Some readers may be put off by the slightly mathematical nature of the initial section on clinical pharmacokinetics. Any feedback would be appreciated, especially in terms of improving the user-friendliness of the book.
Pharmacokinetics
Under steady-state conditions, the plasma concentration (Cp) is in equilibrium with the sites of action. AUC Area under the curve Cpo Plasma concentration at time =o F Partial oral availability Cpss Steady-state plasma concentration fu fraction excreted unchanged Amount of Ab in body.
Drug Clearance
Plasma Cl is usually determined from the area under the plasma concentration vs time curve (AUC) after IV administration. Calculation of loading dose (LD) It follows from the above that to achieve a target Cp, the Vd of the drug must be known.
Volume of Distribution
If the Cp at time zero (Cpo) is known, the Vd can be calculated. Time Course of Drug Accumulation If a drug is started as a constant infusion, Cp will accumulate to approach steady state (>90% of steady state concentration) after four half-lives.
The Half-Life
This refers to the drug's ability to cross a biological barrier into the blood. However, food usually increases the oral availability of drugs that are subject to high first-pass metabolism.
Oral Availability
Effect of food on oral availability Interestingly, food affects absorption and first-pass metabolism in opposite ways. Food usually reduces the oral availability of poorly lipid-soluble drugs that are subject to absorptive problems, e.g.
Protein Binding
While drugs may compete for protein binding sites, particularly on albumin, this does not affect the free concentration. Protein binding 'problems' arise as a result of the measured drug concentration being total drug (bound + unbound).
Similarly, weak bases with pKa values between 5 and 11 may show changes in the unionized/ionized ratio. Reabsorption from the renal tubular lumen into the blood will occur if the drug is in the unionized state.
2 Factors affecting dosing
Drug Metabolism
2 High Blood Flow Increased blood flow in the liver, such as after food, delivers more drug to the metabolizing enzymes, sometimes saturating them. NB Below Km the elimination rate is almost directly proportional to the plasma concentration (i.e. RE ∝Cp.
Saturable Metabolism
Km (the Michaelis constant) is the concentration at which half of the maximum reaction rate occurs. Phenytoin has a Km of about 7 mg/L and therefore saturates at or around the lower end of the therapeutic range (10-20 mg/L).
Pharmacogenetics
Absolute and partial DPD deficiency occur in approximately 0.1–3% of Caucasians, and excessive toxicity may be seen in these patients. Liver diseases that decrease drug metabolism include: cirrhosis (any cause), alcoholic liver disease, viral hepatitis (may increase or decrease metabolism), porphyria, and hepatoma.
Dosing in Liver Disease and Other Disease States
Dosing in Cardiovascular Disease The main caution is with high-clearance, flow-dependent drugs (see table). 1 reduce dose by 50% for drugs with high clearance (both affected by blood flow and enzyme capacity).
Renal Drug Elimination
Drug clearance and renal function For drugs that are excreted entirely via the kidneys, drug clearance varies in relation to creatinine clearance (CrCl). For these drugs, doses should be reduced in direct proportion to the degree of CrCl deterioration.
Dosing in Renal Impairment
Dosing in the Elderly
Homeostatic adaptation is less efficient and target organ sensitivity may be altered in the elderly. It is especially useful in the elderly to follow all the rules to improve compliance.
Dosing in Children
Absorption of some compounds in the skin may be increased due to a thinner stratum corneum and a higher degree of skin hydration. At delivery, excess effects (eg, tricyclics) and withdrawal syndromes (eg, opiates, selective serotonin reuptake inhibitors [SSRIs]) may be seen in neonates following maternal use.
Drugs in Pregnancy
The FDA classifies drugs (see below), in ascending order of potential toxicity. b) Pharmacological risks: These are risks that are generally predictable based on the known pharmacology of the drug, e.g. 1 Avoid all drugs, including social drugs (e.g. smoking, alcohol, caffeine) if possible. 2 Avoid drugs in the first trimester.
Drugs in Human Milk
Breastfeeding during maternal intake of even small amounts of some highly toxic agents (eg antineoplastic agents) is unlikely. sensible even if the likely concentration in the baby is low. 2Weigh the risk/benefit ratio 3Be more careful with toxic substances 4Feed baby just before the next dose 5Alternate breastfeeding with bottle feeding to reduce possible exposure.
3 Altered drug effect
Pharmacodynamic mechanisms: Some patients experience a type A ADR at a normal concentration, while others do not, reflecting natural variation. Similarly, underlying disease can shift the concentration-response curve to favor an ADR at a normal concentration, e.g.
Adverse Drug Reactions
These are less common, less predictable, can be severe and result from different mechanisms. Serum sickness (urticaria, arthralgia, lymphadenopathy, and fever), is a classic presentation (eg, serum sickness due to sulfonamides or penicillins).
Drug-Induced Allergy
The drug changes a protein in the body so that the protein is no longer recognized as May be due to the drug itself, a metabolite or an excipient in the formulation.
Adverse Drug Events
Patient Information: Clinical information, laboratory test results, drug history and allergies, current medications and dosages should be available and known at the time of drug use. A computerized prescription system linked to drug and patient information databases can solve many of the above problems.
Preventing Adverse Drug Events
The effect of enzyme induction is to increase first-pass metabolism, increase clearance, decrease t1/2, and decrease mean steady-state concentrations.
Drug/Drug Interactions
Enzyme inhibition causes less first-pass metabolism, decreased clearance, longer t1/2, and higher mean steady-state concentrations. Some inhibitions are so profound that average steady-state concentrations increase more than 10-fold, e.g.
Inducers of Drug Metabolism
Inhibitors of Drug Metabolism
Drug/Food Interactions
4 Pharmacovigilance
Drug Development
These are large-scale, randomized, controlled (versus placebo or active comparator) clinical trials in the patient population for which the drug is intended, designed to convincingly demonstrate that the drug has the desired effect and is reasonably safe. Clinical evidence (Phase I, II and III) is evaluated to approve the drug to be marketed.
Therapeutic Drug Monitoring (TDM)
Drugs with pharmacokinetic problems and drugs with a weak dose-concentration relationship have a weak dose-effect relationship (eg non-linear kinetics of phenytoin). A low concentration (ie just before the next dose) is the usual measure of drug accumulation.
Drugs Involved in Therapeutic Drug
Overdose/Poisoning
Hemodialysis: This may be useful in severe poisonings with dialyzable drugs (low BP, small molecules) that have small Vd and significant increases in Cl, e.g. It may be more effective than hemodialysis and is not limited by high protein binding.
Common Poisonings
Characteristics of psychoactive drugs (i) Rapid delivery to the brain: The drugs are usually highly lipid soluble, well assimilated in the body and easily cross into the brain.
Pharmacological Aspects of Drug Dependence
The dose of the substituted drug is then tapered in a controlled manner. iv) Withdrawal symptoms: 'the urgent consequences of drug-induced neuroadaptation.'. Absence of drug results in a 'deficiency state' characterized by symptoms opposite to those induced by the drug itself, e.g. sedative withdrawals →agitation, seizures stimulating withdrawals →sedation,. depression The duration of the withdrawal syndrome is directly related to the drug's half-life.
5 Optimal therapeutics
These expressions can be more easily understood with graphs using the log of the concentration. From the shape of the concentration-effect curve, it can be seen that the law of diminishing returns applies.
Principles of Drug Action
NB: C, rather than Cp, is used for the concentrations as it is the concentration at the site of activity (the biophase). However, if the biophase is somewhere outside in the tissues, the concentration in that peripheral compartment is relevant, and not the Cp.
Applied Pharmacology
Cl, the determinant of maintenance dose, may change with age, disease states, other medications, genetics, or autoinduction. The therapeutic plan includes all of the above, but also takes into account therapeutic goals, monitoring and possible dose tapering.
Compliance with Medication
Compliance aids should be provided where appropriate. ii) The prescription (things you should think about). A less condescending approach by doctors who recognize that non-adherence should indeed be expected is likely to reap dividends.
Principles of Therapeutics
A medication card (locally called the 'yellow card') is a useful reminder to the patient about what medicines they are taking, when and why. They should be worn by the patient wherever possible, and certainly on every visit to medical, paramedical staff or hospital.
Patients and their Drugs
Information/devices to be given to appropriate patients at the time of discharge or at the end of an outpatient appointment. Patient Information Leaflets (PILs) There is increasing pressure, both medical and legal, on patients to receive simple, written information about their medicines that they can take with them and access in their own time.
The Drug Profile
Signs/Symptoms: Potentially dangerous in overdose — serotonin syndrome, especially in combination with other 5-HT enhancers (see list in interactions above). Blinding is usually "double-blind", meaning that both the patient and the observer do not know which patient is in which group.
Evidence-based Medicine
Cost-utility analysis (CUA): This is similar to CEA, but the alternative therapies are compared across multiple outcomes (e.g., effectiveness, morbidity, mortality). Direct costs: These include the actual cost of the medicines and everything associated with their delivery.
Pharmacoeconomics
These include specialist texts that cover very specific details in relevant areas of interest (eg drugs during pregnancy or lactation, drug interactions, adverse drug reactions). Analysis of our drug information service database reveals that most queries come from the following categories.
Drug Information/
Resources
Epocrates(Palm OS) www.epocrates.com Drdrugs(Win CE) www.skyscape.com Martindale a The Complete Drug Refer-.
6 Appendix
Important Equations in Pharmacology
The Pharmacokinetic Triangle
Glossary/Abbreviations
The concentration of a drug at which effect is 50% maximum
Pharmacokinetics: The study of the movement of drugs in, in and out of the body. Therapeutic range: The range of drug concentrations associated with a reasonable probability of efficacy without undue toxicity in most patients.
Test Questions
What practical dose of quinapril is required by an 80-year-old, 60-kg woman with a serum creatinine of 0.10 mmol/L. The usual dose for normal kidney function is 20 mg/day. If the maintenance dose of a drug for a 70 kg adult is 100 mg per day, what is the appropriate dose for a 15 kg child. i) Calculate the dose of medicine that the baby will receive. ii).
Test Answers
Index
