Pharmacokinetics and Drug Metabolism

Roger McFadden 2007

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Pharmacokinetics
Pharmacokinetics* what the body does to a drug Pharmacodynamics what the drug does to the body There are three stages in the physiological handling of a drug 1. absorption into blood stream 2. distribution around body 3. elimination *technically the quantification of absorption, distribution and elimination

Absorption through membranes

Apart from injection - intra-venous / muscular delivery etc. drugs generally must pass through membranes Various membranes can be used to absorb drugs Gastric mucosa oral drugs Buccal cavity e.g. sub-lingual Rectal membranes - suppositories Vaginal membranes - pessaries Skin transdermal patches Pulmonary epithelium - inhaled drugs

Absorption through membranes

Buccal cavity can be useful for drugs that are denatured by stomach acid e.g. anti-angina drug glyceryl trinitrate (GTN) Suppositories and pessaries useful when medication by mouth is difficult e.g. example post-operative patients and of course for pathologies affecting rectum and vagina Absorption of drugs through the skin generally poor (due to their insolubility in lipids) but corticosteroids and oestrogen (as patches) can be delivered transdermally

Inhaled drugs include anti-asthma drugs salbutamol and ipratropium bromide (atrovent) plus inhaled anaesthetics such as nitrous oxide and sevoflurane.

Oral absorption
There are several physiological factors that can affect oral absorption, such as digestive enzymes - can denature drugs such as insulin stomach acid - can denature drugs GI motility - can reduce or increase the rate of absorption presence of food - can reduce or alter the rate of absorption

First - pass metabolism

An important feature in the oral absorption of drugs The venous blood flow from the digestive system does not flow directly into the vena cava but instead goes through the liver via the hepatic portal vein The liver processes and stores much of the material arriving from the stomach and, acting as a buffer, thus prevents surges in blood nutrient levels As well as controlling nutrients, the liver can have an important effect on drugs.

Orally ingested drugs

Metabolism of drugs by liver enzymes

Parenteral / IV drugs etc.

Liver

Pharmacodynamic activity in body hepatic vein

GIT
Kidney Renal artery First pass metabolism through liver via hepatic portal vein

Excretion of metabolites and intact drugs in urine

First - pass metabolism

Cytochrome P450 (microsomal) enzymes are a large family of enzymes found in the liver that are part of the bodys defence mechanism against toxic substances The body treats drugs as foreign, potentially toxic substances Microsomal enzymes change drugs by biochemical reactions. There are several families of these enzymes, the most clinically significant being CYP1, CYP2 and CYP3 (CYP = CYtochrome P450).

First - pass metabolism

The various cytochromes have specific affinities for particular drugs. This is why there is so much variation in the metabolism of drugs half life etc. The products of drug metabolism, the metabolites, are generally excreted via the kidney in the urine although some are excreted via the bile duct in the faeces

First - pass metabolism

Sometime the activity of the P450 enzymes activates the drug but mostly it deactivates drugs. Drugs that are inactive until activated by the liver are called prodrugs and include enalapril (an ACE inhibitor) and aspirin. The reactions that modify the chemical structure of a drug are referred to as Phase 1 reactions. Some drugs can induce P450 enzymes, increasing their metabolic activity and other drugs can inhibit them, so reducing their metabolic activity. This is the basis for many drug interactions

Interactions
When particular P450 isozymes are induced and their activity increases, this means that other drugs that are substrates for those isozymes are metabolised more quickly, generally decreasing their bioavailability*. When particular P450 isozymes are inhibited and their activity decreases, this means that other drugs that are substrates for those isozymes are metabolised more slowly, generally increasing their bioavailability. *Bioavailability is the proportion of a drug that appears in the systemic circulation after passing through the gastric mucosa and P450 enzymes in the liver. The term is unquantifiable because absorption varies between individuals and individual circumstances

Interactions
Certain foods can affect hepatic metabolism Grapefruit juice contains flavonoids and psoralen derivatives that inhibit CYP3A4 enzymes and so reduces the rate of first pass metabolism. The plasma concentration of drugs such as calcium channel blockers (verapamil etc.), simvastatin, ciclosporin etc. is increased See BNF, Appendix 01 for full details.

Interactions
Drugs that inhibit drug metabolising enzymes Cimetidine Corticosteroids Drugs affected by inhibition (concentration increased) Amiodarone, phenytoin, pethidine, warfarin Tricyclic anti-depressants

Ciprofloxacin
MOA inhibitors e.g. phenelzine

Theophylline
Pethidine

Interactions
Drugs that induce drug metabolising enzymes Phenobarbital Drugs affected by induction (concentration decreased)

Rifampicin
Griseofulvin

Phenytoin
Ethanol Carbamazepine St Johns wort
(Hypericum perforatum)

Warfarin Oral contraceptives Corticosteroids Ciclosporin Simvastatin

Parenteral administration / injection etc.

Successful absorption depends on a good blood supply which needs to be adequate around the injection site. The acidity of a drug is an important determinant of absorption

Generally, strong basic drugs e.g. the muscle relaxant suxamethonium are poorly absorbed so need to be given intravenously.

Absorption kinetics
For some drugs poor absorption is beneficial because their target is further along the digestive tract. The anti-bacterial vancomycin is poorly absorbed so is useful to treat the gut bacterium Clostridium difficile. Other drugs can be packed in capsules that resist absorption until the capsules degrade in the colon. Colpermin used to treat irritable bowel syndrome is an example.

Distribution of drugs around the body

Most drugs travel in the blood bound to plasma proteins, especially albumin and there are several factors that can affect distribution plasma protein levels - low plasma proteins can increase bioavailability may be a problem in the elderly blood supply to target tissues - needs to be adequate

solubility of drug - solubility increases delivery rate

Elimination
Elimination - involves two key processes metabolism and excretion

Most drugs are broken down by liver enzymes and the metabolites usually excreted by kidneys, although all body fluids can eliminate drugs. Some drugs are excreted via the bile duct into the gut
Processes sometimes referred to as Phase II reactions may be involved in the elimination of drugs. Generally increases a drugs solubility so enhances excretion These reactions take place predominantly in the liver and chemically change the drug to enhance its excretion.

Drug interactions
Drugs can affect the action of other drugs by inducing or inhibiting the activity of P450 hepatic enzymes, as has been described above. Herbal remedies such as St Johns Wort and even grapefruit juice can also affect drug metabolism via the P450 enzymes. Some drugs can occupy the receptor targets of other drugs. For example, the b-blockers such as propranolol that target b1 receptors on the heart also bind antagonistically to b2 receptors in the bronchioles. b2 receptors are prime targets for b2 agonist bronchodilators such as salbutamol.

Blocking the b2 receptors prevents salbutamol producing its bronchodilatory action. Not surprisingly, b-blockers are contraindicated for asthmatics.

Drug interactions
Diuretics may lower plasma K+ levels which can enhance the action of cardiac glycosides such as digoxin. Antibiotics that reduce bacterial production of vitamin K in the intestines can enhance the action of warfarin because vitamin K competes with warfarin for the enzyme vitamin K reductase. Anticoagulation activity is enhanced. Aspirin and warfarin can both cause bleeding in the stomach and their concurrent use increases the risk.

Drug interactions
NSAIDs such as indometacin and ibuprofen can produce unpredictable effects in patients being treated for hypertension. This is believed to be by their effect on prostaglandins in the kidney

Some drugs can affect the absorption of other drugs.

For example, drugs that enhance or inhibit gut motility can respectively inhibit or enhance drug absorption.

Bile acid sequestrants such as colestyramine bind to drugs such as warfarin and prevent their absorption.

Unwanted effects from drugs

All drugs, to a larger or lesser extent cause unwanted effects. Generally, this is due to drugs binding to an unintended enzyme, receptor etc. Mostly the effect is predictable or obvious. For example, a drug that reduces cardiac preload by vasodilation is very likely to result in hypotension. Other effects are understood but are less obvious, for example, ACE inhibitors such as captopril and ramipril causing a dry cough in some patients.

Unwanted effects from drugs

Generally, unwanted effects are dose related. The higher the dose, the more pronounced is the unwanted effect. Sometimes a high dose can result in a toxic effect such as hepatotoxicity from excess paracetamol. These effects are well characterised and predictable and are sometimes referred to as Type A reactions.

Unwanted effects from drugs

Very occasionally, patients experience idiosyncratic reactions to an otherwise predictable drug. These reactions are sometimes referred to as Type B (B = bizarre). Generally, Type B reactions are fairly severe, otherwise they would go unnoticed..

Unwanted effects from drugs type B

Reasons for idiosyncratic reactions vary but they are often due to individual genetic variation immune responses producing anaphylaxis other hypersensitivity reactions such as skin rashes Because of their infrequency, Type B reactions may be difficult to detect in clinical trials with only moderate sample sizes

General factors affecting absorption, distribution & elimination - Age

Children Dosages need to be carefully assessed as recommended and determined by body weight or surface area. Neonates have immature elimination systems. Their liver enzymes may not be fully functional and kidneys not fully developed. This can cause the delayed elimination of drugs and thus increase their half-life.

General factors affecting absorption, distribution & elimination - Age

The Elderly Absorption: Changes in drug absorption tend to be clinically inconsequential.

Distribution: Lean mass to fat ratio can change with age resulting in higher concentrations of water-soluble drugs and lower concentrations of fat soluble drugs Serum albumin decreases so in a patient with malnutrition, this may enhance drug effects because serum concentrations of unbound drug are increased.

General factors affecting absorption, distribution & elimination - Age

Hepatic metabolism: mass and blood flow decreases which can affect hepatic drug elimination. The hepatic metabolism is reduced and clearance can fall by 30 to 40%. However, the rate of drug metabolism can vary greatly from person to person. The possibility of hepatotoxicity is generally enhanced in the elderly.

General factors affecting absorption, distribution & elimination - Age

Reduction in hepatic metabolism

Presystemic (first-pass) metabolism of some drugs given orally (eg, labetalol, propranolol, verapamil) is decreased, increasing their serum concentration and bioavailability.
Many drugs produce active metabolites in clinically relevant concentrations. Examples are some benzodiazepines, amitriptyline and opioid analgesics such as morphine. The accumulation of active metabolites can cause toxicity in the elderly due to age-related decreases in renal clearance. Toxicity is likely to be severe in those with renal disease.

General factors affecting absorption, distribution & elimination - Age

Reduction in renal clearance with age The renal mass and renal blood flow decreases significantly Renal physiological changes decrease renal drug elimination. Because renal function continues to decline, the dose of drugs given long-term needs to be reviewed periodically. Elderly people may also have a reduced rate of compliance Disease - Liver and renal disease reduces rate of elimination (see BNF Appx. 2 & 3)

Maintaining drug levels in the body

The objective of administering a drug is to produce a therapeutically appropriate level in the blood There are two key factors that affect the serum concentration 1. the rate of absorption 2. the rate of elimination. Generally elimination is constant (for a particular drug) as drugs are metabolised by the liver and excreted by the kidneys (if functioning normally) Administration tends to be episodic

Maintaining drug levels in the body

Maximum safe concentration

Minimum effective concentration

Maintaining drug levels in the body

Delivery is often episodic with regular injections or oral ingestion. Parenteral administration resolves this problem with continuous delivery. Patient controlled analgesia (PCA), must also achieve a reasonably steady state via negative pain feedback. Loading doses are often used to obtain quick therapeutic levels

Maintaining drug levels in the body

Once the rate of elimination has been determined, it is possible to calculate the dose required to reach therapeutic levels. If levels too low, the drug will be ineffective If levels too high, the drug may be toxic. There are two terms used to describe this level Minimum effective concentration - MEC Maximum safe concentration - MSC

Maintaining drug levels in the body

The difference between them is sometimes called the therapeutic window. The therapeutic index (TI) quantifies the therapeutic window and is defined as the ratio of MEC to MSC so TI = MSC MEC The larger the therapeutic index, the safer is the drug However, given normal physiological variation in the patient population, drugs with a small TI such as heparin may require regular monitoring of their plasma levels to ensure they remain within the therapeutic window.

Maintaining drug levels in the body

Establishing the therapeutic index does not tell us how much drug to administer because it takes no account of the rate of elimination. The rate at which a drug is eliminated is quantified by its half-life (T), the rate at which the concentration of a drug will decrease by half. The longer the half-life, the longer it will remain in the circulation and vice versa. The shorter the half life, the more frequently a drug needs to be administered and vice versa. Look at these two drugs.

Half life of drugs

100

80 Plasma concentration of drug 60 (g / L) 40

Drug A

Drug B

20

0 0 1 2 3 4 5 Time (hours) 6 7 8 9 10

Half life of drugs

The time take for drug A and drug B to fall from a plasma concentration of 100 mg / L to 50 mg / L (i.e. by half) is different. T for drug A is around 2 hours T for drug B is over 5 hours. If 100 mg / L is the desired plasma concentration for the drug then drug A will need to be delivered more frequently. However, if it has a larger therapeutic index, a larger dose of drug A may be safely given at less frequent intervals.

End of Presentation