How drugs act 2 Flashcards
What is ADME
Absorbtion
Distribution
Metabolism
Excretion
What is Pharmacokinetics:
Factors that determine the ACTIVE concentration of the drug at the ACTIVE site.
What is Absorbtion:
The mechanism of accumulation of a drug in a body compartment following administration.
What is Distribution
The way in which a drug reaches each organ of the body
What is Metabolism
The chemical alteration of a drug into (ultimately) its inactive forms
What is Excretion
Removal of the drug/or its metabolites from the body
True or False Most drugs (eventually) pass through lipid membrane
But acids and bases ionise
True
what do Unionised drug differ in
lipophilicity
where are drugs ionised?
when pH opposite to pKa
what type of drugs are absorbed?
unionised drugs
which drugs are ionised and what is its pKa
Pethidine
Weak base pKa 8.6
which drugs are not ionised much and what is its pKa
Aspirin
Weak acid pKa 3.5
pH of the stomach
3
pH of the jejunum
7.5
how is the free drug distributed and give an example
Free drug is distributed according to lipophilicity eg thiopentone
where is disribution found and give an example of the drug
Drugs bind to plasma/tissue proteins
Bound drug is inactive
Important site of drug interactions. Warfarin
what is Volume of Distribution and what is it measurd in
A theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma.
in ml
what happens in the Volume of Distribution is low
if ionised and restricted to plasma water
70 Kg + Heparin =7000mls
what happens in the Volume of Distribution is equal to body volume
if lipophilic
70Kg + Thiopental=70,000mls
what happens in the Volume of Distribution is high
if protein bound i.e. apparent
70Kg + Digoxin=350,000mls
what different ways can drugs be metabolised in the liver
Oxidation Reduction Hydrolysis Hydration
Conjugation Condensation Isomerization
what is the principal site of drug metabolism?
the liver
how does liver metabolism work?
Liver metabolism typically inactivates drugs
Drug metabolites however may remain pharmacologically active
And even more active than the parent compound!
what is a prodrug and give examples
An inactive or weakly active substance that has an active metabolite is called a prodrug (e.g. bambuterol -terbutaline)
what is the point of drug metabolism
make the drug easier to excrete.
what is involved in phase one metabolism?
Cytochromes
what are Cytochrome P450 (CYP) enzymes
haem proteins
how many CYP gene families are there
74
which 3 CYP genes families are involved in metabolism?
CYP1, CYP2 and CYP3
how do CYP1, CYP2 and CYP3 differ
another in amino acid sequence and in the specificity of the reactions that they catalyze
what supplies the electrons
NADPH–CYP450 reductase
what is NADPH–CYP450 reductase
a flavoprotein that transfers electrons from NADPH (the reduced form of Nicotinamide Adenine Dinucleotide Phosphate) to CYP450.
what happens as a result of the CYP450 enzumes being induced or inhibited by many substances
drug interactions in which one drug enhances the toxicity or reduces the therapeutic effect of another drug.
What is does induction and give examples of drugs
decrease plasma drug conc’n.
ethanol in heavy drinkers
Rifampicin and contraceptive steroids
what does inhibition do and give examples of drugs
increase plasma drug conc’n
Ketaconazole and terfenadine
what is the most common phase 2 metabolism reaction
Glucuronidation
which is the only part of th phase 2 reacrion that happens in tthe liver microsomal enzyme system
Glucuronidation
what does conjugation do ergo why is it good
makes most drugs more soluble and easily excreted by the kidney
where are Glucuronides are secreted
bile
where are Glucuronides are excreted
urine
what happens in Amino acid conjugation
conjugation with glutamine or glycine produces conjugates that are readily excreted in urine but not extensively secreted in bile.
three types of conjugation in phase 2 metabolism
Glucuronidation
Amino acid conjugation
Sulfoconjugation
what is good about sulfate esters
Sulfate esters are polar and readily excreted in urine
what happens in terms of amino acid conjugation - in neonates
conversion to glucuronide is slow, potentially resulting in serious side effects of some drugs (eg, chloramphenicol)
which organ regulates the fluid and electrolyte balance of the body by continually filtering the blood.
the kidney
why is it vital that the kidney regulates the fluid and electrolyte balance of the body by continually filtering the blood.
to maintain a constant extracellular fluid volume and composition
the kidney maintains a constant extracellular fluid volume and composition, how does it do this?
excrete or conserve salt and water;
control body pH, and
free the body of waste products of metabolism and drugs
what are the three main mechanistic processes that enable the kidneys to regulate the chemical constituents of blood?
excrete or conserve salt and water;
control body pH, and
free the body of waste products of metabolism and drugs
where does elimination happen
the kidney
what does Pharmacokinetics focus on?
on concentration in plasma (Cp).
what is Cp
Cp is assumed to relate to extracellular fluid surrounding cells.
wht is the the target concentration strategy:
individual variation in response to drug is greater than Cp variation at that dose.
examples of drugs used in therapeutic drug monitoring
cyclosporine, digoxin, phenytoin, methotrexate
what is Pharmacokinetics used for
in therapeutic drug monitoring (TDM)
apart from Cp, what else is useful
Concentrations in other body fluids may also be useful.
how to measure
Fit concentration vs. time data to a theoretical model and determine parameters.
what is Cmax:
maximum plasma concentration following a given dose.
what is Tmax:
time between drug dose and achieving Cmax.
Parameters are used to adjust dosing regimen, what are they based on?
experimental estimates, patient data
what is slow absorption from administration site into the plasma is equivalent to
a slow infusion at a variable rate.
what is transfer of drug to central compartment is governed by
rate constant, kabs
what does varation in rate of absoption assume
Assumes that kabs is directly proportional to amount of drug still unabsorbed
what is the result of slow absorption
reduces Cmax but increases duration of action
what happens once absoption is complete?
Cp declines with the same t1/2, irrespective of rate of absorption.
how can you estimate C0
extrapolating semi log plot of Cp vs. time back to time 0.
what is the single compartment model
Initial concentration (C0) following bolus dose of Q mg: C0 = Q/Vd
what is elimination half life
is the time taken for Cp to fall by 50%.
what does elimination half life predict
What will happen after drug administration, before reaching steady state
What will happen after stopping infusion, as Cp declines towards 0.
what does a longer t1/2 mean
longer persistence of drug in body after dosing is stopped.
more time is needed to accumulate drug to steady state therapeutic level.
why would clinitians may use a loading dose
to achieve therapeutic concentration more rapidly (dependent on Vd).
what is the clinical urgency of elimination half life
cardiac dysrhythmias, e.g. amiodarone, digoxin
what is the effect of repeated dosing
More common than single injections or constant infusion.
Same pattern as for IV infusion
Oscillation through range Q/Vd
Steady state achieved after 3-5 half-lives
limitation of single compartment model
Oversimplification.
Assumes that rates of absorption, metabolism and excretion are directly proportional to drug concentration in the compartment.
Different tissue compartments, e.g. brain, fat, muscle, may affect time courses of drug distribution.
Two-compartment model
Tissues represent a peripheral compartment.
Drugs enter second compartment via central (plasma) compartment.
Result: add a second exponential component to the Cp time course
Double exponential kinetics limintation
Limitation: some drugs are not equally soluble across all tissues (e.g. fat soluble drugs)
Cp time course has a fast and slow phase.
Often found experimentally.
talk bout the Fast phase
represents transfer between central and peripheral compartments (plasma – tissues)
Cp after fast phase is complete allows measure of combined Vd of both compartments.
Cp time course has a fast and slow phase.
Often found experimentally.
talk bout the slow phase
t1/2 for slow phase (β) provides an estimate of rate of elimination.
what happens if metabolism is rapid
then α and β are not well separated.
which drugs dont follow single or double exponential kinetics for elimination from plasma.
ethanol, phenytoin, salicylate
discribe how ethanol is secreated and explain why in terms of saturation kinetics
: disappearance from plasma is linear, irrespective of dose or Cp.
Explanation: rate of oxidation by alcohol dehydrogenase saturates at low ethanol concentrations.
Implications of saturation
Duration of action is more dependent on dose.
Relationship between dose and steady state Cp is steep and unpredictable.
Maximum rate of metabolism sets a limit to dosing rate.
Drugs with saturating kinetics are difficult to administer effectively and may be rejected in development.
