Pharmacokinetics

INTRODUCTION TO

PHARMACOLOGY CONCEPTS

Dr Sufyan Akram

WHAT ARE DRUGS? Pharmacology studies the effects of chemical substances on the function of living organisms.

Initially, tissue and animal experiments enabled observation of the qualitative effects and measurement of quantitative effects of these chemicals.

Therapeutic uses were discovered for human beings, and later, drugs were developed and even designed to exert specific effects.

WHAT ARE DRUGS? More recently, advances in the study of cell and molecular biology have moved the theoretical basis of pharmacology rapidly forward. Newer concepts have replaced the historical theories, and biotechnology now underpins the development of drugs.

The typing and cloning of the human genome has given further, exciting prospects for therapeutic development. The genetic makeup of individuals determines their response to drugs, and genetic variation is complex. Pharmacogenetics is an evolving subject, and although still theoretical, the future of pharmacogenomics could be very promising.

PHARMACOKINETICS

The route of administration determines the degree of absorption, and thus the dose required for sufficient drug to enter plasma in the systemic circulation. The drug leaves the plasma to be distributed to its site of action and to storage sites (fat deposits). Finally, the majority of drugs are metabolised before excretion.

PHARMACOKINETICSAbsorption, into the body and into cells

Distribution, around the different compartments of the body

Metabolism, when the drug is broken down and inactivated, or sometimes transformed into an active form

Elimination or excretion from the body

ABSORPTION Absorption is important for all routes of drug administration except intravenous injection.

A drug must cross at least one cell membrane to be absorbed, reach its site of action and eventually be eliminated.

The ways that drugs, nutrients and other substances (solutes) in aqueous solution cross a membrane barrier are by: Passive diffusion through cell membranes Carrier-mediated transport Endocytosis and exocytosis Diffusion through aqueous pores and intracellular pores

Absorption Distribution Metabolism Elimination

PASSIVE(No Energy Required)

ACTIVE(Requires Energy)

Kinds of Transport

No Help

Membrane Proteins

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Diffusion

Facilitated

DiffusionPumps Endocyt

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Exocytosis

e.g. O2 and CO2

Carrier

Proteins

Channels

e.g. Glucose

Aquaporins

Ion Chann

else.g. H2O e.g.

Na+ and K+

e.g. Na+- K+ pump

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e.g. Phagocyto

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A. PASSIVE DIFFUSION The majority of drugs pass through cell membranes by the passive diffusion of molecules down a concentration gradient, which does not involve energy expenditure.

The rate of diffusion across the membrane depends on: The lipid solubility of the drug The area over which absorption occurs The concentration gradient across the membrane

A drug must be water soluble to be distributed throughout the body. However, cell membranes are mostly composed of lipids !


A. PASSIVE DIFFUSION Ionised and non-ionised forms of a drug Most drug molecules exist in solution as a mixture of ionised and non-ionised forms

The ionised form carries an electrical charge, has very low lipid solubility and cannot easily permeate lipid membranes. The non-ionised form carries no charge, is lipid soluble and easily diffuses across cell membranes

If the pH on either side of a cell membrane is different, the degree of ionisation of a drug on either side will also be different

The effect of pH partitioning results in the accumulation of weak acids in compartments with relatively high pH (basic), and weak bases accumulate in compartments with a relatively low pH (acidic). This is the concept of ion trapping


A. PASSIVE DIFFUSION Changes in plasma pH due to acidosis or alkalosis can have a significant effect on the pH partitioning or ‘ion trapping’ of drugs: In acidosis, blood pH falls so that the pH difference, or gradient, between the extracellular and intracellular fluids rises. An acidic drug would be retained in the cells.

In alkalosis, blood pH rises so that indirectly, the difference between interstitial pH and intracellular pH decreases. Acidic drugs would tend to accumulate in the extracellular fluid.

The effects of metabolic or respiratory acidosis or alkalosis on drug absorption and distribution are of importance when treating patients with conditions such as respiratory failure and diabetic ketoacidosis.


B. CARRIER-MEDIATED TRANSPORT Drugs that are ionised in plasma and will not diffuse into the cells, require specialist transmembrane proteins to carry them across cell membranes.

Cells have two major classes of transmembrane proteins: Transporters (carrier proteins) Ion channel proteins

Transporters (Carrier Proteins): A given transporter is specific for a small group of related substrate molecules, which compete for the transporter. Protein transporters can be the sites of drug action, when the drug is similar to the substrate and competitively binds to the transporter.


B. CARRIER-MEDIATED TRANSPORT There are three classes of transporters: Uniporters Symporters Antiporters


B. CARRIER-MEDIATED TRANSPORT Ion Channel Proteins: Ion channel proteins are large proteins forming water-filled pores that span the lipid bilayer of cell membranes. These channels allow ions of appropriate size and charge to be transferred across.

All ion channel proteins allow solutes to cross membranes by facilitated diffusion without energy expenditure. The channel, or pore structure, is either open or closed and the conformational change is called gating, as in opening and closing a gate


C. ENDOCYTOSIS & EXOCYTOSIS Very large molecules (macromolecules), such as proteins, cannot be transported across the cell membrane by transporters, and have to be taken into or out of the cells through the processes of endocytosis and exocytosis.

Drugs can facilitate or inhibit these processes.


D. AQUEOUS & INTRACELLULAR PORES Most biological membranes are relatively permeable to water that passes across the cell membrane via aqueous pores that results from osmotic differences across the membrane, carrying extremely small, water-soluble molecules of less than 100 daltons in diameter with it (e.g. lithium, urea, ethanol).

Gap Junctions: Gap Junctions between cells may allow the transfer of free, not protein bound, drug molecules in solution.

Other junctions prevent the transfer of molecules, and are known as tight junctions.


D. INTRACELLULAR PORES The ability of drugs to penetrate the endothelial membrane varies from one tissue to another.

Gap junctions in vascular endothelium allow bulk transfer of drug molecules free in solution but not those bound to plasma proteins.

In contrast, in the blood–brain barrier and the placenta, the capillary membranes are tightly joined together with only a few tight junctions, so that drugs can only pass through the membrane either by passive diffusion (lipid soluble molecules) or carrier-mediated transport.


DISTRIBUTION Depending on pH, ionisation and lipid solubility, drugs can be moved for short distances by diffusion and membrane transport.

Rapid transport over long distances around the body has to be done in the bloodstream, partly in solution as free (unbound) drug and partly bound to blood components (plasma proteins, blood cells).

The bound and unbound forms are in equilibrium, and only the unbound drug is available for passive diffusion from the bloodstream to tissue sites where the pharmacological effects occur.


DISTRIBUTION Drug distribution is the process by which a drug is transferred from the bloodstream (plasma) to tissues (interstitial fluid and cells). The rate and degree of drug distribution throughout the body depends on: Blood flow Capillary permeability Protein binding Accumulation in and redistribution to other sites

Once a drug enters the body, it can be distributed between four major aqueous compartments: Plasma Interstitial Intracellular Transcellular


BODY FLUID COMPARTMENTS Total body water, as a percentage of body weight, varies from approximately 50% to 75%, depending on age and sex. Women tend to have lower body water due to increased body fat

The pattern, or extent of drug distribution into the fluid compartments depends on: Permeability between cell membranes Protein binding within compartments pH partitioning Accumulation in adipose tissue

The estimated amount of drug that is distributed from plasma to other aqueous compartments is important, because the pharmacological effects of drugs are exerted in those compartments


BODY FLUID COMPARTMENTS Some drugs remain in the plasma because their molecules are too big to cross capillary membranes into tissues (e.g. heparin).

Highly protein-bound drugs tend to remain in the plasma.

The amount of drug needed to reach a plasma concentration that enables adequate distribution to effector tissues depends on the extent of distribution from plasma. This will determine the therapeutic dosage that needs to be administered

While it is possible to measure drug concentration in total body water in animal experiments, only plasma concentration is measurable in humans


BODY FLUID COMPARTMENTS The apparent volume of distribution measures the concentration of free and protein-bound drug remaining in the plasma after distribution is completed, and is used to predict distribution of the drug in the various compartments of the body.

However, it does not indicate where and how much drug has been taken up by effector tissues.

Apparent volume of distribution: Gives an estimate of total drug in the body in relation to plasma concentration, and the concept is useful for monitoring progress when treating drug toxicity and overdose.

Is related to drug clearance from the body and indicates the overall rate of drug elimination

Can predict tissue drug concentration from the above two estimates


OTHER FACTORS… Protein-binding of Drugs: At therapeutic plasma concentrations, many drugs bind extensively to plasma and intracellular proteins. This limits the amount of drug available for distribution outside the bloodstream. The protein-bound drug molecules cannot permeate cell membranes, be metabolised, excreted or produce their effect.

Drug Distribution to Special Organs: Many drugs cannot gain access to the brain because of the blood–brain barrier by virtue of tight junctions.

Lipid-soluble drugs given to the pregnant mother can cross the placental barrier to the fetus by passive diffusion.


METABOLISM Drug metabolism is the process by which the body produces a change to the chemical structure of a drug molecule by enzyme activity.

The outcomes of drug metabolism may be: The inactivation of drug so that it no longer has any biological activity

To produce metabolites with less biological activity To produce active metabolites that may be more potent and persist longer than the parent compound

To convert an inactive pro-drug to the active form To produce toxic metabolites To produce inactive metabolites that are water soluble for excretion


METABOLISM The liver is the major organ for drug metabolism. After absorption from the gastrointestinal tract, orally administered drugs pass through the liver via the portal vein before distribution to other organs. The liver may extensively metabolise and inactivate some drugs. This is the concept of first pass metabolism.

Metabolic reactions for drugs are classified as: Phase I reactions, or pre-conjugation reactions followed by Phase II reactions, consisting mainly of conjugation

The enzymes involved in both phases are located in: Smooth endoplasmic reticulum (Microsomal Enzymes) Cytoplasm Mitochondria


‘PHASE I’ REACTIONS Phase I reactions, or pre-conjugation consisting of oxidation, reduction and hydrolysis reactions

Mainly take place in the liver and are mediated by microsomal enzymes. The collective term, the mixed function oxidase (MFO) system, is used to describe the hepatic microsomal enzymes

Oxidation is the most important of phase I reactions Cytochrome P-450 is the most important enzyme system in the diverse group of enzymes that catalyse oxidation in humans

The cytochrome P-450 system is a superfamily of related but distinct microsomal liver enzymes, subject to genetic variation


‘PHASE I’ REACTIONS Some drugs cause enzyme induction or inhibition, thereby reducing or enhancing the therapeutic effect of another, co-administered drug Some anticonvulsants (e.g. phenytoin) and rifampicin induce cytochrome P-450 enzymes, which increase the rate of metabolism and thus reduce the therapeutic effect of warfarin if administered at the same time. Patients on anticoagulant therapy being prescribed rifampicin or phenytoin will need a higher dose of warfarin

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‘PHASE II’ REACTIONS Phase II reactions, consisting of conjugation and acetylation reactions

Synthesis of a covalent bond between a highly polar, normal substance in the body (endogenous) with a phase I metabolite or sometimes with the parent drug

Energy is needed for synthesising the bond. The conjugate is a less lipid-soluble, more water-soluble compound that is readily excreted in urine and/or bile and usually pharmacologically inactive

The most important phase II reaction is glucuronidation, when a molecule of glucuronic acid is transferred to the drug molecule

Conjugation with glutathione represents a major detoxification pathway for a number of drugs


FACTORS AFFECTING DRUG METABOLISM Genetic factors When known, differences in the expression of metabolic enzymes in different groups of people need to be taken into account when prescribing. There is genetic variation in the ability of unrelated individuals to metabolise drugs

Environmental contaminants and drugs The activity of drug metabolising enzymes can be induced (increased) or inhibited (decreased) by chemicals contained in environmental contaminants and drugs (e.g; Organophosphate pesticides, Polycyclic aromatic hydrocarbons (contained in cigarette smoke), Alcohol in chronic alcohol consumption)


EXCRETION Water-soluble drugs may be excreted unchanged, whereas metabolic inactivation makes drugs more soluble for excretion. The main routes of excretion for drugs and their metabolites are via: The renal system The hepatic/biliary system The lungs: this route is important in the excretion of gaseous anaesthetics


A. THE RENAL SYSTEM Glomerular filtration Drugs and metabolites are excreted via renal glomeruli by filtration. The kidneys are highly perfused organs and receive about 25% of cardiac output of which 20% is filtered (180 L/day) to produce the initial urine.

Glomerular capillaries allow the filtration of molecules with a molecular weight of below 20 000, irrespective of whether they are anions or cations, ionised or non-ionised.

Plasma proteins, which have a molecular weight of 68 000 or more, and protein-bound drugs are not normally filtered. Therefore protein binding of drugs significantly affects their elimination via glomerular filtration.


A. THE RENAL SYSTEM Tubular secretion Tubular secretion takes place in the proximal renal tubules. Here the tubule removes a wide variety of substances from plasma into the lumen of the tubule through active transport.

In the proximal tubule there are two non-specific carrier-mediated transport processes: A cation transporter for weak bases (e.g. quinine, morphine) An anion transporter for weak acids (e.g. penicillin, furosemide)

These two processes are rapid and saturable. In contrast to glomerular filtration, protein binding of the drug has no effect on drug clearance via tubular secretion.


A. THE RENAL SYSTEM Tubular reabsorption Tubular reabsorption of drugs takes place in the distal convoluted tubules of the kidney.

There are specific transporters in the nephron for the reabsorption of essential constituents of tubular filtrate (e.g. amino acids, glucose, vitamins, water), but only very rarely are drugs reabsorbed in this way.

The majority of drugs that are reabsorbed are lipid soluble and pass through the distal convoluted tubule membranes by passive diffusion.


A. THE RENAL SYSTEM As the degree of ionisation of a drug depends upon the pH of the urine and pKa of the drug, altering the pH of urine can promote drug excretion !


B. HEPATOBILIARY EXCRETION Drugs, and glucuronide conjugates formed in the liver, can be secreted into the bile by active transport processes similar to those found in the renal tubules for anions and cations.

Basic drugs (e.g. atropine) and non-ionised molecules (e.g. digoxin) can also be secreted into bile. Biliary secretion becomes more important as the molecular weight exceeds 300.

Drugs and their metabolites with molecular weight exceeding 300 are released into the alimentary tract where: Either the drug or conjugate can be excreted via the faeces Or the bacterial flora of the lower intestine may hydrolyse the conjugated drug back to the original drug, which is then reabsorbed by the intestine (e.g. oestrogens, morphine). This is known as enterohepatic circulation


ROUTES OF DRUG ADMINISTRATION Choosing how any particular drug is administered depends on how quickly effective plasma concentrations must be achieved, and how the drug is absorbed into the systemic circulation, metabolised and excreted.

The main routes of administration of a drug are: Oral (PO) Parenteral: intravenous (IV), intramuscular (IM), subcutaneous (SC)

Buccal/sublingual Rectal (PR) Transdermal and topical (vaginal, nasal, ocular) Inhalation

SOME BASIC MATHEMATICS The mathematical basis of pharmacokinetics seeks to analyse the drug concentration in different parts of the body, over time from administration to arrival at the site of action.

The mathematics is complicated, attempting to synthesise the four basic processes of drug absorption, distribution, metabolism and excretion. These processes affect: The amount of drug that arrives at the site of action The intensity of action The duration of action

SOME BASIC MATHEMATICS First-order Kinetics

Zero-order Kinetics

Multiple Dosing and Steady State

Drug Accumulation

and Steady State

Concentration

REFERENCES Naish et al. Medical Sciences (2011) Chapter 4

Lippincott Illustrated Reviews: Pharmacology 5th ed (2011) Chapter 1

Pharmacokinetics

Health & Medicine

Transcript of Pharmacokinetics