Introduction to pharmacokinetics Flashcards
Pharmacokinetics
The branch of pharmacology dedicated to determining the fate of chemical substances administered to a living organism- ‘what the body does to a drug’.
4 stages of drug disposition
- absorption
- distribution
- metabolism
- excretion
ADME
Pharmacokinetic data
Maps drug concentration over time. Plasma concentration of a drug is often used, as it reflects the concentration of the drug in extracellular fluid, where receptors/other targets are present. Drug concentrations in other body fluids (eg. urine, saliva, cerebrospinal fluid, milk) may also add useful information.
Routes of administration
- enteral; oral, rectal
- parenteral; subcutaneous, intravenous, intramuscular, intraarterial, intrathecal, intraperitoneal, intravitreal
- percutaneous; inhalation, sublingual, topical/transdermal
Absorption
Movement of a drug from its site of administration to the plasma.
Factors affecting absorption
- site of administration; blood flow, surface area
- dose of drug
- drug solubility; hydrophilic/lipophilic
- pharmaceutical interventions; slow release capsules, dry powder inhalers
Distribution
Reversible transfer of a drug from one location to another within the body.
Factors affecting distribution
- blood flow
- lipid solubility
- diffusion barriers; blood brain barrier and placenta
- tissue binding
- plasma protein binding; albumin most common
Albumin
A lipophilic protein with many binding sites. Drug binding establishes an additional equilibrium of the drug within the plasma, retaining higher concentrations in the blood.
The one-component model
Treats the human body as a single vessel, measuring blood plasma concentration against time as a basic model of how much of a drug goes in vs how much goes out.
Pharmacokinetic features of the human body
- fat (lipophilic) or no fat (hydrophilic)
- plasma membranes
- pH value
- active perfusion/pumping
- large SA or compact shape
- diffusion barriers
- inactivating enzymes
Apparent volume of distribution
The theoretical volume of fluid required to dilute the absorbed dose to the concentration found in plasma.
AVD=dose/plasma concentration
Drugs that are heavily tissue bound or basic have a large AVD, whereas drugs that are heavily protein bound or acidic have a small AVD.
Two-component model
Considers more complex mechanisms of drug disposition, like drug reservoirs and re-absorption.
Modes of transport
- passive diffusion; through cells or intracellular pores
- facilitated diffusion
- active transport
- pinocytosis
Lipid solubility
Lipophilicity determines whether a compound can pass through phospholipid cell membranes.
Ionisation
Many drugs are weak acids or bases, whose degree of ionisation depends on local pH. They exist in an equilibrium between ionised and unionised forms. Only the unionised form is lipophilic enough to diffuse through membranes.
Ion trapping
Drugs will tend to accumulate where ionisation is favoured, as the ions cannot be absorbed through membranes.
Elimination
The irreversible loss of drug from the body, resulting from metabolism and excretion.
Routes of excretion
- the kidneys
- the liver
- the lungs
- the salivary glands
- the mammary glands
- sweat glands
Renal excretion
Low molecular weight substances (ie. most free drugs) are removed from the blood through glomerular filtration and tubular secretion. If the renal tubule is freely permeable to certain drugs, some will be passively reabsorbed, reducing the amount excreted.
Biliary excretion
Liver cells transport various substances, including drugs, from plasma to bile. Some drugs are excreted fairly unchanged in bile, ending up in the faeces, while others have to undergo modification to prevent re-absorption.
Enterohepatic circulation
Various hydrophilic drug conjugates (particularly glucuronides) are delivered in bile to the intestine, where they can be hydrolysed, activating the free drug, which can be reabsorbed. The cycle can then be repeated when the drug is returned to the liver, known as enterohepatic circulation.
Phase I reactions
Involve ‘functionalisation’ of the drug via catabolic reactions (eg. oxidation, reduction, hydrolysis), which attach a functional group (eg. hydroxyl). Oxidation reactions mainly take place on the monooxygenase system, involving cytochrome P450 enzymes found in the liver. The products are more hydrophilic and often more reactive, and therefore can be more toxic/carcinogenic than the parent drug.
Phase II reactions
Involve ‘conjugation’ of the intermediate molecule via anabolic reactions, attaching a conjugate group (eg. sulfate, glucuronyl, methyl, acetyl) to the functional ‘hook’. This usually renders the drug less reactive, and even more hydrophilic, so it can be excreted.
Acid dissociation constant
pKa values are a quantitative expression of the strength of an acid or base.
Ka=(H+)(A-)/(HA)
pKa=-log(Ka)
The smaller the pKa value, the stronger the acid/base.
Cytochrome P450 enzymes (CYP)
A superfamily of enzymes, found primarily as part of the monooxygenase system in the liver. They are involved in biotransformation phase I reactions during the metabolism of potentially toxic compounds, eg. drugs.
