Download INTRODUCTION to Pharmacology

BIOAVAILABILITY
 Defined
as the proportion of drug conc
that reach the systemic circulation
following administration.
 This is measured by the area under the
curve AUC
AUC= A / Ke
 A:
the point or concentration where the
drug reach max plasma concentrated
 Ke: elimination rate constant (0.7/ t½)
f = AUC PO/AUC IV
• Ke: the time were the concentration of the
drug in plasma drop by 50% (elimination
constant)
• IV doses have 100% bioavailability, f = 1
Factors affecting Bioavailability
A- Extent of absorption:
 Usually any drug taken by oral administration is
incompletely absorbed
B- First- pass metabolism:
 After absorption of a drug it goes to the liver
through portal circulation were it is metabolized
to active or inactive compounds (can occur in
the gut).
 Some of these compounds are excreted in bile.
Hepatic Extraction ratio (ER)
 It
is affected by: rate of hepatic
clearance of the drug and hepatic
blood flow
ER= CL liver/ Q
 CL liver: liver clearance of the drug
 Q: hepatic blood flow
Systemic Bioavailability (F)
F= f(1-ER)
f: the extent of absorption of the drug
Example:
A drug like morphine if taken orally almost
completely absorbed f=1 hepatic
ER=0.67 so
F=(1-ER)=1-0.67=0.33
F= 0.33×100=33%

VOLUME OF DISTRIBUTION
 Vd:
relates to the amount of drug in the body
to the concentration of the drug in blood or
plasma
Vd= amount of drug in body
C
 It is affected by protein binding.
 Only unbound drug (free fraction) exerts
pharmacolological effects

The higher the Vd, the lower the plasma
concentration and vice versa

Vd is low when a high % of drug is bound
to plasma proteins
Special Barriers to Distribution
Placental
 Most drugs cross the placental barrier, but fetal
blood level is usually lower than maternal
Blood-Brain
 Permeable to lipid soluble or very small drug
molecules
Redistribution
 Lipid-soluble drugs redistribute into fat tissues
prior to elimination - repeated doses cause
saturation – may prolong duration of action
DRUG ELIMINATION
It involves the following:
1- Drug metabolism: which include enzymatic
conversion of one chemical entity to another

2- Drug excretion: includes the elimination of
drugs either unchanged or metabolized
 It occurs through the kidney, hepato-billiary
and lung.
Drug Metabolism
 Lipophilic
compound are not excreted by the
kidney and they need to become more
soluble or polar to be excreted.
 Metabolism occurs mainly in the liver
(CYP450 system)
 Metabolism may result in formation of active
metabolites (diazepam – nordiazepam)
 Prodrugs lack activity until they undergo
bioactivation (clorazepate – nordiazepam)
Metabolism involves two phases:
Phase -1 reaction: (catabolic)
 it
includes: oxidation, reduction, and
hydrolysis reaction.
 It is called “the microsomal mixed function
oxidase system”.
 Major phase 1 enzymes – localized in smooth
ER of liver, GI tract, lungs, and kidneys
 It


includes two enzymes:
1) NADPH cytochrome reductase
2) CYP450 system
Require O2 and NADPH
Multiple CYP families vary by substrate
specificity and sensitivity to inhibitors &
inducing agents
CYP3A4

Major isoform with wide substrate range

Inhibited by cimetidine, macrolides, azoles
& ethanol (acute)

Induced by carbamazepine, phenobarbital,
phenytoin, rifampicin, & ethanol (chronic)
CYP2D6

Genotypic variations in hydroxylation (fast /
slow)

Substrates include codeine, debrisoquin &
metoprolol

Inhibited by haloperidol & quinidine; not
inducible
Other Phase 1 metabolism
Monoamine oxidases metabolize NE, 5HT,
and tyramine
 Alcohols
metabolized
via
alcohol
dehydrogenase (ADH) to aldehydes then
aldehyde dehydrogenoase (inhibited by
disulfram)

Phase -2 reaction:
 It include conjugation with other groups to
make it more soluble.
 Groups used in conjugation:
 glucoronyl,
 sulfate,
 methyl,
 acetyl,
 glycyl
 glutathione

This phase can occur in the kidneys

Acetylation is genetically determined. Fast
acetylators and slow acetylators (develop SLE
like syndrome when given INH, hydralazine,
procainamid or INH
Transferases: usually inactivate drugs, but may
activate (e.g. morphine, minoxidil). May follow a
phase I hydroxylation, but also occur directly
 Glucuronidation – inducible; reduced activity in
neonate

RENAL EXCRETION
There are 3 main process for Renal excretion
of a drug:
1- Glumerular filtration rate: (GFR)
 This depends on the molecular weight of the
drug and the extents of binding to plasma
proteins.
2- Tubular secretion:
 Here drug molecules are transferred by two
independent and non-selective carrier systems
i.e. Transport of acidic compounds or basic
compounds
 They
transport drug molecules against
conc. gradient so can reduce the plasma
conc. of the drug to zero.
 E.g. penicillin
3- Diffusion across the renal tubules:
 Renal tubes can be freely permeable (the
drug concentration in the plasma and in the
renal tube is equal)
DRUG ELIMINATION (CLEARANCE)
 Defined
as the volume of plasma containing
the amount of substance that is removed by
the kidney in unite time
CL= Cu Vu
Cp
CL: Clearance
Cu: Urine Concentration
Cp: Plasma Concentration
Vu: Volume of Urine
CLEARANCE





Equals rate of elimination divided by plasma level
Constant for 1st order elimination
Total body clearance CL = CLR + CLER (extra
renal)
With no secretion or reabsorption renal clearance
is the same as glomerular filtration rate, CLR =
GFR
If drug is protein bound then CLR = GFR x free
fraction
There are two ways for
drug elimination:
1- First Order Kinetic
2- Zero Order Kinetic
First Order Kinetic (un- saturable)

Defined as the amount of drug removed
is direct proportion to its concentration in
plasma.
ZERO- ORDER KINETICS
(SATURABLE)
 Here
drugs are removed at a constant rate
regardless the plasma concentration
levels because it is an enzyme dependent
process so it has limited capacity.
Example:
 Ethanol
 Phenytoin
 Salicylates
Blood Alcohol concentration
t½
10.9
7.6
4.3
TIME
Dose Administration
Alcohol is eliminated
at a rate of 4mmol/l
regard less the
plasma concentration
t½ HALF LIFE OF A DRUG
Is the time required by the body to eliminate 50%
of the drug concentration
t½= Vd x 0.7
CL
 It is important to indicate the time required to
attain 50% of the steady state
 This helps in the setting up of a dosage regime
which produces:
 stable plasma drug concentrations
 keeps the level of drug below toxic levels but
above the minimum effective level


Loading Dose
 This is given when an effective plasma level
of drug must be reached quickly.
 This requires a dose of the drug which is
larger than is normally given.
 This dose is given as a one off.

Maintenance dose:
 This is the dose given when the required
plasma level of drug has been reached.
 It is the normal recommended dose.
 This is then continued at regular intervals to
maintain a stable plasma level .