ADME Flashcards
Why is the ADME of a drug important to know
Important to know if a drug is going to be absorbed if given by a particular route - insulin cannot be given orally as it won’t be absorbed
to estimate accurate plasma concentrations (Cp) of drug as a function of time - plasma drug
concentration is dynamic - it changes with time
To know where the drug goes once inside the body – how it distributes
Drug metabolism – are the metabolites safe?
What are the different routes of drug administration?
Enteral = via GI tract - oral - easiest form of administration - compliance, the patient might forget to take or cannot take if unconscious of vomiting.
Parenteral = not via GI tract
Intravenous (I.V) - thiopentone
not absorption phase and rapid effect
Intramuscular (I.M) - fluphenazine
Subcutaneous - insulin
relatively easy for the patient to self administer compared with I.M. and I.V.
Define the oral bioavailability (F) of a drug
The fraction of oral dose that reaches the systemic circulation
How do you measure oral bioavailability (F) experimentally and the equation to calculate it
Compare the plasma concentration vs time curves of the drug being administered orally vs iv
F= area under curve for oral administration/ area under curve for iv.
Which factors affect oral bioavailability of a drug.
Poor absorption from the gut
breaking down in gut
first pass effect- when andrug is heavily broken down on their first pass through the liver not reaching the main circulatory system
Which factors affect drug absorption at membrane.
Lipid solubility of the drug
Drug preparation
Area of absorbing surface
Rate of blood flow to other side of absorbing surface
Presence of food in gut
Effect of other drugs taken by patient
pKa of the drug (pH at which it is 50% ionised)
pH at absorbing surface
Define drug distribution
Penetration of drug into tissues and organs from the blood
How is drug distribution measured
Apparent volume of distribution (Vd) is the volume of water in which a drug would have to be distributed in to give its plasma concentration
Vd = amount of drug in body / plasma conc
vd can be volume (litres) or volume/mass (1L/kg
Examples of drugs with high and small Vd
Small Vd = insulin, warphin
high Vd =prozac, imipramine
Why is drug distribution (Vd) important to measure
Important when calculating dosing schedules
partly determines the plasma half-life of a drug.
How is a drug eliminated
The metabolism and excretion of drugs
Define metabolism
the chemical changes of drug structure.
Define drug excretion
The movement of a drug from the inside to the outside of the body.
Name sites of metabolism for drugs
Liver, lungs, kidney plasma
What are the features of a first order elimination graph
Constant half life, most common one
What are the features of a zero order elimination graph.
Constant gradient, (straight Line), happens because the metabolic pathways have become fully saturated, and cannot eliminate any faster.
What are the features of a pseudozero order elimination graph.
first half looks like a 0 order line because the metabolic pathways are fully saturated, the second half looks like first order, the metabolic pathways are no fully saturated.
What is first order elimination described by.
The standard exponential equation.
Ct = Co e^-k/t
Ct = plasma conc at time
Co = plasma conc when t =0
k = rate constant of elimination
t = time
Describe the influence of body compartment pH and drug ionisation on the absorption
Most drugs are either weakly ionising acids or bases. weak acids tend to be absorbed better in acidic conditions and weak bases in basic conditions.
This is due to the fact that ionised drugs do not cross membranes and the pH determines how the ratio of ionised to unionised.
Describe the influence of body compartment pH and drug ionisation on the elimination
Urinary excretion: The pH of urine effects how much of a drug is excreted. If the drug is weak base then more of it will be excreted if the urine is more alkaline. (e.g. aluminium chloride)
the same with acidic drug and acidic urine using sodium bicarbonate.
Describe how drugs cross membranes and are distributed from the blood to tissue. what the extent and rate of distribution are dependant on and
The drug distributes into the tissues from the blood reversibly.
The degree of distribution into the tissue depends on lipid solubility, plasma protein binding (within the blood).
The rate is dependant on the rate of blood flow to the tissue/organ
What is clearance
A measure of how much of a drug is eliminated. It is equal to
Rate of Elim/Cp
What drugs are eliminated with first order kinetics
Ethanol, aspirin, Phenytoin
Describe what is happening at steady state.
The rate of elimination of the drug is equal to its rate of absorption.
How is steady state achieved
A drug is administered to a patient using i.v infusion. the plasma concentration rises until it is equal to the rate of elimination.
the drug must be eliminated using first order kinetics
How long does it take to reach steady state
Roughly 4-5 half lives regardless of the rate of infusion
the
What are the 3 process that determine renal drug excretion
Glomerular filtration, active secretion, passive reabsorption.
What types of metabolites can be formed
Active drugs can form inactive and active metabolites
benefits of active metabolites is that it stays in the body for longer.
Inactive drugs (prodrugs) can form active metabolites.
Active drugs can also form toxic metabolites.
Why would a prodrug be used
If the drug cannot get the the site of active or to decrease toxicity.
What is the product of phase 1 hepatic metabolism and how are they formed
A derivative which is more reactive than the drug formed by oxidation reduction or hydrolysis.
What is the product of phase 2 hepatic metabolism
Conjugate - a combination of the derivative and a polar molecule to make the conjugate less lipid soluble to Make it easier to excrete from the liver.
Where does Phase 1 hepatic metabolism occur
the endoplasmic reticulum of the cells in the liver.
Why is an paracetamol overdoes toxic
Paracetamol is metabolised using only phase 2 hepatic metabolism. when this metabolic pathway is fully saturated it is metabolised using phase 1 hepatic metabolism producing toxic metabolites
Explain enzyme induction
Some drugs and environmental pollutants induce increased expression of cytochrome P450 enzymes over a number of days/weeks. This can cause the failure of some drugs (and itself) to produce a significant therapeutic effect.
Explain enzyme Inhibition
Some drugs directly inhibit cytochrome P450 enzymes. This can increase the likelihood of seeing adverse effects/toxicity in the patient.
