WEEK 3 Flashcards
What is Pharmacokinetics?
The study of what the body does to a drug-drug movement into, through and out of the body
What is the therapeutic window?
The difference between the toxic and effective concentrations
What are the four stages of pharmacokinetics?
ADME: Absorption Distribution Metabolism Excretion
What is efficacy?
The maximum response achievable from a drug
What is potency?
The drug activity expressed in terms of the amount required to produce an effect
What is drug compliance?
Whether the drug is taken up at all
What is the one-compartment model of pharmacokinetic modelling?
The assumption that the entire body acts like a single, uniform compartment
What is zero-order elimination kinetics?
A constant amount of the drug is lost per unit time
What is 1st order elimination kinetics?
The elimination rate depends on the amount of drug that remains
What is the difference between log concentration/time curves for i.v and oral distribution?
C0 is lower in oral than i.v., takes some time for oral to reach Cmax before it decreases whereas i.v. Cmax occurs at t=0
What does distribution depend on?
Blood flow
Lipid solubility and diffusion barriers
Tissue binding (some drugs immobilised in tissue due to ECM interaction)
Plasma protein binding (complicates drug movement as plasma protein needs to dissociate from drug before s-o-a)
Where does metabolism occur?
Liver (first pass metabolism HPV connects GIT to liver so all contents can be metabolised first) Kidney Skin Lungs Microbiome
What causes metabolism?
Mainly oxidation and conjugation (biotransformation phases I and II) but also reduction, hydrolysis, hydration, condensation, isomerisation
What is the predominant effect of metabolism?
Drug inactivation (not always-eg. ‘prodrugs’-not active until metabolism/paracetamol-produces toxic metabolites)
Describe Cytochrome P450 (CYP)?
Heme iron usually in ferric (Fe3+) state but, when reduced, forms ferrous (Fe2+) state. Complex between ferrous P450 and CO absorbs light maximally at 450nm
Describe Phase I of First Pass Metabolism
Oxidation via Cytochrome P450 enzyme:
introduction of polar groups (hydroxyl group via hydroxylation) causing compounds to get more hydrophilic
Describe Phase II of First Pass Metabolism
Conjugation reactions:
Polar/Charged (sulfate/glucoronidate) groups are conjugated (linked) to compounds=compounds get more hydrophilic
What is the effect of increased hydrophilicity in Phase I and II of FPM?
Easier excretion via the kidneys
What is the role of cytoplasmic sulfotransferase in FPM?
Has a bound substrate and cofactor PAPS and is used in sulfate conjugation
Where does excretion take place?
Kidneys (into urine)
Liver (into bile/enterohepatic circulation)
Lungs (expired)
Saliva/sweat/milk
What are the Pre-clinical outcome from a pharmacokinetics study?
Select compounds with maximum potential of reaching target (PK)
Select appropriate route of administration
Understand how blood levels relate to efficacy (PK-PD) or toxicity (TK-TD) to select safe doses
Deduce frequency and duration of dosing
Predict human pharmacokinetics (eg. age/gender/size)
What are the ways to quantitatively detect a drug in urine/blood?
Liquid chromatography and mass spectrometry
What is the dose interval dependent on?
The plasma half-life
What is the plasma half-life?
The time taken for half the drug to be eliminated from plasma
What are the five ‘rights’ of drug administration?
1) Right patient
2) Right drug
3) Right route of administration
4) Right dose
5) Right time
Define absorption
The movement of a drug from its site of administration into the plasma
Define distribution
The reversible transfer of a drug from one location to another within the body
What do both absorption and distribution processes tend to involve?
Passage through layers of cells
What are the two ways in which drugs pass through layers of cells?
Passive diffusion and pinocytosis
How do drugs pass through layers of cells via passive diffusion?
through cells via diffusion through the lipid membrane or through intercellular pores via diffusion of small water-soluble molecules
How do drugs pass through layers of cells via pinocytosis?
facilitated diffusion and active transport
What strongly influences whether a compound can pass through membranes?
Lipophilicity
What is ‘ion trapping’?
The notion that ionised compounds are unable to pass across the lipid membrane and therefore accumulate where this is favoured
Which equation explains the notion of ‘ion trapping’?
H+ + A- ⇌ HA
Which form of a drug is able to diffuse through membranes?
The unionised form
Are drugs strong acids/bases or weak acids/bases?
Weak acids/bases meaning their degree of ionisation depends on local pH
Where do drugs tend to accumulate?
Places where ionisation is favoured (‘ion trapping’)
What is the Henderson-Hasselbalch equation?
pH=pKa + log10([A-]/[HA])
pKa=acid strength
A-=deprotonated acid
HA=acid yet deprotonated
What is the pKa value?
A quantitative expression of the strength of an acid/base
What does a higher pKa value indicate?
Greater alkalinity
What does it mean if Acetate acid has a pKa value of 4.76?
At pH of 4.76, there are the same amounts of free acid and acetate ions
Where do weak acids have higher concentrations?
Areas of higher pH due to being ionised in alkaline conditions (acidic->basic environment)
Where do weak bases have higher concentraitons?
Areas of lower pH due to being ionised in acidic conditions (basic->acidic environment)
Define bioavailability
The fraction of the total dose administered that reaches the plasma
What chemical properties does absorption depend on?
Chemical nature
Molecular weight
Solubility
Partition coefficient
What physiological variables does absorption depend on?
Gastric motility pH at absorption site Area of absorbing surface Blood flow Presystemic elimination Ingestion with or without food
What factors affect drug absorption from the GI tract?
Dispersal/solubility of drug in gut contents (formulation)
Stability of drug
Lipid solubility of drug
Transit time-decreased due to D&V
What are pharmaceutical interventions affecting transit time?
Particle size
Dry-powder inhaler
Enteric coated tablets (slow release)
Slowed/delayed release preparations
What are the factors affecting transdermal absorption?
Lipid solubility Formulation Skin thickness Hydration Blood flow
What is the equation for AVD (apparent volume of distribution)?
AVD(vol)=dose(mass)/plasma conc. (mass/vol)
Define the Apparent Volume of Distribution (AVD)
the notional volume of fluid required to dilute the absorbed dose to the concentration found in plasma
What is the AVD if the drug is heavily plasma-protein bound?
roughly 6 litres (greater proportion in plasma)
What is the AVD if the drug is heavily tissue-bound?
> 70 litres (lower proportion in plasma)
What is the two-compartment model of pharmacokinetic modelling?
Divides the body into a central and peripheral compartment
What are the routes of drug administration?
Enteral (oral, rectal)
Parenteral (subcutaneous [s.c.], intra-venous [i.v.], intra-muscular [i.m.], intra-arterial, intra-thecal, intra-peritoneal)
Percutaneous-‘by way of the skin’ (inhalation, sublingual, topical/transdermal)
What major factors does absorption depend on?
Route of administration (blood flow and SA of site)
Dose of drug
Drug solubility (lipid/water solubility)
LOOK AT AND DRAW DIAGRAM OF ADMINISTRATION->ELIMINATION
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