Pharmacokinetics

and Metabolism
Pharmacokinetics

Body’s effect on a drug:

1. Absorbtion
2. Distribution
3. Metabolism
4. Elimination (clearanse)

These let us calculate loading and

maintenance doses.
Terminology

► Volume of distribution: The ratio of the amount of drug in the body to

the drug concentration in the plasma or blood.
► Clearance: The speed at which the active form of drug leaves the
blood/plasma
► Half-life (t1/2): The time required for the amount of drug in the body or
blood to fall by 50%.
► Bioavailability (F): The fraction (or percentage) of the administered
dose of drug that reaches the systemic circulation
► Biodisposition: Often used as a synonym for pharmacokinetics;
Sometimes used more narrowly to describe elimination
Ways of drug administration

► Enteral: Uses GI tract:

Oral, sublingual, rectal
► Parenteral: Doesn’t use GI tract
IV (intravenous), IM (intramuscular), SQ (under
the skin)
► Others:
Inhalation, intranasal, intrathecal (in csf),
topical (applied to the skin)
Bioavailability
The fraction (or percentage) of the administered
dose of drug that reaches the systemic circulation
(F)
IV F = 100%
Enteral F < 100% (Incomplete absorption, liver
metabolism). In patients with the liver disease more
active form of the medication gets to the
circulation.
EFFECTIVE DRUG CONCENTRATION

The effective drug concentration is the

concentration of a drug at the receptor site,
readily measured in the blood. (Except for
topically applied agents)
In order to determine this variable we must know:
1. Volume of the injected drug (dose).
2. Distribution volume.
3. Elimination.
VOLUME OF DISTRIBUTION Vd
The theoretical volume occupied by the drug.
Can be measured by injecting a know dose and
measuring the concentration afterwards
For example, after injecting 10mg of medication
we reached the concentration of 0.5mg/L, which
means that Vd = 20L
Clinical use: Effective dose of the drug is 10mg/L
and it’s Vd = 10L. Therefore the required dose to
achieve therapeutic effect is 10x10=100mg
VOLUME OF DISTRIBUTION
Average human body is 60% water.
60kg human is 36L water
1/3 exracellular (Blood) 12L, 2/3 Intracellular 24L
Extracellular ¼ 3L is Plasma, Interstitial ¾ 9L

Drugs with large molecules or those bound to blood

proteins can not leave vessels and their
concentration is higher than usual leading to
abnormally low Vd. For example Warfarin Vd = 9.8
On the other side drugs that are lipophilic molecules
do not distribute evenly in the body, therefore they
collect in the tissues. For example Chloroquine (For
malaria) Vd = 13000L.
Other factors
Protein binding. Drugs like many other molecules in the blood bind
to the Albumin, which restricts their free movement.
Patients with hypoalbuminemia (Liver diseases, nephrotic syndrome)
may need dose adjustment.
Elimination (clearance)
It’s a summarized effect of all the organs/tissues
effecting it (e.g kidneys, liver, lungs etc.)
The drug elimination from the body follows 2
different systems:
Zero order elimination: When drug gets
metabolized almost instantly therefore the only
limiting factor is the blood flow to the eliminating
organ/tissue. Therefore the medications can stay
longer in the blood of the patients with cardiac
insufficiency.
First order elimination: When drug gets
metabolized slowly, and the reaction speed
depends on the concentration (higher = faster)
Clearance
Defined as the volume of blood filtered in a given period of time
(Speed of elimination)
For example in the medication concentration is 5g/L, this means
that 5 grams of the medication is diluted in 1 liter of blood.
Therefore in order to fully eliminate this medication, body has to
filter out 1 liter of blood.
Kidney and liver pathologies can decrease clearance and
therefore cause toxicity.
Comparison
Zero Order Elimination:
► Elimination speed is constant
► NOT depended on concentration
of the drug
► No Half-Life
► Ethanol, Phenytoin, aspirin
First Order Elimination
► The speed changes with the
concentration
► The speed of the change is constant
(time it takes to eliminate half the dose)
► Characteristic to most of the medications
Zero order elimination

First order elimination

Urine PH effect on elimination
Affect drugs that get excreted in the urine
High Urine acidity (Low pH, more H+), helps produce more acidic
molecules and decreases their secretion, at the same time having
opposite effect on basic molecules)
Weak acidic drugs: Aspirin, Phenobarbital (Luminal, CNS depressant). In
case of overdose, Sodium Bicarbonate (basic) transfusion can increase
their secretion.
Weak basic drugs: Amphetamines, Quinidine, Phencyclidine (Angel
dust). There are medication that acidify urine, but this also acidifies
blood which can lead to toxicity and is not used anymore.
 Metabolism

There are a lot of metabolic drug reactions.

Liver bio transforms medications, turns lipophilic (fat soluble) medications into
hydrophilic (water soluble) in order to secrete them in the urine.
These reactions can be divided into 2 phases:
Phase I: Reduction, Oxidation, Hydrolysis. Produce active metabolites, slows
down with aging and contains Cytochrom p450 sytem.
Substances that effect this system are: Cyclosporins (immunosuppressant),
macrolides (antibiotics), antifungals, and grapefruit juice. Warfarin also uses this
system.
Phase II – Conjugation reactions: Glucuronidation, acetylation, sulfation. Creates
inactive metabolites that get secreted via kidneys.
Doze calculation
Maintenance dose: Dose of the drug required to
replace the eliminated amount.
Loading dose: First dose of the drug given to achive
necessary concentrations. (When half-life is too
high)
Liver/Kidney pathologies maintenance dose can
be lower, but not the loading dose.
While administrating the drug we have to consider
bioavailability. For example if F=50% the dose is
doubled.
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BASIC AND CLINICAL PHARMACOLOGY G. KATZUNG 2020 15TH ED.
KATZUNG & TREVOR’S PHARMACOLOGY EXAMINATION AND
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