GENERAL PHARMACOLOGY

PHARMACOKINETICS

      
DR. AHMED ALARWALI 
      
GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

PHARMACOKINETICS

INTRODUCTION
Pharmacokinetics:
 The movement of drugs inside the body
 Describes the actions of body on the drug.
 What the body does to the drug.
 Drug disposition is divided into four stages designated by the acronym ‘ADME’:
 Absorption (A)
 Distribution or Disposition (D)
 Metabolism (M)
 Elimination or Excretion (E)
The physical processes of diffusion, penetration of membranes, binding to plasma
protein and partition into fat and other tissues underlie the absorption and distribution
of drugs

Drug molecules move around the body in two ways:

 Bulk flow (i.e. in the bloodstream, lymphatics or cerebrospinal fluid).
 Diffusion (i.e. molecule by molecule, over short distances).

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

ROUTES OF DRUG ADMINISTRATION

The route of administration is determined by:
1- Properties of the drug (for example, water or lipid solubility, ionization).
2- Therapeutic objectives (for example, the need for a rapid onset, the need for long-term treatment, or restriction of delivery
to a local site).

A- Enteral
Enteral administration (administering a drug by mouth) is the most common, convenient, and economical method of drug
administration.
The drug may be swallowed, allowing oral delivery, or it may be placed under the tongue (sublingual) or between the gums and
cheek (buccal), facilitating direct absorption into the bloodstream.

1- Oral:
Oral administration provides many advantages. Oral drugs are easily self-administered, and toxicities and/or overdose
of oral drugs may be overcome with antidotes, such as activated charcoal.
However, the pathways involved in oral drug absorption are the most complicated, and the low gastric pH inactivates some drugs.
A wide range of oral preparations is available including enteric-coated and extended-release preparations.

a. Enteric-coated preparations:
- It’s covered with a chemical coat that protects the drug from stomach acid, delivering it
instead to the less acidic intestine, where the coating dissolves and releases the drug. (PH
sensitive cover)
- It’s useful for certain drugs (for example, omeprazole) that are acid labile, and for drugs
that are irritating to the stomach, such as aspirin.

b. Extended-release preparations:
- Abbreviated ER, XR, XL, SR, etc. , medications have special coatings or ingredients that
control drug release, thereby allowing for slower absorption and prolonged duration of
action.
- ER formulations can be dosed less frequently and may improve patient compliance.
- ER formulations may maintain concentrations within the therapeutic range over a longer
duration, as opposed to immediate-release dosage forms, which may result in larger peaks
and troughs in plasma concentration.
- ER formulations are advantageous for drugs with short half-lives.
o For example, the half-life of oral morphine is 2 to 4 hours, and it must be administered six
times daily to provide continuous pain relief.
o However, only two doses are needed when extended-release tablets are used.

2- Sublingual/buccal:
- The sublingual route involves placement of drug under the tongue.
- The buccal route involves placement of drug between the cheek and gum.
- Both the sublingual and buccal routes of absorption have several advantages, including ease of administration, rapid absorption,
bypass of the tough gastrointestinal (GI) environment, and avoidance of first-pass metabolism.

B- Parenteral
- Introduces drugs directly into the systemic circulation.
- It’s used for drugs that are:
o Poorly absorbed from the Gl tract (for example, heparin)
o Unstable in the Gl tract (for example, insulin).
- It’s also used for patients:
o Unable to take oral medications (unconscious patients)
o In circumstances that require a rapid onset of action.
- Parenteral administration provides the most control over the dose of drug delivered to the body.
- This route of administration is irreversible and may cause pain, fear, local tissue damage, and infections.
- The four major parenteral routes are intravascular (intravenous or intra-arterial), intramuscular, subcutaneous, and intradermal

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

1. Intravenous (IV):
- IV injection is the most common parenteral route.
- It is useful for drugs that are not absorbed orally, such as the neuromuscular blocker rocuronium.
- IV delivery permits a rapid effect.
- IV delivery permits a maximum degree of control over the amount of drug delivered.
- When injected as a bolus, the full amount of drug is delivered to the systemic circulation almost immediately.
- If administered as an IV infusion, the drug is infused over a longer period, resulting in lower peak plasma concentrations
and an increased duration of circulating drug.
2. Intramuscular (IM):
Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which
are absorbed slowly.
Depot preparations often consist of a suspension of drug in a non-aqueous vehicle, such as polyethylene glycol.
As the vehicle diffuses out of the muscle, drug precipitates at the site of injection.
The drug then dissolves slowly, providing a sustained dose over an extended interval.
3. Subcutaneous (SC):
Like IM injection, SC injection provides absorption via simple diffusion and is slower than the IV route.
SC injection minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow,
and sustained effects.
This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur.
4. Intradermal (ID):
The intradermal (I D) route involves injection into the dermis, the more vascular layer of skin under the epidermis.
Agents for diagnostic determination and desensitization are usually administered by this route.

C- Other
1. Oral inhalation and nasal preparations:
Both the oral inhalation and nasal routes of administration provide rapid delivery of drug across the large surface area of
mucous membranes of the respiratory tract and pulmonary epithelium.
Drug effects are almost as rapid as are those with IV bolus.
Drugs that are gases (for example, some anesthetics) and those that can be dispersed in an aerosol are administered via
inhalation.
This route is effective and convenient for patients with respiratory disorders such as asthma or chronic obstructive
pulmonary disease, because drug is delivered directly to the site of action, thereby minimizing systemic side effects.
The nasal route involves topical administration of drugs directly into the nose, and it is often used for patients with allergic
rhinitis.

2. Intrathecal/intraventricular:
The blood-brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When
local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid.
3. Topical: Topical application is used when a local effect of the drug is desired.

4. Transdermal:
This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. The
rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as
the lipid solubility of the drug.

5. Rectal:
Because 50% of the drainage of the rectal region bypasses the portal circulation, the biotransformation of drugs by the liver is
minimized with rectal administration. The rectal route has the additional advantage of preventing destruction of the drug in the
GI environment.
This route is also useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is
unconscious.
Rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa.

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

Drug Absorption
- It is the passage (transfer} of the drug from the site of administration to the systemic circulation.
- Absorption is the process by which a drug enters the bloodstream without being chemically altered (transfer the drug from site
of administration to the general circulation).
- It is obvious that absorption from any site (GIT, lung, skeletal muscles, skin and mucous membranes occurs by passage of the
drug across the cell membrane (which is made of phospholipid bi-layer and contains minute water-filled channels and ion
channels}.
- Mathematically it is define in terms of Bioavailability (Rate and extent of absorption). i.e.
 Ka (Absorption constant)………. Rate of absorption
 Area under curve (AUC)………. extent of absorption:
- For I.V.: 100%.
- For non I.V.: ranges from 0-100%
- Example: lidocaine bioavailability is 35% due to destruction in gastric acid and liver metabolism

Bioavailability:
- The fraction (%) of administered drug that reaches the systemic circulation in an unchanged form.
- Bioavailability is 100% after I.V. & most variable after oral administration.

Why Pharmacokinetics is important?

The study of pharmacokinetics is important to design a proper dosage

schedule (Dose, route, frequency of administration) and to determine the
drug's bioavailability.

Process of Absorption

In order for a drug to be absorbed, it must be able to pass through

cell membranes (which is a lipid barrier).
Lipid soluble drugs would be ideal to pass through the
membrane easily.

There are 5 main ways drugs can be absorbed:

1. Passive Diffusion (Lipid & Aqueous diffusion). 2. Facilitated diffusion.
3. Co-absorption with lipids. 4. Active transport.

5. Pinocytosis

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

Mechanisms of absorption of drugs from the GI tract

1- Passive Filtration (Diffusion –Filtration) :

The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body
compartments. In other words, the drug moves from a region of high concentration to one of lower concentration. Passive
diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. DEGREE OF IONIZATION
A. Lipid diffusion:
Small and Highly lipid soluble drugs are able to pass across cell membranes quite easily driven by passive diffusion.
B. Aqueous diffusion:
Drugs that are small and easily dissolved in solution will be able to pass through the cell membrane via aquaporin – special
protein channels designed for the movement of water into cells.

2- Facilitated diffusion
A carrier-mediated transport process in which the driving force is simply the electrochemical gradient of the transported solute.
Other agents can enter the cell through specialized transmembrane carrier proteins (highly selective) that facilitate the passage of
large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules
into the interior of cells and moving them from an area of high concentration to an area of low concentration.
This process is known as facilitated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds
that compete for the carrier.
For example, the organic cation transporter OCT1 (SLC22A1) facilitates the movement of a physiologic solute, thiamine, and
drugs, including metformin, which is used in treating type 2 diabetes.

3- Active transport:
This mode of drug entry also involves specific carrier proteins that span the membrane. However, active transport is
energy dependent, e.g: driven by the hydrolysis of adenosine triphosphate (ATP).
It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher
concentration. The process is saturable.
Active transport systems are selective and may be competitively inhibited by other co-transported substances.
Transport systems which allow the active (require energy) uptake of materials which are structurally similar to the transporter
compound. e.g. Levadopa
N.B: Active transport and facilitated diffusion are known as "carrier-mediated transport".

4- Pinocytosis (Endocytosis or Cell drinking):

It is an active process (energy-dependent) in which the drug is "engulfed" by the cell membrane and transport into the cell by
pinching off the drug-filled vesicle.
This type of absorption is used to transport drugs of exceptionally large size across the cell membrane.
Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar
process of vesicle formation.
e.g. absorption of vitamin B12 by intrinsic factor complex by the ileum and transported across the gut wall by endocytosis ,
whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and
released by exocytosis.
5- Co-absorption with lipids:
Some drugs can be absorbed in conjunction with lipids via micelles formation. e.g. Vitamin A, digitoxin.

Factors, which influence the absorption

1. Routes of drug administration 2. The physicochemical properties of the 3. Dosage forms
drug
4. Concentration of the drug 5. Contacted Surface area. 6. Contact time at the absorption
7. Health state of contacted Surface 9. f
Presence of food or other drugs.
8. Circulation at the site of absorption
10. Expression of P-glycoprotein. 11. Specific Factors 12. Pharmacogenetics factors:
13. Diseases State

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

1. Routes of drug administration

- IV > IM > Oral > Skin. (figure p-5)

2. The physicochemical properties of the drug:

 Physical state:
Liquids are absorbed better than solids and crystalloids absorbed better than colloids. Drug molecule weight and
size is very important, the smaller the better and faster absorption.
 Lipid or water solubility:
Drugs in aqueous solution mix more readily than those in oily solution However, at the cell surface; the lipid
soluble drugs penetrate into the cell more rapidly than the water soluble drugs.
 Ionization:
Most of the drugs are organic compounds.
Unlike inorganic compounds, the organic drugs are not completely ionized in the fluid. Unionized component is
predominantly lipid soluble and is absorbed rapidly and an ionized is often water soluble component which is
absorbed poorly.
For weak base and acid drugs
The unionized (non-polar) form is lipid soluble and easily absorbed.
Ionized (polar) form of drugs is lipid insoluble and not easily absorbed but easily excreted.

a. It depends upon pH of the medium & pKa of the drug.

b. (pKa = Dissociation constant of drug = pH at which 50% of drug is ionized).
c. Low Ionization = High lipid solubility = Better passage.
d. Degree of ionization is determined by the Henderson Hasselbalch equation :
e. For weak ACID drugs: pKa = PH+ log (Unionized form / Ionized form).
f. For weak BASE drugs: pKa = PH + Log (Ionized form / Unionized form).
Most of the drugs are weak acids or weak bases. The theory, the mucosal lining of the G.I.T is impermeable to the ionized form of
a weak organic acid or a weak organic base. These drugs exist in two forms.
 Acidic drugs:
Rapidly absorbed from the stomach e.g. Aspirin and barbiturates.
 Basic drugs:
Not absorbed until they reach to the alkaline environment i.e. small intestine when administered orally e.g. pethidine & ephedrine.
 Valence: Ferrous iron (Fe2+)> Ferric Iron (Fe3+)
 Nature: Inorganic (small molecules) > Organic (Big molecules)

Effect of pH on Oral Absorption & Renal Excretion of Drugs

 According to Henderson- Hasselbalch equation :
a. Weak acid drugs are more unionized in acid & more ionized in alkaline media.
b. Weak base drugs are more unionized in alkaline & more ionized in acid media.
 Weak acid drugs e.g. Aspirin and Barbiturates:
a. Better absorbed in acid medium e.g. Stomach.
b. Alkalinization of urine by sodium or potassium acetate, bicarbonate, benzoate or citrate increase Their urinary excretion.
c. Acidification of urine decrease Their urinary excretion.
 Weak base drugs e. g. Ephedrine & Amphetamine :
a. Better absorbed in alkaline medium e.g. Intestine.
b. Alkalinization of urine decrease their urinary excretion.
c. Acidification of urine by ammonium chloride or ascorbic acid increase their urinary excretion.

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

3. Dosage forms
Particle size:
Small particle size is important for drug absorption.
Drugs given in a dispersed or emulsified state are absorbed better e.g. vitamin D and vitamin A.
Disintegration time and dissolution rate:
Disintegration time: The rate of break up of the tablet or capsule into the drug granules.
Dissolution rate: The rate at which the drug goes into solution.
Formulation:
Usually substances like lactose, sucrose, starch and calcium e are used as inert diluents in formulating powders or tablets.
Fillers may not be totally inert but may affect the absorption as well as stability of the medicament.
Thus, a faulty formulation can render a useful drug totally useless therapeutically.

4. Concentration of the drug

Higher dose of drug (concentration), increase drug absorption> (limitations?)
5. Contacted Surface area.
Drugs can be absorbed better from the small intestine than from the stomach because of the larger surface area of the former.
( With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach)
6. Contact time at the absorption surface
More contact time, means more absorption. e.g: long G.I.T transit time or delay emptying.
If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything
that delays the transport of the drug from the stomach to the intestine delays the rate of absorption. [Note: The presence of food in the
stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.]
7. Health state of contacted Surface area.
May increase or decrease drug absorption.
Oral absorption is greatly decreased in the presence of diseases of GIT as malabsorption.
8. Circulation at the site of absorption
Increased vascular supply can increase the absorption.
[Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing absorption from SC administration.]

9. Presence of food or other drugs.

Rapid absorption occurs when the drug is given on empty stomach. However, certain irritant drugs like salicylates and iron
preparations are deliberately administered after food to minimize the gastrointestinal irritation. However, some times the presence
of food in the G.I tract aids the absorption of certain drugs e.g. griseofulvin, propranolol and riboflavin.
Moreover, the opposite happen for other drugs, the presence of food will decrease or the drug absorption.

The same with presence of drugs, e.g. Vitamin C enhances the absorption of iron from the G.I.T. ,
Calcium present in milk and in antacids forms insoluble complexes with the tetracycline antibiotics and reduces their absorption.
Adrenaline S.C. cause V.C that decrease the absorption of Local anesthetics leads to longer duration of action

10. Expression of P-glycoprotein.

P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell
membranes
It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved
in transportation of drugs from tissues to blood.
That is, it "pumps" drugs out of cells. Thus, in areas of high expression, P-glycoprotein reduces drug absorption.
In addition to transporting many drugs out of cells, it is also associated with multidrug resistance.

11. Specific factors:

Intrinsic factor for Vit B- 12 and apoferritin system for Iron.

12. Pharmacogenetics factors:

Individual variations occur due to the genetically mediated reason in drug absorption and response.

13. Disease states:

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali
Absorption and first pass metabolism may be affected in conditions like malabsorption, thyrotoxicosis, achlorhydria and liver
cirrhosis

Clinical Significance of pK„

GIT
Aspirin is mostly non-ionized in the empty stomach so it crosses the cell membrane of the gastric mucosal cells to be trapped inside
these cells (aspirin trap) may cause death of the cells inducing "peptic ulceration".
So through drug pk, we know the possible site of drug absorption.

Kidney
In drug poisoning cases, renal drug elimination can be enhanced by changing urinary PH.
This increases drug ionization and inhibits tubular reabsorption:
Alkalization of urine (to increase urine PH above drug pKa) is useful in acidic drug poisoning e.g. aspirin & phenobarbital.
Acidification of urine (to decrease urine PH below drug pKa) is used in basic drug poisoning, e.g. amphetamine.

Ion trapping in breast milk:

The pH of the breast milk is 7 VS plasma pH 7.4 (more acidic).
Basic drugs (with pKa > 7.2) tend to be ionized, and thus trapped inside breast milk more than acidic drugs.

Enterohepatic cycling:
Some drugs move in between liver and intestines .
This may increases the bioavailability (will be describe later).

Pre-Systemic Metabolism of drug/first pass effect:

When a drug is absorbed from the GI tract, it enters the portal circulation before entering the
systemic circulation.
If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of
unchanged drug entering the systemic circulation is decreased.
This is referred to as first-pass effect or metabolism.

Gut First Pass Effect:

a. Gastric Acidity: Benzyl Penicillin.
b. Digestive Enzymes: Insulin & Pituitary hormones
c. Mucosal enzymes: Tyramine, L-DOPA, a-Methyldopa & Chlorpromazine

Hepatic First Pass Effect:

a. Extensive: Nitroglycerine, Lidocaine & Natural sex hormones.
b. Partial: Propranolol & Morphine.
c. Minimal: Atenolol, Nadolol & Barbitone.

Factors reducing Hepatic 1st pass metabolism

a. • Reduction in portal blood flow: portal hypertension, propranolol.
b. • Inhibition of hepatic enzymes: liver failure - enzyme inhibitors; erythromycin.

How to OVERCOME Hepatic First Pass Metabolism?

- Increase the oral dose of the drug e.g. Morphine & Propranolol
(in doses sufficient to ensure that enough active drug reaches the desired site of action).
- Use other routes ( NOT ORAL) e.g. Sublingual " Nitroglycerine".

Pulmonary metabolism:
- After aerosol inhalation (nicotine).

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

BIOAVAILABILITY

Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100 mg of a
drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%.

Percentage of the drug that reaches central compartment (plasma) in unchanged form after specific route of administration.
Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration.

Determination of bioavailability:
Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration(for example, oral
administration) with levels achieved by IV administration.

Factors that influence bioavailability:

a) Route of administration
IV > IM > Oral > Skin.
b) First-pass hepatic metabolism.
When a drug is absorbed from the Gl tract, it enters the portal circulation before entering the systemic circulation.
If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug
entering the systemic circulation is decreased.
(For example, more than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is administered via the sublingual,
transdermal, or intravenous route.)

c) Solubility of the drug.

Very hydrophilic drugs are poorly ,absorbed because of the inability to cross lipid-rich cell membranes.
Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous
body fluids and, therefore, cannot gain access to the surface of cells.
For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions.
This is one reason why many drugs are either weak acids or weak bases.

d) Chemical instability.
Some drugs, such as penicillin G, are unstable in the pH of gastric contents.
Others, such as insulin, are destroyed in the GI tract by degradative enzymes.
e) Nature of the drug formulation.
Drug absorption may be altered by factors unrelated to the chemistry of the drug.
For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such
as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.

And all factors affecting ABSORPTION

Bioequivalence and other types of equivalence:

Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood
concentrations.

Therapeutic equivalence: two drugs have the same efficacy and safety.

Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent (that is, they have the same
dosage form, contain the same active ingredient at the same strength, and use the same route of administration) with similar
clinical and safety profiles.
Thus, therapeutic equivalence requires that drug products are bioequivalent and pharmaceutically equivalent.

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

Drug distribution
 Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular
fluid and tissues.
 After absorption drug will distributed throughout the body and it depends on the blood circulation.
 For drugs administered IV, absorption is not a factor, and the initial phase immediately following administration
represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues.
 The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow,
capillary permeability, tissue volume, degree of binding of the drug to plasma and tissue proteins, and relative
lipophilicity of the drug.
 Distribution controls drug actions, efficacy and side effect.
 Distribution of drugs is rarely uniform.
 Drugs are simultaneously being eliminated and distributed, but distribution is usually faster.

Steps of drug distribution:

 Dilution in blood: The drug has to reach equilibrium with itself in the blood.
 Movement into extracellular fluid: Drugs need to be able to get out from vascular system.
 Uptake into cells: The drug must be able to cross the cell membrane.

A- Volume of Distribution (Vd)

Drug distribution is interpreted mathematically as the apparent volume of distribution (Vd).
It is defined as the volume that would accommodate the entire amount of drug in body if its concentration throughout body
was the same as that in plasma.
Vd = Amount of drug in the body / Plasma concentration

Importance of Vd
1- The term "apparent" indicates that it is a hypothetical - not always a true value -as in the case of digoxin which has a Vd
of 500 liters which is much higher that the total fluid volume (42 L. in an average 70 Kg. person).
2- It is an estimate of the extent of tissue uptake of drugs:
 Small Vd (e.g. Fursemide) indicates that tissue uptake is limited.
(Low Vd indicates that the drug is retained in plasma (intravascular, one compartment model) mostly due to high binding to plasma
proteins.)
 Large Vd (e.g. digoxin) indicates extensive tissue distribution.
(High Vd indicates that the drug is distributed as a multicompartment model or has high tissue concentration (highly bound to
tissue proteins). Drugs with very high Vd have slow rate of elimination and long Tl/2.)

3- In cases of drug toxicity:

 Dialysis is not useful for high Vd drugs (most of drug is in the tissues).
 Dialysis is useful for low Vd drugs (most of drug is in blood and ECF).
Drugs with low Vd as aspirin are highly bound to plasma proteins meaning that they a have high plasma concentration, that is why
hemodialysis is useful in treatment of acute toxicity by these drugs.

It is clear that hemodialysis is not beneficial in treatment of acute toxicity by drugs with high Vd because they have low plasma
concentration being highly distributed or highly concentrated in tissues.

4- Vd can be used to calculate the loading dose (LD), which is the initial dose required to reach a specific drug
concentration, and also allows measurement of the total amount of the drug in the body
LD =Vd X Steady state plasma concentration (Css)

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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali
B- Compartment Model:
The body fluids = 42 L. representing 60% of the total body weight (TBW) of an average 70 Kg. person and include plasma (4
L.), interstitial fluid (10 L.), and intracellular fluid (28 L.).
The plasma is referred to as "intravascular compartment", whereas the plasma and the interstitial fluid together (14 L.) are
referred to as "extracellular compartment".
Drugs are distributed according to one of the following patterns of distribution:

1- One Compartment Model:

Drugs that are extensively bound to plasma proteins and drugs that have a very high molecular weight as high molecular
weight heparin (HMWH) and dextran (plasma expander) can not pass through the capillary endothelium and are distributed in
plasma only = intravascular compartment = 4 L.

2- Two Compartment Model:

Drugs that are hydrophilic and with low molecular weight can pass through the capillary endothelium but can not pass the cell
membranes being lipid insoluble and ionized-as quaternary ammonium compounds (neostigmine)-and accordingly are
distributed in 2 compartments: plasma and interstitial fluid =extracellular compartment = 14 L.

3- Multicompartment Model:
Drugs that are of low molecular weight, non-ionized, and lipophilic are distributed in all compartments-both extracellular and
intracellular-and accordingly are distributed in 42L.

4- Special Distribution (Selective distribution Tissue reservoir):

Some drugs are concentrated in certain tissues, e.g. tetracyclines are concentrated in bone and teeth (Ca2+ -containing)-iodine
is concentrated in thyroid tissue-thiopentone in fatty tissues-heavy metals as lead and arsenic in hair and skin-digitalis in
cardiac muscles-thiopentone in fat-Vitamin B12 and chloroquine in the liver.

C- Binding of Drugs to Plasma Proteins:

After reaching the systemic circulation, any drug will be found in 2 forms;
1- Bound fraction is inactive, non-diffusible, cannot be metabolized or excreted and Acts as a reservoir.
2- Free fraction is active, diffusible and can be metabolized and excreted.
The two forms exist in equilibrium; when the free form is metabolized and/or excreted, another part is released from plasma proteins.

Significance of Binding to Plasma Proteins

 Drugs are bound reversibly mainly to albumin and to a lesser extent to globulin and α-acid glycoprotein.
 Binding facilitates drug absorption by decreasing its free concentration in plasma this limits its tissue penetration &
decreases its Vd.
 The bound drug can not be eliminated and provides a reservoir which continuously releases the free part. This
prolongs the t1/2 of the drug.( The more the bound form of the drug, the longer its duration. This is shown with some
sulphonamides)
 The concentration of the active or free part of highly protein-bound drugs may be too low to be effective against
dangerous infections.
 Some drugs as aspirin and sulphonamides have a highly affinity (are highly bound) to plasma proteins - Drugs that
bind to the acidic binding site of albumin (low capacity binding site) - and they displace other drugs with lower
affinity as digoxin, sulphonylureas (oral hypoglycemics), and warfarin (oral anticoagulant) if administered together,
which results in increase in the free active form of the latter drugs and this may lead to severe adverse (toxic) effects:
 Aspirin and sulphonamides displace digoxin leading to digitalis toxicity.
 Aspirin and sulphonamides displace sulphonylureas (as Tolbutamide) leading to hypoglycemia.
 Aspirin and sulphonamides displace warfarin leading to bleeding.
 Sulphonamides displace bilirubin from plasma proteins, which increases free bilirubin causing hyperbilirubinemia and may be
kernicterus in neonates.
 In conditions causing .. hypoalbuminemia .. as in old age, liver diseases, malnutrition or starvation; the free form of drugs as
phenytoin (antiepileptic) is higher than in normal individuals and toxic effects may occur with therapeutic doses.
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GENERAL PHARMACOLOGY – PHARMACOKINETICS Dr. Ahmed Al-Arwali

Binding to cell and tissue constituents:

It is due to an affinity to some cellular constituents. Examples:
 Chloroquine is concentrated in the liver.
 Tetracyclines deposit in bone and teeth as they chelate Ca2+.
 Iodides are concentrated in thyroid and salivary glands.

D- Passage across Barriers:

1- Passage across blood brain barrier (B. B. B.):

Lipid soluble unionized drugs can penetrate B.B.B. and exert C.N.S. actions, whereas hydrophilic ionized drugs cannot pass
across B.B.B. and have almost no C.N.S. actions in normal conditions.
o Penicillins cannot penetrate normal meninges but can pass across inflamed meninges to C.S.F. in case of
meningitis (due to increased permeability), and so are useful in treatment of meningitis.

2- Passage across placental barrier to fetus:

Most drugs can pass across the placental barrier from the maternal circulation to the fetus.
Lipid soluble unionized drugs pass more easily than hydrophilic ionized drugs.
Some drugs as aspirin, cortisone, ACE inhibitors, benzodiazepines, phenytoin, etc., cause fetal malformations known as
teratogenicity or fetotoxicity especially if given in early pregnancy (1st trimester).
 Thalidomide (which was used as anxiolytic and hypnotic) caused amelia or phocomelia on a large number of
newborn infants which was known as Thalidomide disaster.
 Recently drugs are classified into categories: A, B, C, D, and X according to their possible teratogenic effect.

3- Passage through breast milk:

Most drugs can pass through breast milk to the suckling babies; some of which may cause serious adverse effects as
morphine, fluroquinolones, radioactive iodine, etc ...
Basic drugs are ionized and trapped in breast milk because its pH is relatively more acidic =7, compared to plasma pH = 7.4.
Lipophilic drugs are retained in breast milk because of its rich fat content.

Factors affecting drug distribution:

1- Protein binding- More protein binding less distribution
2- Ability of the drug to cross cell membranes depends on drug lipid solubility.
3- Extent of blood perfusion: If a tissue is well perfused, the drug is able to get there faster. e.g. Adipose tissue
has a low blood perfusion so drugs will not be able to reach these places very quickly.
4- PH differences across membrane barriers- A drug will pass through the membrane better if it is unionized
(lipophilic). An acid drug will be unionized in an acid environment; a basic drug will be unionized in a basic
environment.

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