Pharmacokinetics and Drug Metabolism

1. Pharmacokinetics and Drug Metabolism Roger McFadden 2010 Click mouse to move show forward

2. Pharmacokinetics Pharmacokinetics – what the body does to a drug Pharmacodynamics – what the drug does to the body There are four stages in the physiological handling of a drug Absorption into blood stream Distribution around body Metabolism Elimination

3. 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

4. Routes of Administration

5. Absorption through membranes Buccal cavity can be useful for drugs that are denatured by stomach acid or liver 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, GTN, hyoscine, oestrogen and fentanyl and nicotine (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.

6. Distribution of drugs around the body Most drugs travel in the blood bound to plasma proteins, especially albumin  low plasma proteins can increase bioavailability because more of drug circulates in unbound form therefore bioavailability greater may be a problem in the elderly and emaciated

7. Elimination Elimination - involves two key processes – metabolism and excretion Most drugs are modified by the liver enzymes and the metabolites usually excreted by kidneys, although all body fluids can eliminate drugs. Metabolism reactions take place predominantly in the liver and chemically change the drug to enhance its excretion – e.g. glycosylation, Some drugs are excreted via the bile duct into the gut, including antibacterials such as ciprofloxacin etc.

9. 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.

10. First - pass metabolism Cytochrome P450 (microsomal) enzymes are a large family of enzymes found in the liver that are part of the body’s defence mechanism against toxic substances The body treats drugs as foreign, potentially toxic substances Microsomal enzymes change drugs by biochemical reactions. Drugs are made more soluble to aid excretion by the kidneys

11. 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. There is also genetic variation in the population so there are individual differences in the metabolising of drugs 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

12. 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 pro-drugs and include enalapril (an ACE inhibitor), clopidogrel and aspirin. (many other drugs are inactive until activated in the tissues or cells) 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

13. Drug Interactions – P450 inhibitors P450 enzymes metabolise drugs, allowing their elimination by the kidneys Some drugs can inhibit enzymes that eliminate drugs This slows the rate of elimination resulting in increased plasma levels

14. Interactions

15. Drug Interactions – P450 inducers P450 enzymes metabolise drugs in Phase 1 reactions, allowing their elimination by the kidneys Some drugs induce P450 enzymes, speeding the rate of elimination of other drugs

16. Interactions

17. 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. 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. Concurrent use of similar drugs can cause additive effects e.g. aspirin and warfarin Drugs that affect gut motility can affect absorption of other drugs

18. 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.

19. Interactions Certain foods can affect hepatic metabolism Grapefruit juice contains flavonoids and psoralen derivatives that inhibit CYP3A enzymes (in the gut) that normally have significant pre-systemic metabolic activity Grapefruit juice blocks CYP3A* and so absorption of certain drugs is unopposed The plasma concentration of drugs such as calcium channel blockers (verapamil etc.), simvastatin, ciclosporin, ivabradine etc. is increased. Many others - see BNF, Appendix 01 for full details. *Generally has less effect on CYP34A enzymes in liver at normal consumption levels

20. Unwanted side-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.

21. Unwanted side-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. Type B reactions (B = bizarre) are unpredictable and often immune reactions, individual hypersensitivity

22. 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 effectively increase their half-life.

23. General factors affecting absorption, distribution & elimination - Age The Elderly Absorption: Changes in drug absorption tend to be clinically inconsequential. Distribution: Serum albumin decreases so in a patient with malnutrition, this may enhance drug effects because serum concentrations of unbound drug are increased.

24. 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% so drug levels increase. However, the rate of drug metabolism can vary greatly from person to person. The renal mass and renal blood flow decreases significantly in the elderly, decreasing renal drug elimination so drug levels increase. Liver and renal disease reduces rate of elimination

25. 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… the rate of absorption 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) Except when parenteral, administration can be episodic

26. Maintaining drug levels in the body

27. 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

28. 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.

29. 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 (T½), the time by 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….

30. Half –life of drugs

31. 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. T½ for drug A is around 2½ hours T½ for drug B is over 5 hours. If 100 microgrammes / 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.

32. End of Presentation