NURS2001 - Wk 2 lec Pharmacokinetics

Pharmacokinetics

What the body does to the drug (does & conc of drug in the blood)

Pharmacodynamics

What the drug does to the body (pharmacological effect)

Drug action & Disposition of Pharmacokinetics

ADMe =

Distribution (bound or unbound to plasma proteins around body), Absorption (release of drug), Metabolism, elimination (Kidney —> Urine, or Liver —> Bile)

Methods of medication absorption and routes of its administration

Journey of drug molecule into the plasma (blood) through to circulation

Routes:

• Oral

• Sublingual

• Rectal

• Inhalation

• Injection (eg. Subcut, IV, intramuscular)

Oral Administration Absorption - where does it occur?

Occurs through GIT

• Stomach

Mucous barriers on stomach lining reduce absorption, + low pH (acidic environment favours weak acid)

Drugs can be protected from the acidic pH with an enteric protein coat surrounding the drug (should the drug be weak in low pH)

• Small Intestine

Large SA (villi & microvilli), No mucous barrier, fastest Gi site absorption for drugs

• Large Intestine

Less villi, Slower absorption compared to SI

Factors affecting oral absorption

• Gastric emptying

Rapid emptying (before meal) gives rapid absorption into SI, should you take a drug with a faster onset of action

Slow emptying (with food) for slower absorption to give the drug more time to be absorbed

• GI motility

Increased motility (eg. diarrhoea) causes decreased absorption

Bioavailability (F)

Fraction of dose that is absorbed into the systemic circulation (0%-100%)

Importance of Bioavailability

To determine dosages for non-IV routes of administration (since IV administrated drugs = 100%, F = 1)

Bioequivalence

Two products that have the same rates of absorption and bioavailability

Important to be able to tell whether different brands of the same drug can be interchanged

First pass hepatic elimination

When a drug is metabolised in the liver before it reaches the systemic circulation, reducing Bioavailability

Why some drugs are not given orally etc. due to high first pass effect

Distribution

How the drug flows throughout the body once entered the systemic circulation

What affects distribution?

Drug characteristics:

Permeability between plasma membranes, size (unbound drug molecules can transport into different compartments), pKa, weight

Physiological characteristics:

Blood flow, Cardiac output

Plasma protein binding

Unbound drug molecules bind to proteins to form drug-protein complexes

• Allows for increased release of unbound drug

• Bound drugs act as a reserve, ready to release (as binding is a reversible reaction) thus allowing for a slower but extended release of active unbound drug molecules

Volume of distribution (Vd)

Volume of fluid required to contain the total amount of drug in the body at the same concentration as plasma that is present

Determined by:

• fu

• Tissue binding

It is a ratio between drug concentration and the amount of dose in the body.

• The drug dose required to uniformly distribute throughout the body, hence high and low Vd is a significant distinguisher

Vd significance

Significance of Vd

Drugs w/ small Vd

• Shorter half life

• Accumulate less in the body

• Safer for use during pregnancy and breastfeeding

Drugs w/ large Vd

• Longer half lives

• Accumulate more in the body

• Requires loading dose (large initial dose for drug to reach therapeutic effect levels in the body

Large vs low Vd

Large = More likely to be found in the fats/tissues of the body

Low = More likely to be found to the blood circulation (confined)

Clearance (CL)

How efficient drug elimination is

• Which allows for the determination of the appropriate dose

Half life

How long a drug stays in the body

• How long it takes the plasma concentration of the drug to reach 50%

Two phases of drug metabolism

Phase 1: OHDDH

Oxidation

Hydroxylation

Dealkylation

Deamination

Hydrolysis

Phase 2:

Conjugation

Routes of elimination

• Metabolism

• Excretion via renal and biliary

• Exhalation

Cytocrome-P450 main enzymes

• CYP3A4

• CYP2C9

Enzyme forms

Substrate = Metabolised by or compete for metabolic (enzyme) sites

Inhibitor = Competes and blocks metabolic sites (INHIBITS)

Inducer = Increases metabolic activity by increasing amount of enzymes (INDUCING)

Differences between the effects of inhibitors and inducers

Inducers = Enhance CYPs effect + Speed up metabolism of drug

Inhibitors = Reduce CYPs effects + Slow down metabolism of drug

Inducers examples

• Cruciferous vegetables

• Phenytoin

Inhibitors examples

• Clarithromycin

• Erythromycin

Pharmacokinetic Parameters

• Clearance (CL)

Efficiency of drug elimination

• Volume of Distribution (Vd)

Extend of distribution in the body eg. fat, tissues, systemic circulation

DETERMINES THE LOADING DOSE

• Bioavailability

Fraction of a dose absorbed into systemic circulation