WEEK 3 Flashcards by Max Dunbavand

What is Pharmacokinetics?

The study of what the body does to a drug-drug movement into, through and out of the body

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What is the therapeutic window?

The difference between the toxic and effective concentrations

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What are the four stages of pharmacokinetics?

ADME:
Absorption
Distribution
Metabolism
Excretion

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What is efficacy?

The maximum response achievable from a drug

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What is potency?

The drug activity expressed in terms of the amount required to produce an effect

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What is drug compliance?

Whether the drug is taken up at all

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What is the one-compartment model of pharmacokinetic modelling?

The assumption that the entire body acts like a single, uniform compartment

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What is zero-order elimination kinetics?

A constant amount of the drug is lost per unit time

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What is 1st order elimination kinetics?

The elimination rate depends on the amount of drug that remains

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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

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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)

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Where does metabolism occur?

Liver (first pass metabolism HPV connects GIT to liver so all contents can be metabolised first)
Kidney
Skin
Lungs
Microbiome

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What causes metabolism?

Mainly oxidation and conjugation (biotransformation phases I and II) but also reduction, hydrolysis, hydration, condensation, isomerisation

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What is the predominant effect of metabolism?

Drug inactivation (not always-eg. ‘prodrugs’-not active until metabolism/paracetamol-produces toxic metabolites)

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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

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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

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Describe Phase II of First Pass Metabolism

Conjugation reactions:

Polar/Charged (sulfate/glucoronidate) groups are conjugated (linked) to compounds=compounds get more hydrophilic

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What is the effect of increased hydrophilicity in Phase I and II of FPM?

Easier excretion via the kidneys

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What is the role of cytoplasmic sulfotransferase in FPM?

Has a bound substrate and cofactor PAPS and is used in sulfate conjugation

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Where does excretion take place?

Kidneys (into urine)
Liver (into bile/enterohepatic circulation)
Lungs (expired)
Saliva/sweat/milk

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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)

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What are the ways to quantitatively detect a drug in urine/blood?

Liquid chromatography and mass spectrometry

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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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