1. ADME/T(ox)
Absorption
Distribution
Metabolism
Excretion
Toxicology

2. ---- and reach the cellular target
Overview - ABSORPTION
Some drugs work outside the body (barrier creams, some laxatives) but most must:
enter the body:
ENTERAL (entering the intestine) - oral, sublingual (under the tongue), rectal
PARENTERAL - intravenous, subcutaneous, intramuscular
be transported by the blood to the target organ but note local delivery (asthma)
cross lipid barriers / cell walls: gut wall, capillary wall, cell wall, blood brain barrier
---- and reach the cellular target

3. Oral Administration

4. Oral Administration Advantages Disadvantages
Generally the safest route
Economical
Convenient for owner
No need for sterile equipment
Systemic distribution
Disadvantages
Absorption may be variable
Gastric irritation may cause vomiting
Not useful if patient is vomiting
Requires cooperation of patient
Drug may be destroyed by gastric acidity, gut flora, mucosal enzymes, liver enzymes
Onset of effect is slow
Drug dilution

5. Factors affecting oral absorption
Disintegration of dosage form
Dissolution of particles
Chemical stability of drug
Stability of drug to enzymes
Motility and mixing in GI tract
Presence and type of food
Passage across GI tract wall
Blood flow to GI tract
Gastric emptying time

6. Intravenous Injection

7. Intravenous Injection
Advantages
Extremely rapid
Initial absorption step is by-passed
Drug levels are more accurately controlled
Good for irritant drugs
Suitable for large volumes
Disadvantages
Most dangerous route
Drug must be in aqueous solution
Must be performed slowly
Once injected, drug cannot be removed

8. Bioavailability
the proportion of the drug in a dosage form available to the body
i.v injection gives 100% bioavailability.
Says nothing about effectiveness.

9. Overview - DISTRIBUTION
The body is a container in which a drug is distributed - but the body is not homogeneous
plasma; extracellular fluid; intracellular fluid; + special areas (fetus, brain)
----- affects concentration at site of action/elimination

10. Drug Distribution Factors
Blood Flow
The rate at which a drug reaches different organs and tissues will depend on the blood flow to those regions. Equilibration is rapidly achieved with heart, lungs, liver, kidneys and brain where blood flow is high. Skin, bone, and fat equilibrate much more slowly.
Lipid Solubility
Lipid solubility will affect the ability of the drug to bind to plasma proteins and to cross lipid membrane barriers. Very high lipid solubility can result in a drug initially partitioning preferentially into highly vascular lipid-rich areas. Subsequently these drugs slowly redistribute into body fat where they may remain for long periods of time.

11. Drug Distribution Factors
Capillary Permeability
The capillaries in liver are extremely permeable, while those at the blood-brain barrier lie at the other extreme. Molecular size is the major factor affecting the permeability of water-soluble drugs across capillaries.

12. … metabolism is what the body does to the drug
Overview - METABOLISM
Drug molecules are processed by enzymes evolved to cope with natural compounds
Drug may have actions increased or decreased or changed
Individual variation genetically determined
May be several routes of metabolism
May not be what terminates drug action
May take place anywhere BUT liver is prime site
Not constant - can be changed by other drugs; basic of many drug-drug interactions
… metabolism is what the body does to the drug

13. Sites of biotransformation
where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and
LIVER
the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation

14. Factors affecting biotransformation
age (reduced in aged patients & children)
sex (women more sensitive to ethanol)
species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); route of biotransformation can also change
Race, clinical or physiological condition

15. Biotransformation of Drugs
Phase I
Usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Often these metabolites are inactive, although in some instances activity is only modified. If Phase I metabolites are sufficiently polar, they may be readily excreted.
Phase II
Parent drugs or their Phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance (glutathione, glucouronic acid, and sulfuric acid) to yield drug conjugates. In general, conjugates are polar molecules that are readily excreted and often inactive

16. Overview - EXCRETION Urine is the main but NOT the only route.
Glomerular (kidney) filtration allows drugs <25K MW to pass into urine; reduced by plasma protein binding; only a portion of plasma is filtered.
Tubular secretion active carrier process for cations and for anions; inhibited by probenicid.
Passive re-absorption of lipid soluble drugs back into the body across the tubule cells.

17. Special aspects of excretion
lactating women in milk
little excreted in feces unless poor formulation or diarrhea
volatile agents (general anesthetics) via lungs