Pharmacokinetic 1

Professor Nageeb A.G.M. Hassan

Reference
Lippincott illustrated Reviews of Pharmacology 7th edition Chapter 1
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 Pharmacokinetics
“What the body does to the drug”

✓ The study of the movement of drugs in the body:

✓ How it reaches the site of action (absorption & distribution) &
✓ How it leaves its site of action (elimination “metabolism &
excretion”) & at what concentration

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 Absorption: First, absorption from the site of
administration permits entry of the drug (either
directly or indirectly) into plasma.

Distribution: Second, the drug may reversibly

leave the bloodstream and distribute into the
interstitial and intracellular fluids.

Metabolism: Third, the drug may be

biotransformed through metabolism by the liver
or other tissues.

Elimination: Finally, the drug and its metabolites

are eliminated from the body in urine, bile, or
feces.

Using knowledge of pharmacokinetic parameters,

clinicians can design optimal drug regimens, including
the route of administration, dose, frequency, and
duration of treatment.

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Professor Nageeb A.G.M. Hassan Pharmacokinetic 1
 HOW DO DRUGS GET INTO THE BODY?

➢ Absorption of the drug.

➢ Methods of drugs cross cell “biological” membranes
➢ Factors affecting absorption of the drug.

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Absorption of drug
concerns the process of entry of a drug into systemic circulation
from the site of its administration.

The faster the absorption, the faster the action starts.

Vascular System

(1) (2)
BIOLOGICAL
Routes of BARRIER
drug
Administration

(3)
Factors affecting the absorption

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 WHAT ARE THE ROUTES OF DRUG ADMINISTRATION?

Systemic Local

Enteral “FPM” ✓ - Parenteral Topical Deeper tissues

“Skip FPM” “Surface”
- Oral GIT & Liver - Intra-arterial
✓ IV - Skin & mucous
- Rectal membrane - Intra-articular
- Upper rectum ✓ IM “In joints”
- Lower rectum - Eye, Nasal,
✓ ID Ear, oral - Intra-thecal
cavity. e.g. “In SF”
✓ SC
✓ Buccal e.g. Sublingual (Drops, Ointment,
✓ Mucosal Cream, Gels)
• Inhalation
• Transdermal
• Topical.

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 Commonly used
routes of drug
administration.
IV = intravenous;
IM = intramuscular;
SC = subcutaneous.

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 Routes of drug administration

The choice of route of administration depends on:

1- Properties of the drug.

2- Systemic vs local effects
3- Desired onset of action.
4- patient characteristics
5- Patient compliance

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Oral administration (PO)

Advantages:

- Convenient - can be self- administered, pain free, easy to take

- Absorption - takes place along the whole length of the GI tract
- Cheap – formulation compared to other parenteral routes.

Disadvantages:

• Delayed onset so unsuitable for emergencies.

• Some drugs are not absorbed orally e.g. Streptomycin (so act locally on gut).
• Not suitable for irritant drugs.
• Unpleasant taste of some drugs.
• Unsuitable for unconscious patient.
• Over dosage – misuse.
• Some drugs are subjected to first-pass effect – GUT gastric acid (benzyl
penicillin) and digestive enzymes (insulin) & LIVER before reaching systemic
circulation e.g. testosterone, lidocaine.

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Sublingual/Buccal (SL) e.g. Nitroglycerine (Angina pectoris).
- Some drugs are taken as smaller tablets which are held under the tongue
which directly absorbed to the general circulation.
- It has rich blood supply.
- The drug must be highly lipid soluble.
- The drug is effective in small dose & stable at alkaline pH.

- Advantages
• Easy to take & to remove.
• Rapid absorption → rapid onset of action
• Avoid (bypass) first-pass effect.

- Disadvantages
• Inconvenient
• Small doses
• Unpleasant taste of some drugs
• Irritant drugs should not be given by this route.

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 Rectal administration
Inserted through the rectum.

Fluids (Enema)
Solid (Suppository) It is
dissolved at the body temperature
(melt) releasing active compounds from
the gelatin cover. Evacuation (Cleaning) Retention (Nutrient)
e.g. Aminophylline in a cone of - Small volume
- Large volume
gelatin or cocoa butter.
- High head pressure - low head pressure
Glycerin suppository can
also be used to evacuate - Mild irritant - Non irritant
the colon

Advantages:
Disadvantages:
1. Useful in unconscious patients and children
2. Useful in patient is nauseous or vomiting 1- Psychological
3. Good for drugs affecting the bowel such as not accepted by some patients
laxatives for local effect –constipation. 2- Laxative effect
4. Useful in mild irritating drugs. 3- Irritation of the rectum
5. Useful in large volume drugs. 4- Absorption may be variable
6. Escape or little FPE. 5- Not suitable in case of diarrhoea.

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Parenteral Routes
- All drugs must be STERILE & PYROGEN FREE.
- Used when:
- Drugs poorly absorbed / unstable in GIT
- Patient unconscious. / drugs producing irritation.
- Immediate onset required (emergency)

- Intravascular (IV, IA)- placing a drug directly into

the blood stream (always the drug vehicle is watery
(aqueous). It has fastest onset. F=1, bolus or
infusion (Heparin)

- Intramuscular (IM) - drug injected into skeletal

muscle, absorption rate depends of site: deltoid >
thigh > buttocks (Vaccines, Morphine. (Drug vehicle
either aqueous or oily)

- Subcutaneous (SC)- slow absorption but can be

enhanced by heat etc. (Insulin). (Drug vehicle either
aqueous or oily). Concerning oily vehicle drug take A. Schematic representation of subcutaneous
long term effect because the drug is released slow. & intramuscular injection.
B. Plasma concentrations of midazolam after
9/27/2022 intravenous1and intramuscular injection.
Professor Nageeb A.G.M. Hassan Pharmacokinetic 12
Intramuscular (IM)

1- Very rapid absorption of drugs in aqueous solution

(advantage), suspension, oily, non-irritant or
mild irritant.

2- Better absorption than SC.

3- Some drugs (Diazepam & Phenytoin) bound to muscle

Proteins leading to irregular absorption.

4- Pain at injection sites for certain drugs (disadvantage).

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Subcutaneous (SC)

1. Slow and constant absorption

2. Absorption is limited by blood flow, affected if circulatory
problems exist.
3. Concurrent administration of vasoconstrictor will slow absorption.
See before.

Subcutaneous Pellet implantation

Sterile pellet under the skin → fibrosis →slow absorption →long

duration e.g. hormones (Contraceptives)

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Intravenous (IV) injection

Advantages:

1. Fast onset of action (Emergency).

2. large quantities can be given, fairly pain free
3. (100% bioavailability); No first pass metabolism
4. Useful for irritant drugs.
** Slow bolus injection or
Disadvantages: infusion (drip) method
only water solution
1. Need to be sterilized to avoid infection.
2. Greater risk of embolism.
3. If allergy leading to anaphylactic shock.
4. If very irritant leading to thrombophlebitis.
5. It rapid IV leading to velocity reaction resulting in cardiac problems
e.g. Aminophylline.
6. Extravasation of irritant drug leading to severe pain & inflammation.
7. Expensive.
8. Transmission of diseases (IV). What?
9. Overdose toxicity is very difficult to be removed.

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Topical administration
1- Inhalation “Pulmonary”: Inhalation – absorption through the lungs

a. Gaseous and Volatile liquid e.g. Systemic effect - general anaesthesia

Rapid onset of action due to rapid access to circulation
a. large surface area
b. thin membranes separates alveoli from circulation
c. high blood flow
Also, endotracheal administered of drugs e.g. adrenaline or
atropine in cardiac emergencies.

b. Aerosols / Nebulizer e.g. Local effect bronchial asthma)

“Solution such as Salbutamol -agonist & Powder such as
Di-sodium Cromoglycate “mast cell stabilizer”
What are the advantage and disadvantages?

2- Mucosal membranes:
e.g. (eye & ear drops, antiseptic, sunscreen, nasal, vaginal, …etc. as
solution, ointment, powder)

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 3- Skin:
a. Dermal - rubbing in of oil or ointment, cream (local action).

b. Transdermal Drug Delivery System (TDDS) = Skin patch.

absorption of drug through skin (systemic action).
i. stable blood levels
ii. no first pass metabolism
iii. Better patient compliance
e.g. Hyoscine & Nitroglycerine
4- Injection
as infiltration anaesthesia e.g. adrenaline & intra- articular e.g.
hydrocortisone

5- Intradermal Injection (ID): e.g. used for sensitivity tests &

Vaccinations.
** Usually skin absorption not wanted & harmful. e.g. Cortisone in infants (Moon face)
- Estrogen in female (cancer breast)
- Insecticides (toxicity)

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- The interval between the time a drug is administered & the first sign of
its effect is named ONSET.

- Duration of action: is the time from the start of action to when it ends.

Drug taken Drug starts to work Drug action disappears

X X X
Onset of action Duration of action

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Methods of drugs cross cell “biological” membranes

- There are several useful routes of drugs administration but almost all
require that the drugs cross a biological membrane to reach its site of
action.

- Cell membrane is formed mainly of bimolecular LIPID layer, attached from

both its side to a protein macromolecule layer (receptors, carriers, enzymes,
..etc.), water filled pores & ion channels.

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- The ability of the drug to cross the cell membrane is very important factor
that determine its clinical use , whether to be taken orally or systemically.

- So, the highly polar drug is not given orally, as it will not be absorbed from
GIT.

Also, this ability determine whether the drug can cross the blood brain
barrier (BBB) or not. As all drugs that are intended to be used clinically
for management of brain disorders should pass the BBB (Being lipophilic
state).

N.B:
All the membranes in the body have pores in between EXCEPT in the
blood capillaries of brain.

The major Mechanism of drug absorption

1- Passive diffusion
2- Active transport

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Schematic representation of drugs crossing a cell membrane. ATP = adenosine triphosphate;
ADP = adenosine diphosphate.
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Methods of drugs cross cell “biological” membranes

Help of Energy or
Nature of drugs Way
Carrier
-Passive diffusion Along concentration gradient,
unsaturable process
(95%) Most common method

- Lipid diffusion Lipid soluble drug Diffuse through the phospholipid

whatever the bilayer
molecular weight. Non No Energy or Carrier
ionizable.

- Aqueous diffusion Water soluble drug & Diffuse through the water filled
small molecular weight. pores, the drug should be water.
Ionizable
- Facilitated Similar to Simple Along concentration gradient. Pass
Help of a carrier but no
diffusion; e.g. glucose, through capillary endothelium &
diffusion amino acid glomerular.
energy is needed

-Active transport e.g. Penicillin, Against concentration gradient,

saturable process (Competitive)
Help of a carrier &
Na+, K+ pump, L-dopa cellular Energy (Provided
by break of ATP)

- Filtration method Small molecule; Along hydrostatic or osmotic

pressure No Energy or Carrier
water soluble

- Pinocytosis “Cell Vitamin B12 & intrinsic Drug is engulfed by invagination of

drinking” factor the cell membrane ”terminal ileum” Energy is needed

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Most drugs which are used in medicine are either
weak acids or weak bases

and each drug has dissociation constant (pka).

The pka of a drug: is the pH at which 50% of the drug is ionized & 50% non-
ionized.

The degree of ionization of a weak acid or a weak base is determined by pka

of drug and pH of environment “medium” according to Henderson- Hasselbalch
equation.

NOTE:
Lipid solubility is measured by lipid/water partition coefficient
Absorption is proportional to lipid solubility. e.g. barium chloride is lipid insoluble
therefore not absorbed orally.

Degree of ionization:
The more the drug is ionized the lesser the absorption because ionized drug are
less lipophilic.

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- In the biological fluid, a drug is present in two forms:
ionized Or non-ionized

- The non-ionized particles is lipid soluble (Lipophilic & Hydrophobia)

i.e. can cross the biological membrane.

- The ionized particles is lipid insoluble (Hydrophilic & Lipophobia)

i.e. can not therefore cross the membrane.

Therefore, the factors control the crossing of the drugs

through the biological fluids are the nature of the drug & the
pH of the biological fluid.

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Summary of drug absorption
- Most drug absorption occurs through passive “diffusion” absorption.
- Lipid soluble drugs are more readily absorbed than non-lipid soluble drugs.
- Non-polar drugs are more readily absorbed than polar drugs.
- Non-ionized drugs are more readily absorbed than ionized drugs.
- Basic drugs are more readily absorbed in the small intestine than acid drugs.
- Overall, the majority of drug absorption occurs in the small intestine.

**Drugs are absorbed at same pH environment & excreted to the opposite pH.

Drugs Absorption Excretion

1- Acidic e.g. Aspirin Acid media Alkaline media
“Stomach” “Urine”
2- Basic e.g. Ephedrine Alkaline media Acid media
“Intestine” “Urine”
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Factors affecting oral drug absorption (from the GIT)

1- Lipid solubility
2- Non-ionized drugs
3- State of health of GIT mucosa: Diarrhoea &
Mal absorption → decrease oral absorption.
4- Systemic circulation
Shock & Heart failure → decrease absorption
5- Specific factors
Intrinsic factor for Vitamin B12 absorption.
6. Surface area of absorption
Drugs are mostly absorbed from intestine when
orally administered regardless of its nature
because intestine provides large surface area of
absorption and long time absorption.
7- Vascularity of absorbing surface
8- pH within the gut. See later.
9- Gut contents – food, other medicines.

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What is Bioavailability of a drug
Is a fraction (%) of the dose “drug” that
reaches the systemic circulation in an
unchanged form following administration by any
route.
- After IV (Intravascular) administration do not involve absorption &
there is no loss of drug, so bioavailability will be 100%, BUT with
extravascular administration e.g. (PO; oral), Intramuscular (IM),
Subcutaneous (SC), Inhalation], less than 100% of a dose may reach
the systemic circulation because of variation in bioavailability.
So extravascular administration depends on:
1- Amount absorbed & rate of absorption. Variability in absorption
may be due to pharmaceutical factors (size of particles,
dissolution rate & nature of diluent or vehicle).
2- Amount metabolized either in gut epithelium or liver.
i.e. first pass effect.

Bioavailability = Area under the curve (AUC) of the oral route X 100
Area under the curve (AUC) of IV route

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First Pass Effects

After a drug is swallowed, it is

absorbed by the digestive system
and enters the portal circulation.
The absorbed drug is carried
through the portal vein in to the
Liver.

The liver is a metabolic machine &

often inactivates “metabolized”
drugs on their way from the GIT to
the body. This is known First Pass
Effect.

First-pass metabolism can occur with orally administered drugs. IV = intravenous.

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