Clinical Kinetics Flashcards
What is the most common route where a drug can act
- oral administraiton is the most commonly used route
When is the gut the site of action
- Erythromycin as a prokinetic agent
- vancomycin for clostridium difficile infection
- neomycin for gut decontamination
What are the enteral realted routes
- oral route
- rectal route
what is the downside of the rectal route
- rectal mucosa is vascular, absoprtion is inconsistent and may by pass the portal circulation
What routes allow the drug to be absrobed directly intot he systemic circulation
- buccal
- sublingual
- intranasal routes
What is a buccal route
- drug is held next to the cheek
what is an example of a drug that uses the buccal route
- midazolam for sedation in children
What is an example of a drug that uses a sublingual route
- sublingual glyceryl trinitrates to relieve anginal pain
What drugs use the inhalational route
- used for anaesthetic gases
- pulmonary vasodilators (nitric oxide)
- bronchodilators (salbutamol)
What does parenteral mean
- bypasses the gut
describe when you can use a drug by parenteral administration
- your patient is unable to take drugs orally as they are vomiting
- rapid onset of action is required (anaesthetic induction)
- the drug is not available as an oral formulation (adrenaline, insulin)
What are the two ways to deliver a drug Intravenously
- bolus - single dose
- infusion - over a defined peroid of time
What is the dowside of giving a drug via the intramuscular route
- has to be absorbed from the muscle into the systemic circulation and this can be slow and inconsistent
Describe giving drugs through subcutaneous administration
- involves direct injection of a drug into the fatty tissue beneath the skin
- allows a drug reseroir effect with slow release
- absorption can be inconsistent
What is topical application useful for
- Skin conditions such as antifungal or corticosteroid cream
- local anaesthetic e.g. lidocaine wiht prilocaine as an EMLA cream
- systemic absorption of drugs to act as a slow release prearation (e.g. nicotine patch for smoking cessation)
What is bioavailability
- this is the extent to which a drug reaches the systemic circulation where it is available to act at the effector site
what way to administer the drug results in 100% bioavailability
- if the drug was given intravenously
What factors that effect bioavailability
- route of administration
- properties of the drug
- plasma protien binding
- metabolism
- elimination
Describe the factors that effect bioavailability of drugs
Route of administration
- a drug given orally has to be asborbed in the gut before reaching the systemic circulation
Properties of the drug
- a highly lipid soluble drug will be absorbed better
Plasma protien binding
- highly protein bound drugs have less free drug to act at the receptor site
Metabolism
- drugs absorbed by the gut pass through the liver via the portal circulation where they are metabolised
Elimination
- a drug eliminated through the kidneys will accumulate in renal dysfunction
What happens when you give a drug as an IV bolus
- its plasma concentration rises to a peak almost at once before falling
- fall is due to the uptake of the drug into tissues, metabolism and elimination from the body
What ahppens when a drug is given enterally
- its plasma concentration will still rise but more slowly as absorption from the gut takes time
What are the key pharmacokinetic parameters that describe bioavailability
- Area under the curve (AUC)
- Peak plasma concentration (Cmax)
- time to peak plasam concentration (Tmax)
What is a steady state concentration
- When the inflow rate is less than rate of outflow
- this causes the plasma concentration to begin to fall
What is the half life
- the time for plasma concentration to fall by half is called the half life (T1/2) of the drug
- for most drugs the fall is related to elimination from the body and so it is called the elimination half life
What is the primary location for drug absorption
- Small intestine which is the primary location for drug absorption
Where are acidic and basic drugs better absorbed in
- acidic drugs - better absorbed in the stomach
- basic drugs - better absorbed in the small intestine
Give examples of concomitant drug administration
- erythromycin inhibits warfarin metabolism
- phenytoin increases metabolism of other antiepileptics
- rifampicin increases the metabolism of oestrogen in the oral contraceptive pill
What do formulation coatings do
- these are designed to protect the drug from degradation along the GI tract or utilise these changes to control the rate of delivery and absorption of drug into the systemic circulation
give examples of formulation coatings
- enteric coatings
- modified release (MR) coatings
What can alter a drug formulation and thus alter its pharmacokinetics
- altering a drug formulation through crushing and splitting can markedly alter its pharmacokinetics
- this can lead to an unexpected clinical response associated with toxicity or limited clinical response
What drugs should not be crushed
- drugs formulated as modified release (nifedipine) or enteric coated (aspirin)
- as well as potentially altering the pharmacokinetic profile of a drug crushed formualtions may taste bad (ibuprofen) and can affect the skin of staff handling them (hydroxycarbamide)
What can first metabolism do
- pre-systemic metabolism of oral drugs can significnatly reduce drug bioavailability
- some pro-drugs are converted to pharmacologically active forms by first pass metabolism
Give examples of pro drugs
- Codeine
- azathioprine = mercaptopurine
- Enalapril = enalaprilat
- cyclophosphamide = phosphoramide mustard
What is the volume of distribution
- also known as apparaent volume of distribution
- defined as the theoretical volume of fluid that would be needed to achieve the actual plasma drug concentraiton
What is the volume of distribution ratio
Vd = total amount of drug in the body/ plasma drug concentration
What is the units for volume of distribution
- ml or L/Kg body weight
What is a volume of distirbution a reflection of
- it is a reflection of how a drug will distirbute in the body
What is the volume of distribution dependent on
- physiochemical properties of the drug - solubility, charge, size
What drugs have a higher and low Volume Distribution
- Drugs which are highly water soluble (gentamicin, atenolol and insulin_ or extensively protein bound( e.g. warfarin) have a relatively low Vd since they stay in the plasma
- Drugs which are highly lipid soluble (e.g. digoxin, morphine, and diazepam) have a larger volume distribution since these drugs go out of plasma into tissues and organs
describe how being a child effects volume distribution
- children have a higher percetnage of total body water than adults
- water soluble drugs will have a higher Vd therefore they require higher doses on a miligram per kilogram basis of body weight to acheive similar plasma concentrations to adults
- lipid soluble drugs in children will have a lower Vd
describe how being an older adults and dehydrated patients effect volume distribution
- water soluble drugs will have a lower Vd
- lipid soluble drugs will have a higher Vd = this can lead to an increase in the elimination half-life and a prolonged effect, therefore a reduced dose may be required
Describe how pregnancy and oedema effect volume distribution
- in pregnancy and oedema there is an increase in total body water
- water soluble drugs will have a higher volume distribution leading to lower plasma concentrations
- therefore higher doses may be needed for a given therapeutic effect
What are the two body organ groups
- Vascular or central compartment (lungs, kidney, muscle)
- less vascular or peripheral compartment (fat)
describe how drugs diffuse into body organ groups
- When a drug enters the blood it starts to distribute into all perfused areas
- since fat is less vascular a smaller proportion of drug enters this peripheral compartment
- but if you cotninue to give a drug over a peroid of time there is time to diffuse into fat which takes up a larger quantity of the drug due to its larger mass
- when you stop giving the drug the concentration gradinet is reversed and the drug starts going into the blood from the fat therby maintaining serum concentrations
- fat acts as a reservoir of drug with slow release
what drugs can cross biological membranes
- only unbound or free drugs can cross biological membranes and elicit a clinical response
drugs are not metabolised when..
they are protein bound
describe how protein bound drugs can act as reservoirs
- for example warfarin is 97% protein bound and the reamining 3% is active
- if another drug such as the sulphonamide component of co-trimoxazole was to displace warfarin from its plasma protien the risk adverse effects and toxicity will transiently increase
what can alter plasma protien concentration
- disease states
- pregnancy
- malnutrition
What is an elimination half life
- a measure of the time taken for the plasma concentration of a drug to fall by 50%
how many half lifes does it take for most of the drug to be eliminated
5 half lives for 97% of the drug to be eliminated
what can half life be determined from
- half life can be determined from a plasma concentration time profile
What is first order elimination
- this is when half life is independent of drug concentration
what is steady state
- this is when a drug has first order elimination and is given in repeated doses then at a certain point in therapy the amount of drug administered during a dosing interval exactly replaces the amount of drug eliminated
- when this equilibrium occurs a steady state is reached
What is zero order elimination
- when the enzyme is saturated only a fixed amount per hour is removed from the body
How is drugs eliminated from the liver
- hepatic clearance
- renal clearance
What is the clearance of a drug
- this is the hypothetical volume of blood from which the drug is completely removed per unit time
- expressed as units of volume per unit time
why is clearance not an indciator of how much drug is being removed
- because clearance is a first order process, the amount of drug removed depends on the concentration
name the sum of total body clearance
CL=CLh +CLr
- total body clearance is the sum of the individual clearances for each elimination tissue or organ (renal and hepatic)
What can the liver or kidney damage result in
- affects the removal of drugs from the body and results in drug accumulation
What are the three parameters that define the pharacokinetics of a drug in the body
- volume of distribution (Vd)
- elimination half life (t1/2)
- clearance (CL)
what is the elimination rate constant (K)
- K= Cl/Vd
- the greater the fraction of drug removed in unit time the shorter the half life, thereofre half life varies inversely with elimination rate cnstant
What causes the volume distirbution to be changed
- Alterations in plasma protein concentrations
- hepatic disease
- changes in patient physiology
In the liver what metabolises drugs
- cytochrome P450 family of enzymes
what does the drug metabolism in the liver occur in
two phases
What does drug metabolism in the liver depend on
- liver function (presence of cytochrome P450 enzyme)
- hepatic blood flow - can be decreased in shock and GI surgery affecting the amount of drug presented to the liver
a drug that induces the P450 enzyme system can
e. g. phenytoin
- a drug that induces the P450 enzyme system can accelerate the metabolism of concomitant drugs
- conversely an inhibitor of P450 such as erythromycin can slow down the metabolism of other drugs
Why can some people metabolise drugs faster
- genetic variations of P450
What happens if renal function is impaired
- if renal function is impaired the metabolites accumulate and may cause problems
- this can cause the prolonging of half life
How do you assess the degree of renal impairment
- calculate creatine clearance to assess the degree of renal impairment
What drugs is therapeutic drug monitoring necessary for
- necessary for drugs that have a narrow therapeutic window where there is a potential for toxicity with small dose adjustments
What can TDM also be useful to assess
- the nature of treatmetn following an intentional drug overdose
What should you only carry out TDM for
- to ensure that the patient is receiving an effective therapeutic dose for clinical treatment and there is no risk of drug associated toxicity
