Volume of distribution: the measure of the apparent space in the body available to contain the drug.

Volume of distribution= amount of drug in body / clearance 

• Can be defined with respect to blood, plasma or water (unbound drug)
• Often exceeds any physical volume in the body because it is the theoretical/apparent volume necessary to contain the drug homogenously at the concentration found in blood, plasma, or water…but most drugs are not homogenously distributed
• Large Vd = little drug left in plasma → lots of drug distributed into tissues. E.g. lipid-soluble drugs
• Small Vd = much of the drug remains in the bloodstream/extracellular fluid.
• Drugs which are completely retained within the vascular compartment will have a minimum VOD equal to the plasma component in which they are distributed
  • 0.04L/kg (plasma)
  • 0.2-0.35L/kg (fat)
  • 0.08L/kg (blood)
  • 0.6L/kg (total body water)

Bioavailability: the fraction of unchanged drug reaching the systemic circulation following administration by any route. For intravenous dose, bioavailability is assumed to be equal to unity.

Systemic bioavailability (F) = absorption(f) x (1 - extraction ratio)

• Morphine is almost completely absorbed i.e f=1, however its ER is 0.67, so its oral bioavailability is about 33%

Clearance: the volume of plasma completely cleared of drug per unit time (theoretical)

Clearance= Rate of elimination / concentration

• Can be defined with respect to blood, plasma or water (unbound drug)
• Cumulative i.e. Cl_systemic=Cl_kidney + Cl_liver + Cl_other
• Renal clearance is measured by unchanged drug in the urine
• Liver clearance is harder to measure, as drugs are eliminated by biotransformation into metabolites and excretion into bile. It is often assumed to be difference between total systemic clearance and renal clearance
• Systemic clearance impacts bioavailability, because it determines the extraction ratio.

Elimination: the removal of a drug from the body by metabolism or excretion. 

Half-life: the time required to change the amount of drug in the body by one-half during elimination

t 1/2 = (0.7xVolume of Distribution) / Clearance

• As per this formula, a change in elimination half-life will not necessarily reflect a change in drug elimination. This is because, for instance in chronic renal failure, there is both decreased renal clearance of drug AND decreased Vd (due to decreased renal and skeletal muscle mass)

Extraction ratio: the fraction or percentage of a substance (like a drug, oxygen, or waste product) removed from the blood as it passes through an organ such as the liver or kidney

Extraction ratio=CL liver (hepatic blood clearance) / Q(hepatic blood flow)

Fick's law of diffusion: the net diffusion rate of a gas across a membrane is proportional to the difference in partial pressure and the area of the membrane inversely proportional to the thickness of the membrane.

Ka= dissociation constant (how the acid splits apart). Ka= [H+] x [A-]/[HA]. Big Ka= strong acid

pKa= -log10[Ka]. pH at which concentrations of uncharged and charged forms are equal i.e. when pKa is equal to pH, the drug exists as 50% ionised and 50% unionised. When pH=pKa, the buffer is at max efficiency. Low pKa= strong acid. 

Henderson-Hassellbach: determines the concentration of a weak acid in solution.

pH=pKa + log[A-]/[HA]

What is zero order kinetics? Give examples

What is first pass metabolism? Why is it important?

First mass metabolism is the metabolising of a drug by the gut wall, portal blood or (most commonly) the liver. 

• If a drug undergoes extensive first-pass metabolism it has ↓ bioavailability (F)
• Drugs with high extraction ratios will show marked variations in bioavailability between subjects because of differences in hepatic function and blood flow. 
• Morphine, isoniazid, propranolol and TCAs are highly extracted by the liver. GTN also has extensive first-pass metabolism, so it is given sublingually instead of orally

How can you avoid first-pass metabolsm?

Direct to systemic, not via portal veins:

• IV
• Sublingual
• Transdermal
• Rectal (to a lesser extent) (enters middle rectal veins that drain to IVC not the liver…theoretically, but really approx. 50% of a rectally administered dose bypasses the liver)

Although inhalation bypasses liver first-pass effect, lungs are a site of first-pass loss themselves

How do you calculate a loading and maintenance dose?

Maintenance dose= dosing rate x dosing interval

Clearance is the most important pharmacokinetic parameter to be considered in defining a maintenance dose.

Dosing rate= clearance x target concentration

Dosing rate (oral)= dosing rate / oral bioavailability (F)

A loading dose promptly raises the concentration of drug in plasma to the target concentration. It mainly depends on Volume of Distribution.

Loading dose=volume of distribution x target concentration

What is steady state?

Steady state is when the amount given with each dose replaces the drug eliminated since the preceding dose.

At steady state, the dosing rate must equal the rate of elimination.

What is the difference between capacity-dependent and flow-dependent drug elimination?

For most drugs clearance is constant over the concentration range i.e. elimination is not saturable, and is directly proportional to concentration. Clearance can thus be calculated as the dose divided by the area under the curve of the time-concentration profile.

• Capacity-limited elimination (Michaelis-Menten elimination): when clearance depends on the concentration of drug. As the transporters/enzymes involved in elimination get saturated at higher concentrations, elimination reaches a maximum rate. e.g. ethanol, phenytoin, aspirin. In these cases a small increase in dose can mean a big increase in blood concentration as the body cant eliminate the extra drug quick enough.
• Flow-dependent elimination(‘high-extraction’ drugs): when most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through the organ. The elimination of these drugs thus depends primarily on the rate of drug delivery to the organ of elimination. Blood flow to the organ is the main determinant of drug delivery.

+ Large molecules (proteins) elimination: usually have a half life of a couple of weeks. Elimination is, to some extent, determined by the elimination of the target(target-mediated drug disposition) e.g. T cells. When the target is eliminated, clearance of the molecule is increased and the drugs half-life gets shorter.

Describe the phases of drug trials

Phase 1= effect of drug as function of dose in a small healthy group

Phase 2= drug studies for the first time in patients with a target disease to assess efficacy

Phase 3= drug evaluated in a much larger number of patients to determine safety and efficacy

Phase 4= drug approved for marketing, monitoring safety of new drug under actual conditions

What is an enzyme inducer? What is the relevance in prescribing? What is an enzyme inhibitor?

Drug metabolism happens in two phases:

Phase 1 reactions(don’t always precede phase 2): parent drug -->more polar metabolite in sER

• Oxidation (loss of electron, e.g. CYP450), Reduction (gain of electron), Hydrolysis, Deamination, Desulfration

Phase 2 reactions: covalent attachment of hydrophilic molecule to form hydrophilic water-soluble compound via conjugation

An enzyme inducer or enzyme inhibitor is a drug that changes how quickly the body’s drug-metabolising enzymes break down other medicines.

These enzymes are located in smooth ER membranes of the liver

CYP450

Inducers of CYP450 increase activity of P450, increasing drug metabolism, thus reducing drug levels.

• Carbamazepine, rifampicin(e.g. rifampicin+OCP=treatment failure), alcohol, phenytoin, phenobarbital, sulponylurea

Inhibitors of CYPP450 reduce activity of P450, reducing drug metabolism and thus increase drug levels.

• Sodium valproate, isoniazid, cimetidine, ketoconazole, fluconazole, alcohol, chloramphenicol, erythromycin, sulfonamide, ciprofloxacin, omeprazole, metronidazole, grapefruit juice.

CYP3A4 is the most active P450, and the most common.

Inducer: phenytoin, carbamazepine, st johns wart

Inhibitor: erythromycin, chloramphenicol, grapefruit juice

CYP2D6 metabolises cardiac drugs

CYP1A1 metabolises Panadol

CYP2C9 metabolises warfarin