and erythromycin)
• Complexation reaction (tetracyclin with divalent ion)
• Microflora oxidation (digoxin).

N.B: Note that some drugs administered in different forms to overcome these reaction (pivampicillin  pro-drug)

3. First pass metabolism in :

• Liver e.g. propranolol and verpamil.
• Intestine (microflora, estrase enzymes) e.g. oestrogen and progesteron.
• Lung e.g. isoprenaline.

4. Reverse transport reaction with P-glycoprotein (pump out drug from gut wall to the lumen ), this transporter inhibited by grapefruit juice and may enhance drug absorption.

Volume of distribution (Vd):

Is the apparent volume of fluids into which drug is distributed in a concentration same as plasma concentration.

• Apparent means that the volume is not areal anatomical volume but it may reflect a degree and site of drug distribution.
• Large volume of distribution means drug is mainly found in tissues more than in blood while small volume of distribution means the drug is mainly located in blood.

Drug clearance

Defined as volume of fluid from which all drug are removed per unit time.

It depends on:

• Plasma drug concentration. 
• The rate of elimination

Renal clearance

It involve three mechanisms:

1. Glomerular filtration:

• Small Mwt.
• Non protein bound.
• Most of drugs.

2. Active tubular secretion:

• Active carrier mediated process (saturation & competition)
• There are 2 system (one for acidic and the other for basic drug).
• Weak acids and weak bases.

3. Tubular re-absorption :

• Governed by urine PH and drug Pka

 

• Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule, so are not efficiently excreted in the urine. 
• Weak acids are more rapidly excreted in alkaline urine, and vice versa.
•  Excretion also affected in declined renal function (renal failure or elderly).