Pharmacokinetics and dynamics Flashcards by Leah Stevenart

What does ADME mean?

absorption, distribution, metabolism, excretion

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What do we use to measure drug conc and why?

Plasma - all drugs are in equilibrium in the plasma

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What are Cmax and Tmax

Cmax = the peak level of action of a drug
Tmax = the time at which drug action is at its peak

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Give an example of zero order drug kinetics

IV infusion - drug is instantly in plasma

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Give examples of routes of administration that show first order kinetics

IM/SC/oral

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What is Bioavailability (F)?

Measure of extent of absorption from administration site to measurement site (plasma)

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What factors affect bioavailability?

absorption
first-pass metabolism

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What is the distribution phase of drug kinetics?

Distribution around the body occurs after drug reaches circulation
To leave plasma it must pass the plasma membrane

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How do drugs leave the plasma

Only uncharged drugs can pass through membrane passively
Certain ionic compounds may go through as ion pair
Some pass through via active transport/carrier mediated transport

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What are the features of compounds that can rapidly cross plasma membranes?

Low degree of ionisation
High lipid/water partition in non-ionised form
Relatively low molecular weight (small molecules)
biological affinity with transporters/facilitated diffusion

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What is volume of distribution (Vd)

The volume into which a drug appears to be distributed with a concentration equal to that in plasma
A proportionality constant relating the blood/plasma concentration to the amount of drug in the body

Reversible process - drugs can leave and re-enter plasma

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What affects the volume of distribution?

the drugs reversible affinity for tissue proteins vs plasma protein

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What unit is Vd given in?

L/kg

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What are the values of total body water and ECF?

Body water ~ 0.6L/kg
Body ECF ~ 0.1-0.3L/kg

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Where does a drug with a Vd of 0.1-0.3L/kg accumulate?

most likely water soluble so mainly in ECF

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Where does a drug with a high Vd accumulate?

other sites, not ECF e.g., fentanyl in fat

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Give examples of barriers to drug distribution

Blood-brain barrier
Placenta - slows down, not complete barrier

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Describe the blood-brain barrier as a barrier to distribution

Multiple tight junction, transporter and efflux pump
Control entrance and expulsion of molecules
Prevents uptake of most drugs
However, if diseased barrier can become leaky
Similar with the testes

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Describe the placenta as a barrier to distribution

Trans-placental transfer of drug1: if a drug can be absorbed orally it likely to cross the placenta
Ion trapping of drugs in fetus (particularly basic drugs)

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What is the drug elimination rate?

The amount of parent drug eliminated from the body per unit time
Irreversible removal of parent drug (not metabolites)
Unit = mass or moles/t

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What are the main routes of drug elimination?

Kidneys
Hepatobiliary system
Lungs

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What are the secondary routes of drug eliminiation

milk
sweat

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How are drugs metabolised?

Liver converts lipophilic drugs into hydrophilic form (inactive) => excreted

What are CYP enzymes?

non-specific enzymes found in the liver that catabolise drugs
cause: oxidation, reduction, hydrolysis

What is the significance of UGTs (uridine diphosphate glucuronyl transferases)?

Cats are deficient in it -> Limited ability to perform glucuronidation, paracetamol toxicity

What factors affect the passive filtration of drugs in the glomerulus of the kidney?

GFR Plasma binding proteins

What factors affect the secretion of drugs from the proximal tubule of the kidney?

Affinity for transporters Lipophilicity Polarity

What factors affect the re-absorption of drugs in the distal tubule of the kidney?

lipophilicity and polarity Urine pH

What is drug clearance (CL)?

A measure of the efficiency of the body to clear a drug The volume of blood/plasma cleared of parent drug per unit time Unit = L/h/kg

What is the half life of a drug?

The time it takes for the plasma conc of a drug to halve Always the same if the drug experiences first order kinetics

What is polypharmacy?

When multiple drugs are taken simultaneously

What are drug-drug interactions?

Altered pharmacologic response to one drug caused by the presence of a second drug

What types of drug0drug interactions are there?

Pharmaceutical: interaction prior to administration Pharmacokinetic: tissue/plasma levels of one drug altered by another one Pharmacodynamic: action of one drug is altered by another one

What are the possible outcomes of drug-drug interactions?

Summation Potentiation Synergism

What is potentiation in drug-drug interactions?

When a drug on its own does not have an effect but may affect/be affected in combination with another drug

What is summation in drug-drug interactions?

combined effect of two drugs produces a result that equals the sum of the individual effects of each agent

What is synergism in drug-drug interactions?

Drug combinations produce a therapeutic or toxic effect greater than sum of each drug’s action

Give an example of summation in drug-drug interactions

e.g. midazolam lowers the dose of propofol needed for anaesthesia

Give an example of potentiation in drug-drug interaction

e.g. probenecid reduces penicillin excretion in urine and increases effectiveness of penicillin

Give examples of synergism in drug-drug interactions

e.g. sulphonamide-trimethoprim (enhanced effects) Toxicity: aminoglycosides and furosemide

What are the pharmaceutical mechanisms on drug-drug interactions?

Physical Chemical

Describe physical drug-drug interactions

Incompatibility / interaction: - Binding to plastic: Some drugs can adsorb (stick) to plastic materials, such as IV tubing or syringes. This can reduce the actual dose the patient (or animal) receives. - Insolubility in certain solutions: Some drugs do not dissolve well in specific solvents or IV fluids. This can cause precipitation, leading to blockage in IV lines or reduced drug absorption.

Describe the chemical interaction of drugs

Stability of drugs is often pH dependent Oxidation/reduction reactions Complex formation eg chelation of drugs Inactivated by certain vehicles

What are the pharmacokinetic mechanisms of drug-drug interactions?

absorption distribution metabolism excretion

Give examples of absorption as a mechanism of drug-drug interactions

Change in gastric pH and bacterial flora Chelation of drug in stomach Altered gastric emptying: can increase or decrease absorption Interference with intestinal efflux protein (P-glycoprotein)

Give examples of distribution as a mechanism of drug-drug interactions

Competition plasma protein binding Some drugs reduce blood flow to organs, leading to a) reduced absorption from intra-muscular or sub-cutaneous administration or b) reduced clearance

Give examples of metabolism as a mechanism of drug-drug interactions

Inhibition or induction of liver enzymes (CYP P450) leading to decreased or increase drug clearance.

Give examples of excretion as mechanism for drug-drug interactions

Urinary pH will alter clearance of renally excreted drugs i.e. more alkaline will increase excretion of weak acids

Give examples of drug that inhibit CYP P450 metabolism

Chloramphenicol fluoroquinolones, cimetidine azole anti-fungals calcium channel blocker, omeprazole propofol

Give examples of drug that induce CYP P450 metabolism

Barbiturates (eg phenobartibal, primidone) cyclosporin carbamazepine

What are the pharmacodynamic mechanisms of drug-drug interactions?

additive synergistic negation

Describe additive interaction of drugs

can be beneficial or detrimental Enables reduced doses to be administered Can lead to increased toxicity

Describe negation as a mechanism for drug-drug interactions

Opposing action leading to reduced effect

What are adverse events (ADE)?

Unintended or noxious response to a drug that occurs within a reasonable time frame following administration

What are the common 'use-patterns' associated with increased ADE?

Use of human-label drugs Drugs with low therapeutic indices (more likely to have non-specific effects) Inappropriate use Lack of therapeutic goals Multiple drugs altered pharmacokinetics (young, old, lactating, pregnant etc.)

what are the types of adverse events?

lack of expected efficacy unexpected adverse event e.g., exaggerated normal response Serious adverse event (life-threatening, permanent or prolonged) e.g., hypersensitivity - often idiosyncratic