Knowledge of the absorption, distribution/metabolism and excretion of the drug is essential to achieve this aim

TI = TD₅₀ / ED₅₀  OR TD₅/ED₉₅

Physico-chemical properties of the drug

Formulation of the drug

Site/route of administration

high molecular weight drugs can easily cross cell membrane.

true or false

Formulated into a dosage form suitable for a specific route of administration.

The dosage form contains guaranteed amount(s) of active constituent(s), with a shelflife of at least 2 years

Tablets or capsules are very convenient for both patient and medical staff and are cheap to make.

Parenteral injections are required to be isotonic, sterile,

free of pyrogens, may require skilled personnel to give

them, and are expensive

in order to restrict the action of the drug to

particular site(s) in the body (local effect)

or

to allow access of the drug to the whole body

(systemic effect)

Based on lipid/water coefficient

Too lipid - stay in membrane

Too watery - cannot cross the membrane

Drug must be absorbed across a layer of epithelium that forms tight junctions.

Once in the blood it is distributed by passage across capillary endothelial cells into the interstitial fluid.

Then it acts on a surface receptor and do its action

Lipid diffusion

Aqueous diffusion

Active transport

Transcytosis

lipid solubility (partition coefficient)

concentration gradient

Permanent cations are well absorbed from the gut

True or False

False!

Very poorly and often erratically

pKa of drug

pH of the tissue compartments involved

Partition coefficient of the non-ionized drug species

These agents can be toxic if present systemically and

we are relying for protection on the fact that most

drugs are poorly absorbed through intact skin

dimethyl sulfoxide (DMSO) carry KCN, which can penetrate  through the skin

cardiac arrhythmia may be induced by a sudden large increase in epinephrine (β-agonist) in the blood following IV injection

it may also be difficult to give an IV injection due to the

collapsed nature of the circulation

IM or SC injection of a drug salt, ester or complex that

has low water solubility. The formulation may be an

aqueous suspension or an oily solution

ester slowly diffuses out of the oily solution and then hydrolyzed by tissue

a capsule containing granules which dissolve at different

rates in the gut lumen fluid

a solid pellet (implant) of the drug introduced subcutaneously

blood flow

capillary permeability (lipid sol., pH, conc. grad.)

protein binding

Sinusoidal capillaries of the liver lack endothelial layer and permit passage of all molecules.

Brain capillaries do not readily permit passage of drugs unless they are lipid-soluble

lipid soluble drugs

if the meninges become inflamed, then drug penetration can rapidly increase; thus CSF concentration of antibiotic can approach that of plasma

The volume of fluid required to contain all the drug (Q) in the body at the same concentration as that measured in the plasma, C_P

In short: apparent volume into which a drug is able to distribute

Drugs with large Vd usually have high lipid solubility and will reach brain and fetus.

Exceptions are where Vd is a consequence of binding

Polarity of drug with a loss of therapeutic activity

Formation of toxic products

Properties of drugs that increase passage across cell

membranes hinder their excretion as they diffuse back from the tubular lumen

Thus, re-absorption is reduced

Formation of more polar products, which is important for renal and biliary excretion.

Liver and kidney possess specific secretory systems that operate on highly polar compounds

cytochrome P450 and flavoprotein (NADPH-cyt. P450 reductase)

They are sources of electrons for the oxidative reaction

glucuronidation

sulfation

acetylation

amino acid conjugation

glutathione conjugation

transform drugs and metabolites to inactive products –

less lipid soluble AND highly ionized

Therefore easily excreted

Liver cell function is impaired and there are through-channels which shunt blood into the systemic circulation.

This means that first-pass elimination is reduced and exaggerated responses to normal doses of drug will occur

induce liver enzymes, enhance gene transcription that leads to increased levels of microsomal monooxygenases

Thus inducer itself and many other drugs are more rapidly metabolized

variability of drug response in the population/drug tolerance

greater toxicity of paracetamol in regular heavy drinkers due to increased production of hepatotoxic metabolites

failure of medication

Hydrolysis of the conjugate may occur and the active drug is reabsorbed and may go round the cycle again.

This creates a reservoir of drug, which tends to prolong the duration of action of the drug

1. glomerular filtration

2. passive reabsorption

3. active tubular secretion or reabsorption

Lipid soluble

Highly polar drugs will not be reabsorbed and will be concentrated in urine

Via active transport into the tubular lumen

Thus achieve maximal drug clearance since loss of

free drug from the plasma is replaced by protein-bound drug

Forced alkaline diuresis

Peritoneal dialysis

Hemodialysis

placing fluid in the peritoneal cavity to promote passage of drug from intestinal blood vessels into the fluid.

The fluid is then drained

Patient's blood is passed over a semi-permeable membrane of large surface area and then returned to the patient.

The drug diffuses through the membrane into a physiological salt solution that can be replaced

i) Faulty dosage forms

ii) Ethnic differences

iii) Age/sex

iv) Enzyme induction

v) Alteration in receptor density

vi) Disease