BMS261

Pharmacology

General Principles: Pharmacokinetics

Ahmed Fawzy El-Yazbi, Bharm, PhD, BCPS
Faculty of Pharmacy
Pharmacology: The Science of Drug Action
• Pharmacology is the systematic study of how drugs exert their effects
on living systems.

• Pharmacologists also study the ways in which drugs are modified

within organisms.
Drug
• Any agent that, by virtue of its chemical properties, alters
the structure or function of biological systems
(pharmacologist’s view).

• Any agent approved by the Food and Drug Administration

(or Ministry of Health in a given country) for the treatment
or prevention of disease (legal view).
Pharmacokinetics is the study of the kinetics of
drug absorption, distribution, and elimination (ie
how the body affects the drug)
 Why study PK?

• To produce a biological action the drug must

reach its effector
• In order to achieve an effective concentration
at the site of action, several processes need
to occur
• Exceeding a certain drug concentration, the
effects might switch towards a negative
outcome (unwanted effects and toxicity)
• Knowledge of PK is required to understand
and control the drug effect and design
appropriate dosage regimens
Source: Leon Shargel, Andrew B.C. Yu: Applied
Biopharmaceutics & Pharmacokinetics
 Routes of drug administration
• Enteral
• Oral
• Sublingual
• Rectal
• Parenteral
• Intravascular (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Others
• Intranasal
• Topical (mucous membranes and ocular)
• Ocular
Oral
Advantages Disadvantages
• Safest • Limited absorption
• Convenient • Slow action
• Economical • Irritable and unpalatable drugs
• Can be self-administered • Some drugs destroyed by acidity of
• Painless stomach
• First-pass effect
• Uncooperative/unconscious
patients
Preparations for oral administration
• Tablets
• Drug plus binders and fillers (compressed together)
• Differ in their rate of dissolution/disintegration (based on
manufacturing)
• Thus, two tablets containing the same amount of the same
drug may differ in onset and intensity of effect
• Enteric-coated preparations
• Covered with material designed to dissolve in intestine, not
stomach
• Protect drug from stomach and stomach from drug
• Disadvantage: depend on gastric emptying (which is variable)
• Sustained-release preparations
• Capsules filled tiny spheres that dissolve at various rates
• Thus, drug is released steadily (permits reduction in # of daily
doses)
• Disadvantage: high cost and variable absorption
Routes of drug administration
• Sublingual:
• Placement under the tongue allows a drug to diffuse into the
capillary network
• This means it enters the systemic circulation directly
• Thus, it avoids first-pass effect (and also avoids acidity of
stomach/intestinal enzymes)
 Sublingual
Advantages Disadvantages
• Economical • Unpalatable/bitter drugs
• Absorption is quick • Irritation of oral mucosa
• First-pass avoided • Large quantities not
given
• Quick termination (spit
off) • High Mwt. Drugs not
absorbed
• Can be self-administered
Routes of drug administration
• Rectal:
• 50% of the rectal drainage bypasses the first-pass metabolism
• Drugs avoids stomach/small intestine
• Useful if the drug induces vomiting when given orally (or if the
patient is already vomiting)
 Rectal
Advantages Disadvantages
• Used in children • Embarrassing
• Little or no first pass • Inconvenient
effect • Absorption is not very
• Used in vomiting or fast
unconscious • Irritation or
• Higher concentration inflammation of rectal
rapidly achieved mucosa can occur
• Can be used for drugs
that irritate the stomach
Parenteral routes
• Used for drugs that are poorly absorbed in the GI, or
are affected by stomach acidity (insulin)
• Are useful in patients that are unconscious, or under
conditions that require rapid onset of action
• Provides most control over the actual dose delivered
Parenteral routes
 Intravenous
Advantages Disadvantages
• Avoids first-pass • Antiseptic conditions
• Quick onset • Painful
• Uncooperative/unconscious • Risky (can’t be recalled)
patients • Embolism
• Nausea/vomiting
• Suspensions/oily drugs/depots
• Hypertonic solution/irritants cannot be given
• Large volumes • Venous thrombosis and phlebitis
• Very good control of the amount • Necrosis due to extravasation
of drug
Intramuscular

Advantages Disadvantages
• Absorption reasonably uniform • Only up to 10 ml drug given
• Rapid onset of action • Local pain and abscess
• Mild irritants may be given • Not economical
• First pass avoided • Infection
• Gastric factors avoided • Nerve damage (if injection is
• Suitable for poorly soluble drugs done improperly)
 Subcutaneous (under skin)

Advantages Disadvantages
• Smooth but slow absorption • Small volume (1 ml)
• Depot injections/implants • Irritant drugs-sloughing and
necrosis
• not useful in shock
Topical
• Mucous membranes of eye, ear, nose, throat,
mouth, vagina, rectum
• Ointments, creams and lotions

• Example: clotrimazole as a cream on the skin in

dermatophytosis, and atropine into the eye to
dilate the pupil
Factors governing drug absorption from
extra-vascular sites
• Physicochemical properties of the drug and the surrounding
environment (drug degradation?)
• The dosage form used
• The anatomy and physiology of the absorption site (surface area,
motility, blood flow)
Modes of transport across a
membrane

Source: Goodman & Gillman’s: The Pharmacological Basis of Therapeutics

pH and pKa

Source: Goodman & Gillman’s: The Pharmacological Basis of Therapeutics

Distribution
• After absorption or intra-vascular administration,
drug molecules are distributed in the body
• distribution depends on: physicochemical
properties of the drug, tissue perfusion and
regional blood flow, and capillary permeability
• First distribution phase: well-perfused organs, fast,
liver, kidneys, and brain
• Second phase: slower, muscle, viscera, skin, and fat
Penetration, accumulation,
and protein binding
• pH differences between blood and
interstitial fluid are too small to produce
ion trapping
• For most organs (except brain), drug
molecule transfer to interstitial fluid
occurs fast
• Typically, this occurs by diffusion, so lipid
solubility helps increase diffusion
 Protein binding of drugs
• Typically drugs act through
binding to macromolecules
• Binding can be reversible or
irreversible through covalent
bonding
• Reversible binding occur
through hydrogen bonding
and Van Der Waals forces
• Protein binding affect PK,
the bound form is inactive,
does not cross membranes,
is not metabolized or
cleared Source: Leon Shargel, Andrew B.C. Yu: Applied
Biopharmaceutics & Pharmacokinetics
Tissue accumulation
• Drugs accumulate passively in the tissues if they
have a high affinity e.g. high partition coefficient,
thiopental and chlorinated insecticides tend to
accumulate in fat (termination of action by
redistribution)
• Drugs can accumulate in the tissue if it binds
macromolecules e.g. digoxin binding to proteins in
the cardiac tissue
Drug elimination (clearance)
• This process leads to the termination of the
biological action of the drug
• It involves a decrease in the serum concentration
• Accomplished through metabolism and excretion
• The main excretory route occurs through the urine
(aqueous medium)
• The main role of metabolism is to increase drug
solubility in water to allow for urinary excretion
• Drug metabolism can lead to active or toxic products
Drug metabolism (Biotransformation)
• Metabolic reactions are classified into two phases:
• Phase I: functionalization
• Phase II: conjugation
• Phase I involves the generation of a functional group,
usually accomplished by hydrolysis of an ester or
amide group, O- or N- delakylation, deamination,
hydroxylation of an aromatic residue
• Phase I step typically involves the loss of drug activity,
however, some metabolites retain activity
• Prodrugs are usually activated in this step
• Phase II reactions involve the formation of a covalent
link between Phase I product and a highly polar
residues
Drug excretion
• The main route of excretion is the kidney, however, it
can occur through bile, sweat, saliva, and tears
• Renal elimination involves three processes:
• Glomerular filtration
• Passive reabsorption
• Active secretion
• Renal function is not constant even in healthy individuals
• A decline in renal function is expected with age
Glomerular filtration
• Drug excretion by this mechanism is determined
by the GFR and extent of protein binding
• Small molecules (Mwt.<500) are removed by
filtration
• Both ionized and unionized forms are filtered
Active tubular secretion
• Active process requiring energy
• Competition occurs on the carriers e.g. Organic
Anion Transporter, Organic Cation Transporter, P-
glycoprotein transporter
• Active secretion is not affected by protein binding,
penicillins are protein bound but rapidly excreted
because of carrier-mediated secretion (how?)
Passive reabsorption
• The extent of reabsorption depends on the ionization status of the
drug
• The concentration gradient for passive absorption is created by
reabsorption of water and sodium
• Alkalization and acidification of urine can affect the extent of acidic or
basic drug excretion (forced diuresis and alkaline residue diet)