Introduction to Pharmacology. Pharmacokinetics. Routes of administration Drug absorption, distribution, metabolism and Elimination

1. GENERAL PRINCIPLES
OF PHARMACOLOGY

2. OBJECTIVES
At the end of this lecture students will able be to:
1.Understanding the basic concepts of pharmacology and its role in the healthcare field
2.Understanding the relationship between drugs, receptors, and biological systems
3.Knowledge of the various routes of drug administration and their advantages and
disadvantages
4.Understanding of the factors affecting drug absorption, distribution, metabolism, and
elimination
5.Knowledge of the pharmacokinetic parameters and their clinical relevance
6.Understanding of the basic concepts of dose-response relationships and
pharmacodynamics
7.Knowledge of the mechanisms of drug action and the concept of selectivity

3. BASIC TERMS:
▪HALF LIFE:
“The half-life of a drug refers to the time it takes for the concentration of the drug in the
body to decrease by half.”
▪DRUG POTENCY
“Drug potency refers to the amount of a drug required to produce a therapeutic effect.”
▪DRUG EFFICACY:
“Drug efficacy refers to the ability of a drug to produce the desired therapeutic effect in a
patient.”

4. CONTI…
TOXICITY:
“Drug toxicity refers to the harmful effects that a drug can have on the body, particularly
when taken in excessive amounts or when the drug is not used as intended”.
BIOAVAILABILITY:
“Bioavailability refers to the amount of a drug or other substance that enters the systemic
circulation and is able to have an active effect after administration.”
THERAPEUTIC INDEX:
“The therapeutic index is a measure of the safety of a drug and is defined as the ratio of
the dose that produces therapeutic effects to the dose that produces toxic effects.”

5. “Refers to what the body does to the drug”

7. CONTI…
Four pharmacokinetic properties determine the onset, intensity,
and the duration of drug action:
1. Absorption: First Absorption from the site of administration permits
entry of the drug (either directly or indirectly) into plasma.
2. Distribution: Second, the drug may then reversibly leave the
bloodstream and distribute into the interstitial and intracellular fluids.
3. Metabolism: Third, the drug may be biotransformed by metabolism by
the liver or other tissues.
4. Elimination: Finally, the drug and its metabolites are eliminated from the
body in urine, bile, or feces.

8. https://www.researchgate.net/figure/Classification-of-routes-of-drugs-
administration_fig3_359172708

9. ROUTES OF DRUG ADMINISTRATION
1. ENTERAL:
o Administering a drug by mouth.
◦ Safest and most common, convenient, and economical method of
drug administration.
◦ May be swallowed orally.
◦ May be placed under the tongue (sublingual), or between the
gums and cheek (buccal).

10. CONTI…
❑ORAL:
Advantages:
◦ easily self-administered.
◦ toxicities and overdose of oral drugs may be overcome with antidotes.
Disadvantages.
◦ the pathways involved in oral drug absorption are the most complicated.
◦ the low gastric pH inactivates some drugs.

11. CONTI….
Oral drugs maybe available as:
a. Enteric-coated preparations:
An enteric coating is a chemical envelope that protects
the drug from stomach acid, delivering it instead to the less
acidic intestine, where the coating dissolves and releases the
drug.
EXAMPLES:
◦ “omeprazole” (acid unstable)
◦ “Aspirin” (Stomach irritant)

12. CONTI…
b. Extended-release preparations:
▪ Extended-release medications have special coatings or
ingredients that control the drug release, thereby allowing for
slower absorption and a prolonged duration of action.
▪For example, the half-life of oral morphine is 2 to 4 hours,
requires 6 deliveries, with controlled-released we only need
2 doses.

13. CONTI…
❑Sublingual/buccal:
▪Placement under the tongue allows a drug to diffuse into the capillary
network and enter the systemic circulation directly.
▪The buccal route (between the cheek and gum) is similar to the
sublingual route.
Advantages:
• Ease of administration.
•Rapid absorption.
•Bypass of the harsh gastrointestinal (GI) environment.
•Avoidance of firstpass metabolism.

14. CONTI…
❑RECTAL:
▪The biotransformation of drugs by the liver is minimized with rectal
administration
▪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.

15. PARENTERAL ROUTE
▪Introduces drugs directly into the systemic circulation.
▪Used for drugs that are poorly absorbed from the GI tract
(heparin).
▪used if a patient is unable to take oral medications (unconscious
patients)
▪Used in circumstances that require a rapid onset of action.
▪Have highest bioavailability.

16. CONTI…
The three major parenteral routes are
❑ intravascular (intravenous or intra-arterial)
❑ intramuscular
❑ subcutaneous

17. INTRAVENOUS (IV)
▪most common parenteral route.
Advantages
▪useful for drugs that are not absorbed orally.
▪permits a rapid effect and a maximum degree of control over the
amount of drug delivered.
▪Disadvantages:
▪May cause infections through contamination at the site of
injection.
▪Unlike drugs given orally, that are injected cannot be recalled by
strategies such as binding to activated charcoal.
▪rate of infusion must be carefully controlled.

18. Intramuscular (IM)
▪can be in aqueous solutions, which are absorbed rapidly,
▪or in specialized depot preparations, which are absorbed slowly.
▪Examples of sustained-release drugs are haloperidol and depot
medroxyprogesterone.

19. Subcutaneous (SC)
▪ SC injection provides absorption via simple diffusion
▪It is slower than the IV route.
▪SC injection minimizes the risks of hemolysis or thrombosis
associated with IV injection 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.
▪ Drugs commonly administered via the subcutaneous route
include insulin and heparin.

20. OTHER ROUTES
▪INHALATION:
▪provides rapid delivery of a drug across the large surface area
of the mucous membranes of the respiratory tract and
pulmonary epithelium.
▪Drug effects are almost as rapid as 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.
▪EXAMPLE:
▪bronchodilators, such as albuterol,

21. CONTI….
NASAL INHALATION:
▪administration of drugs directly into the nose.
▪Examples of agents include nasal decongestants, such as
oxymetazoline.
INTRATHECAL:
▪Enters drugs into subarachnoid space.
▪When local, rapid effects are needed, it is necessary to
introduce drugs directly into the cerebrospinal fluid.
▪For example, intrathecal amphotericin B is used in treating
cryptococcal meningitis.

22. ❑TOPICAL:
▪used when a local effect of the drug is desired.
▪For example, clotrimazole is a cream applied directly to the
skin for the treatment of fungal infections.
❑TRANSDERMAL:
▪Application of drugs to the skin
▪Usually via a transdermal patch. Ex: nicotine transdermal
patches.

23. ABSORPTION OF DRUGS
▪Absorption is the transfer of a drug from the site of administration to the
bloodstream.
▪The rate and extent of absorption depend on the:
▪ Environment where the drug is absorbed.
▪ Chemical characteristics of the drug.
▪ And the route of administration (which influences bioavailability).

25. B. FACTORS INFLUENCING ABSORPTION
1. Effect of pH on drug absorption:
▪A drug passes through membranes more readily if it is uncharged.
▪Effective concentration of the permeable form of each drug is determined
by the the charged and uncharged forms of drugs.
2. 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.
3. Total surface area available for absorption:
▪ With a surface rich in brush borders containing microvilli, the intestine has
a surface area about 1000-fold that of the stomach, making absorption
more efficient.

26. CONTI…
4. Contact time at the absorption surface:
▪ 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 of the drug.
5. Expression of P-glycoprotein:
▪ P-glycoprotein is a transmembrane transporter protein responsible for
transporting various molecules, including drugs, across cell membranes.
▪It is involved in transportation of drugs from tissues to blood.

27. C. BIOAVAILABILITY
“Bioavailability is the rate and extent to which an administered drug
reaches the systemic circulation.”
Determining bioavailability is important for calculating drug dosages for
nonintravenous routes of administration.
Determination of bioavailability:
▪ Bioavailability of a drug given orally is the ratio of the plasma
concentration of drug following oral administration to the plasma
concentration of drug following IV administration

28. FACTORS THAT INFLUENCE BIOAVAILABILITY:
a. First-pass hepatic metabolism:
▪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 metabolism.
b. Solubility of the drug:
▪ Very hydrophilic drugs are poorly absorbed
▪Paradoxically, drugs that are extremely lipophilic are also poorly absorbed.
▪ 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.

29. CONTI…
c. Chemical instability:
▪ Some drugs, such as penicillin G, are unstable in the pH of the gastric
contents.
▪Others, such as insulin, are destroyed in the GI tract by degradative
enzymes.
d. 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, enteric coatings, and the
presence of excipients (such as binders) can influence the ease of
dissolution and, therefore, alter the rate of absorption.

30. D. BIOEQUIVALENCE
▪Two drug formulations are bioequivalent if they show comparable
bioavailability and similar times to achieve peak blood concentrations.
E. THERAPEUTIC
EQUIVALENCE:
▪Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent (that is, they have the same dosage form,
contain the same active ingredient, and use the same route of
administration) with similar clinical and safety profiles

31. DRUG DISTRIBUTION
“Drug distribution is the process by which a drug reversibly leaves
the bloodstream and enters the interstitium (extracellular fluid) and
the tissues.”
▪The distribution of a drug from the plasma to the interstitium depends on:
▪ Cardiac output and local blood flow.
▪ Capillary permeability.
▪ The tissue volume.
▪ The degree of binding of the drug to plasma and tissue proteins.
▪ And the relative lipophilicity of the drug.

32. CONTI..
A. Blood flow:
▪ The rate of blood flow to the tissue capillaries varies widely. For instance,
blood flow to the “vessel-rich organs” (brain, liver, and kidney) is greater
than that to the skeletal muscles.
B. Capillary permeability:
▪ Capillary permeability is determined by capillary structure and by the
chemical nature of the drug.
▪Capillary structure varies in terms of the fraction of the basement
membrane exposed by slit junctions between endothelial cells.

33. CONTI…
C. Binding to plasma proteins:
▪ Albumin is the major drug-binding protein and may act as a drug reservoir.
▪ This maintains the free drug concentration as a constant fraction of the
total drug in the plasma.
D. Binding to tissue proteins:
▪Many drugs accumulate in tissues, leading to higher concentrations in
tissues than in the extracellular fluid and blood.

34. CONTI…
▪Tissue reservoirs may serve as a major source of drug’s
prolong actions or cause local drug toxicity.
D. Lipophilicity:
▪Lipophilic drugs readily move across most biologic membranes.

35. DRUG CLEARANCE THROUGH
METABOLISM
▪Once a drug enters the body, the process of elimination begins.
▪ The three major routes of elimination are hepatic metabolism, biliary
elimination, and urinary elimination.
▪ Together, these elimination processes decrease the plasma concentration
exponentially.
B. Reactions of drug metabolism:
▪The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell
membranes and are reabsorbed in the distal convoluted tubules.
▪ Therefore, lipid-soluble agents are first metabolized into more polar
(hydrophilic) substances in the liver.

36. CONTI…
PHASE I:
❑Oxidation
❑Reduction
❑Hydrolysis
❑Utilizes CYP450 system.
PHASE II:
❑Conjugation reaction
(reaction with an endogenous substrate such as glucuronic acid, sulfuric acid,
acetic acid and amino acid.)

37. ELEMINATION
A. Renal elimination of a drug
1. Glomerular filtration:
▪Free drug (not bound to albumin) flows through the capillary
slits into the Bowman space as part of the glomerular filtrate
2. Proximal tubular secretion:
▪ Drugs that were not transferred into the glomerular filtrate
leave the glomeruli through efferent arterioles.
▪ Secretion primarily occurs in the proximal tubules by two
energy-requiring active transport systems: one for anions and
one for cations.

38. CONTI…
3. Distal tubular reabsorption:
▪ As a drug moves toward the distal convoluted tubule, its
concentration increases and exceeds that of the perivascular
space.
▪ As a general rule, weak acids can be eliminated by
alkalinization of the urine.
▪Whereas elimination of weak bases may be increased by
acidification of the urine.
▪ This process is called “ion trapping.”

39. DRUGS ELIMINATION BY OTHER
ROUTES
▪Drugs that are not absorbed after oral administration or drugs that are
secreted directly into the intestines or into bile are eliminated in the feces.
▪The lungs are primarily involved in the elimination of anesthetic gases (for
example, isoflurane).
▪ Elimination of drugs in breast milk may expose the breast-feeding infant
to medications and/or metabolites being taken by the mother and is a
potential source of undesirable side effects to the infant.
▪ Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only
to a small extent.

40. REFERENCES:
❑Whalen K. Feild C. & Radhakrishnan R. (2019). Lippincott illustrated reviews :
pharmacology (Seventh). Wolters Kluwer.