Pharmacokinetics Flashcards
Define pharmacokinetics
The measurement and formal interpretation of changes with time of drug concentrations in one or more different regions of the body in relation to dosing
Pharmacokinetics describes what the body does to the drug. This encompasses its abdorption, distribution, metabolism and elimination
Understanding PK profiles of drugs allows us to:
Develop drugs Decide on appropriate dosages Determine dosing regimens Interpret drug interactions Adjust doses according to response
Define clearance
Clearance is expressed as volume over time, eg mL/min
It is defined as the **volume of blood cleared irreversibly of drug, per unit of time
Pharmacokinetic parameter that describes drug elimination
Important for maintenance dosing
Volume of plasma which contains the total amount of drug removed from the body in unit of time
Drug clearance can be determined in an individual patient by measuring plasma concentration of drug until steady state is achieved
Renal Clearance
Net effect of:
Glomerular filtration Active secretion and Passive reabsorption
Only unbound drug is filtered at the glomerulus
Glomerular filtration rate is assumed to be 7.2L/hour for a healthy adult
Describe the volume of distribution
Vd is expressed as volume e.g. mL
It represents teh voleume in whcich the amount of drug in the body would need to be uniformly distributed to produce the observed concentrations in the blood.
It is not a real volume
Indicates accumulation of drugs in tissue compartments
- A drug with a low Vd is mostly water soluble and will stay predominantly in the plasma (ie would not distribute into other sites like adipose tissue)
- A drug with a large Vd is more likley to move outside of the circulation and bind to other sites (like adipose tissue).
*The larger the Vd the more widespread the drug is within the body
Define half-life
Half-life is expressed as time e.g. hours.
Is calculated as 0.693* Vd / Cl*
It is defined as the time taken for blood/plasma drug conentration to fall by one half
Half life will not change with variations in dose for drugs that follow ‘first-order’ kinetics
Can be used to determine the duration of action of a drug after a single dose
It takes 3-5 half-lives to reach steady state (with constant dosing)
Describe the area under the curve
It represents the constant plasma conecntration i.e. - when rate of drug administration is equal to rate of drug elimination.
It is expressed as concentration and time
Describe steady state (Css)
Css is expressed as concentration or mg/L.
It describes the concentration of drug in systemic circulation as a function of time post dose
Describe zero-order kinetics
Elimination rate does not increase in proportion to dose and concentration
Describe first order kinetics
Constant proportion of drug is eliminated per unit of time
Describe the loading dose
It is defined as the inital amount of drug required to reach the target concentration.
It is calculated using Vd.
Loading dose = Vd x target peak concentration or Cp
Describe maximum concentration or Cmax
it is the maximum concentration of the drug, following administration
Describe the time to maximum concentration or Tmax
The time taken to reach Cmax
Describe maintenance dose
Dose required to maintain target plasma concentration at steady state.
It is calculated by multiplting steady state conecentratuon by clearnace. Expressed as mg
List routes of administration
- oral or rectal
- percutaneous
- intravemous
- inhalation
- intrathecal
- IV
- IM
End up in plasma.
If oral –> gut –> plasma but also liver (kidney, urine elimination) - feces direct elimination
IV–> plasma-> breast and seat glands
other routes can end up metabolising drug e.g. IT/CSF end up in plamsa, metabolised by liver etc
Describe absorption, mechanisms of absorption, and variables that affect absorption
Before a drug can be distributed to its site of action it must be absorbed
Drugs need to be able to cross biological membrane(s) to reach systemic circulation.
Lipid soluble drugs readily pass through lipid membranes Ionised drugs have difficulty crossing cell membranes Aquaporins in cell membranes allow the passage of small uncharged water soluble substances
Passive diffusion and carrier-mediated transport allow movement of drugs through the body
Passive diffusion - molecules travel down concentration gradient. This is the most common form of transport and is influenced by: surface area of membrane exposed to drug, concentration gradient of drug, lipophilicity of drug, ionisation state of drug
Carrier-mediated transport - Requires the involvement of membrane protein for the movement of a drug across a biological membrane. Can be ACTIVE (requires energy) or FACILITATED (not requiring energy)
Active transport: Permits movement of a compound against a concentration gradient or electrochemical gradient.
Variables:
Blood flow
Rich blood supply enhances absorption
Solubility
A drug must be in solution to be absorbed
Ionisation
Many drugs are weak acids or bases
Ionised form does not diffuse readily through cell membranes; unionised form is usually more lipid soluble and more capable of crossing cell membranes (Extent of ionisation is dependent on the pH of the environment)
Formulation
Drug formulations can be manipulated to achieve desirable absorption characteristics (eg slow release or enteric formulations)
Route of administration can affect both onset and magnitude of drug action.
A drug can enter systemic circulation by being injected there (IV) or absorbed from extravascular sites
Describe oral absorptio
Most common route of admin for drugs
Safe, convenient and economical
Can be absorbed from the
Oral cavity (sublingual or buccal administration)
Stomach (noting the high pH in this environment)
Small intestine (major site of absorption of orally administered drugs and pH is close to neutral)
Rectal (can be used for local or systemic effects)
Parenteral administration
Parenteral (drugs administered via injection):
Intravenous (IV)
Most rapid way of administering a medication (bioavailability is 100% because entire dose enters the systemic circulation directly)
Subcutaneous (Subcut)
Given beneath the skin into connective tissue or fat immediately underlying the dermis
Intramuscular (IM)
Injection of drug into the muscle (erratic absorption)
Intrathecal (IT)
Drugs administered directly into the spinal subarachnoid space (bypasses blood-brain-barrier)
Epidural
Injection of drug into the spinal canal or outside the dura mater that surrounds the spinal column
Describe distribution
The process of reversible transfer of a drug between one location and another (one is usually blood) in the body. After a drug enters systemic circulation it can be distributed to various compartments of the body.
Some drugs remain exclusively in the blood
Distribution will depend on
Permeability across tissue barriers Binding within the compartments pH partitioning Fat:water partitioning
Describe factors that affect passage across capillaries
Depends on molecue
size lipid solubility protein binding
Types of capillaries
Continuous
Only allow diffusion of water and small solutes through intercellular clefts
e.g. skeletal and smooth muscle, connective tissues, lungs
Fenestrated
More permeable than continuous capillaries, allowing rapid exchange of fluid and solutes as large as small peptides
e.g. kidneys, villi of small intestine, choroid plexus
Sinusoids
Wider and more winding than other capillaries with incomplete basement membrane, large fenestrations, very large clefts. Allow large proteins to pass through
e.g. liver, spleen
Describe how drugs are distributed in adipose and other fluids/compartments
Adipose tissue
Lipid soluble drugs have a high affinity for adipose tissue (and a higher volume of distribution (Vd)
Prone to accumulation –> prolong half life of the drug
Low blood supply to adipose tissue .˙. drugs are delivered there at a slower rate
CNS
Blood brain barrier (BBB) protects the brain from molecules entering (despite high blood-flow)
Allows passage of lipid soluble drugs and small (<400Da) molecules Becomes more permeable when inflamed (eg meningitis) allowing passage in
Foetus
Placental barrier
Separates blood vessels of mother and fetus to work as a protective barrier Allows passage of lipid soluble drugs and small (<500Da) molecules
Breast milk
Almost all drugs pass into breast milk
Most drugs pass into breastmilk via passive diffusionhe concentration of drug in the milk is determined by the Milk to Plasma ratio (M/P ratio)
Milk is more lipid, less protein and slightly more acidic than plasma, therefore, drugs which tend to concentrate in milk:
are weak bases have low plasma protein binding are highly lipid soluble
Describe metabolism and its key components
Metabolism
The process of the chemical modification of a drug
Mainly via enzymes
Liver primary site of metabolism
Other sites include:
Kidneys
Lungs
Intestines
Prodrugs: Drugs that require chemical modification to be activated in order to elicit a therapeutic action (often happens in the liver)
Describe the four fates of drugs
Most drugs are metabolised into more water soluble compounds that can be excreted.
Drugs can be:
1. Excreted unchanged 2. Undergo functionalisation (phase I reactions- can be oxidation, hydroxylation, demaination, hydrolysis; dominated by CYP450, hepatocytes, manuy drugs, many DDIs) and be directly excreted 3. Undergo conjugation (Phase II reactions) and be directly excreted -- to makes more polar/inserts suitable functional group, increase solubility 4. Undergo functionalisation then conjugation prior to excretion
Distinguish between single and multi-compartment models
Single compartment model
Simplified model of a human being
The body is a single compartment in which the drug is distributed
Vd : Links the total amount of drug in the body to plasma concentration
Clearance can be described by half-life
After one T1/2 the concentration of drug in plasma will ↓ to half its initial concentration After two T1/2 the concentration will ↓ to a quarter of initial concentration After three T1/2 the concentration will ↓ to an eighth of the initial concentration The longer the T1/2 of a drug the longer the drug will stay in the body after dosing is discontinued Steady state is achieved after 3-5 x T1/2 of the drug
If the T1/2 means the steady state is not reached soon enough for therapeutic intent then a loading dose may be given to speed up the process.
Size of a loading dose is determined by the Vd Two compartment: Drugs can enter and leave a peripheral compartment only through a central compartment
Describe consequences of zero ordr kinetsics
Consequences of zero-order (saturation) kinetics:
Duration of action strongly dependent on dose
Relationship between dose and steady state is unpredictable
Variations in metabolism can lead to disproportionate large changes in plasma concentration
cl and half life are no longer constant
Define bioavailability
The proportion of administered dose that reaches systemic circulation intact (expressed as a fraction of total dose)
Drug crosses membranes of GIT –> portal vein –> liver
May be metabolised May pass through the liver intact
Describe first-pass metabolism
Extraction and metabolism of orally ingested drugs (by the liver and sometimes gut wall) before they can reach the systemic circulation.
If a percentage of the drug is metabolised by the liver only the remainder of that drug will be able to enter systemic circulation to exert its effect
Variations between individuals
Describe bio-equivalence
Refers to two formulations of the same drug containing an identical concentration of the active ingredient in the same form and administered by the same route
Once a patent expires on a drug other companies can produce generic equivalents of the original drug
Generics must be tested against the original project to determine its relative exposure
To be considered bioequivalent the new (generic) drug must respond within a 20% variance of the original formulation AND have no clinically important differences between their therapeutic or adverse effects
List some special populations where pharmacokinetics of drugs are altered
- pregnancy
- breastfeeding
- children
