Nermein Fawzy 2/15/2023

Pharmacokinetics
Dr. Nermein Fawzy EL Sayed
Lecturer of pharmacology and toxicology,
Faculty of pharmacy, Ahram Canadian university

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What is Pharmacology?
• Includes all aspects of drugs
• Deals with interaction of Drugs with living system.
• Most importantly those that are relevant to effective and safe use for
medicinal purpose.

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Pharmacology

Movement of the
Action of the drug
drug
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Toxic /
side
effect

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•Simply PK is
The study of the basic processes that
determine the duration and Intensity
of drug effect namely and it deals with
how the body acts on the drug

It involves the study of drug:

ADME
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Fundamental Pathways of Drug

Movement & Modification in the Body
• Absorption :
The process of drug entering into systemic circulation= (INPUT) Drug in
plasma
• Distribution :
The dispersion of a substance throughout fluids and tissues of body.
• Metabolism :
The transformation of parent compound into structurally similar
daughter compounds by the liver or other tissues.
• Excretion :
The removal (OUTPUT)of substance (Drug & metabolites) from the
body in urine, feces, or bile

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Why is PK important?
• Pharmacokinetics helps us understand many properties of the drug as:
• How quickly a drug will work.
• Where the drug is primarily distributed.
• Quantities to use when dosing a drug.
• Any metabolites that are produced when the drug is broken down.
• Drug dose adjustment to prevent toxicity in some cases of liver or
renal impairment.

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Routes of Drug Administration:

• Determined primarily by the properties of the drug
• MAJOR ROUTES OF DRUG ADMINISTRATION
1. Topical
2. Systemic
 Enteral
 Parenteral

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Different routes of drug

administration

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IV route → 100% absorption

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For all other routes <100% 14
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• Absorption is the transfer of a drug from the site of administration to

the bloodstream.
• The Plasma Membrane Is Selectively Permeable

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Mechanism of drug absorption

• PASSIVE DIFFUSION = Simple diffusion
• Most common mechanism of drug transport
• The driving force for passive absorption of a drug is the
concentration gradient
• The drug moves from a high concentration to a lower
concentration
• Does not involve a carrier / energy
• The drug moves through aqueous channels (water
soluble drugs) or the drug is soluble directly in the lipid
membrane
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Facilitated diffusion :
• Involves a carrier
• Specialized transmembrane carrier proteins facilitate the
passage of drug molecules according to the concentration
gradient
• It does not require energy
• Can be affected by the presence of a compound that
compete for the carrier
• eg: glucose and amino acids

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Active Transport :
• Involves a specific carrier protein
• Is “energy dependent” & is driven by the hydrolysis of ATP
• Also capable of moving a drug against a concentration gradient
• Used by → too large or too lipid insoluble molecules or ion transfer
Eg: NA+/K+ ATP pump
Endocytosis :
engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug filled
vesicle. Uptake of extracellular material by its inclusion in a vesicle formed by invagination of the
Plasma membrane
eg. Vitamin B 12
Exocytosis:
reverse of endocytosis, the fusion of intracellular vesicle with plasma membrane , releasing the
vesicle contents to extracellular space. Cells use exocytosis to secrete substances out of the cell.
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• Endocytosis : engulfment of a drug by the cell membrane and transport into the cell by
pinching off the drug filled vesicle. Uptake of extracellular material by its inclusion in a
vesicle formed by invagination of the Plasma membrane eg. Vitamin B 12
• Exocytosis: reverse of endocytosis, the fusion of intracellular vesicle with plasma
membrane , releasing the vesicle contents to extracellular space. Cells use exocytosis to
secrete substances out of the cell.
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Passive diffusion : Active processes: CARRIER MEDIATED: Endocytosis

dominates trans- play a role in the Used to transport engulfment of a drug
membrane movement of many drugs of large size by the cell
movement of most drugs, whose across the cell membrane and
drugs. molecules are too membrane. transport into the
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Factors influencing rate of absorption

1. Route of administration- influences bioavailability
IV administration- immediate and complete absorption.
Other routes- shows partial absorption that is carried through various barriers to
reach the blood circulation and their site of action.
I.V > I.M. > S.C. > oral
2. Concentration of drug- the ↑ in conc. → ↑ rate of absorption
3. lipophilicity– influences the lipid solubility
Nonionized → lipophilic → better absorption
N.B. extremely Hydrophilic and extremely lipophilic drugs both are poorly
absorbed
4. Molecular
2/15/2023 size: The smaller in size-----more absorption
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5. Surface area available for absorption - The more absorptive surface

area, the more absorption.
Eg. Brush borders of the intestine -1000-fold SA to that of the
stomach,
- Hence EFFICIENT ABSORPTION.
6. Blood Flow to the absorption site- The intestines receive much
more blood flow than the stomach, so absorption from the intestine is
favored over the stomach.
↑ Blood Flow → Faster rate of uptake
7. Contact time at the absorption surface: If a drug moves through the
GI tract very quickly (in severe diarrhea), it is not well absorbed.
8. Food in the stomach -dilutes the drug and slows gastric emptying.-
drug taken with a meal is generally absorbed more slowly
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9. Expression of P-glycoprotein :

P-glycoprotein is a transmembrane transporter protein

 Phosphorylated protein of MDR (multidrug resistant)
family of ABCs (ATP-binding cassette) transporters
 Expressed in:- liver, kidneys, placenta, intestines etc.
 Involved in transportation of drugs from tissues to
blood = “pumps” drugs out of the cells.
 high expression of P-glycoprotein →↓drug absorption

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10. Effect of pH on drug absorption :

Most drugs are weak organic acids or bases, so they undergo ionization
- Ionization of drugs→↓ LIPOPHILICITY → ↓its ability to permeate membranes
- A drug is present in solution as both :
 The non-ionized form = Lipid-soluble = diffusible across a membrane.
 The ionized form = lipid insoluble = poorly diffusible across a membrane.
- The degree of ionization of a drug is determined by the surrounding pH and pKa of the
drug

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Bioavailability For the IV drug the

• Definition: This is the % of unchanged drug that reaches the systemic concentration starts at the
circulation when a drug is administered. highest point, and over time
↓ as the drug is
• Bioavailability varies between drugs and may be 100%, or it could be much
metabolized /eliminated.
less. (<100% for orally administered drugs)
• Some drugs may be poorly absorbed, meaning a large dose may need to be
given for only a small percentage to actually reach the blood stream.

• When a drug is given IV it is 100% bioavailable. This is because the entire

dose is injected directly into the bloodstream, and therefore bypasses the
poor absorption or extensive first pass metabolism.

For the oral drug the

concentration in the blood
gradually ↑as it’s absorbed,
peaks, then gradually ↓as it’s
eliminated.
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Absorption of drug by different routes

• IV → 100%
• IM/SC / sublingual → >75% (due to local binding of drug)
• Oral → low bioavailability
due to :
(a) incomplete absorption
(b) first pass metabolism

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I.V ,
First Pass Metabolism Sublingual
• Is the metabolism of the drug before it reaches or rectal
the systemic circulation = pre-systemic
metabolism
• Metabolism may occur in :
a) Intestinal lumen ( proteases and
bacterial flora)
b) Intestinal wall (MAO enzymes , CYP450)
c) Liver (Major site of drug metabolism)
d) Lung

First pass metabolism → ↓ Bioavailability

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Hepatic first pass metabolism

• When a drug is absorbed from the GI tract it is not
immediately available to the systemic circulation.
• It must first travel through the hepatic portal vein
and pass through the liver where it is filtered and
exposed to hepatic enzymes which may metabolize
it. → “first pass metabolism”
• Once the drug has passed through the liver it then
reaches the systemic circulation and this is where
the concentration can be measured in the blood.
• Some drugs are extensively metabolized during this
process and this can ↓the bioavailability of the
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&reaches the site of its action

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Factors affecting distribution

• Lipid solubility :
The brain has high lipid content → dissolves a high conc. of lipid soluble drugs
• Blood flow:
↑ blood flow → ↑ distribu on
• Capillary permeability:
 Blood brain barrier →The presence of tight junctions in the brain → Highly lipid
soluble, SMALL and poorly bound to plasma proteins drugs can cross BBB
This junction is lost in meningitis
 The presence of large slit junctions in the liver allows passage of drugs and
large plasma protein
• Protein binding : - Plasma protein binding
- Tissue binding
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Plasma protein binding Liver diseases or

pre-eclampsia
• Drugs reversibly bind to plasma protein. ↓ albumin level
Acidic drug to albumin e.g. Warfarin
Basic drug to α1- glyacoprotein e.g. quinidine
• there is equilibrium between bound and free forms of the drug
• Only the Free, Unbound drug is available to act on target sites in
the tissue, showing a biological response and available for the
process of elimination.
• Bound form → are inert (no ac on) and acts as reservoir
• High affinity to bind to plasma protein makes the drug long acting
and slows its distribution.
• When 2 drugs are given each with high affinity for albumin → they
compete for the available binding site.
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Tissue storage
• Drugs may bound to ssues→ has less plasma conc.
• E.g. – Skeletal muscle, heart & kidney– Digoxin
Liver & Retina - Chloroquine
Thyroid - Iodine
Bone and teeth – Tetracycline
• Act as reservoir → Prolong duration of action.
→↑ ssue toxicity

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High Vd = Highly distributed in

extracellular fluids
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METABOLISM = biotransformation
• Metabolism is biochemical conversion of the parent molecule into metabolites
• The liver is the major site for drug metabolism
but specific drugs may undergo biotransformation in other tissues as: kidney, intestine, lung,
plasma and skin.
• Drug metabolism → a empt to convert lipophilic compounds → more hydrophilic → to be ready for
elimination→ through Bile / Urine
• Metabolites may be :
Drug →→→ Metabolite
 Inactive or less active e.g. ibuprofen, paracetamol, lidocaine
 More active metabolite e.g. Codeine –> Morphine
 Activation of inactive drug e.g. Levo-Dopa (prodrug) –> Dopamine (active drug)

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 Conversion to highly toxic metabolites e.g. Acetaminophen- hepatotoxicity
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Metabolic phases in the liver

Phase 1 (Catabolic) metabolism:
• Phase 1 utilizes: Cytochrome P-450 = microsomal enzymes=CYP450
• Converts lipophilic molecules → more polar molecules (hydrophilic)
1. Introducing a polar group
2. Unmasking a polar group
Reactions that take place: Inducers→ Barbiturates,
Oxidation smoking
Reduction Inhibitors→ Allopurinol
Hydrolysis

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Phase 2 (Anabolic) metabolism

• Is the process of Conjugation with endogenous substrates as :
Glucuronic acid
sulfuric acid
acetic acid
Amino acids
• Generally after phase 1 if the metabolite is still too lipophilic , the drug
undergoes metabolism in phase 2 process to retain a more polar drug
to be easily excreted

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Excretion
• The kidney is the most important excretory organ
• Drug and its metabolites are removed from the body in urine, Bile (feces),
sweat and expired air.
• Renal elimination of drugs:
 The kidney cannot efficiently eliminate lipophilic drugs.
 Only free, ionized, hydrophilic drugs are excreted into the urine
 Unionized, lipid-soluble drugs are reabsorbed into blood.
 Drugs with large Vd are poorly excreted in urine.
 Drugs bound to plasma or tissues proteins cann’t be filtered by
glomerulus.
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Renal elimination of drugs

Renal elimination is the most important route for drug
removal from the body into urine.
• Glomerular filtration: of free unbound drug and
metabolites
• Proximal tubular
a) Active secretion: of polar ionized drugs and
metabolites, nonselective
Penicillin and probenecid compete for the same
transport system→ ↓elimina on of penicillin
=prolongs its action
b) Passive reabsorption of water and important
electrolytes
• Distal tubular passive reabsorption of lipophilic unionized
drugs back to the blood
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Effect of pH on renal elimination :

• PH affects ionization and therefore, polarity of drugs
• Alteration of urine pH can be done to→ ↑ frac on of ionized drug →↑
clearance of an undesirable drug
• Weak acids can be eliminated by alkalinization of the urine (sodium
bicarbonate infusion)
• Weak bases can be eliminated by acidification of the urine (Ascorbic
acid, ammonium chloride, cranberry juice)

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Examples:
In overdose of
phenobarbital (weak acidic drug)
→ therefore; alkalinization of the urine with sodium
bicarbonate infusion will increases urinary excretion.
Amphetamine (weak base)
→Therefore; acidification of urine (Ascorbic acid,
ammonium chloride, cranberry juice) increase ionization
thus urinary excretion.

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• Clearance (CL): ml/min

• Is a hypothetical volume of body fluid from which the
drug is removed/cleared completely in a specific period
of time

• Half-life (t1/2):
oThe time required to eliminate (metabolize and excrete) 50% of the drug from the
body.
oDetermines the frequency of dosing required to maintain therapeutic
plasma levels of a drug
oHalf-life depends on clearance (CL) and volume of distribution (Vd)

t1/2= 0.693 Vd/CL

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REFERENCE:
• Pharmacology for Physiotherapy Book. By Padmaja Udaykumar
Second Edition.
• Basic & clinical pharmacology. Bertram g. Katzung

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