Pharmacology

Basic pharmacology - Agenda

#Definition
#Routes of administration & drug
formulations
#A.D.M.E.
#Dose regimes & plasma levels
Classification of Drugs
#Scheduling of drugs
#Pharmacodynamics
#Drug uses & ADR
Introduction

Pharmacology: study of interactions between chemical compounds and

biological systems.

i.e. - how drugs work

- where drugs act
- how the body processes drugs, etc.
(mechanisms of drug action)

The receptor is the cornerstone of pharmacology

Explains how the organism interacts with a drug and initiates a chain of
biochemical events that results in observed effects

An agonist is a drug whose interaction with the receptor stimulates a biological

response
 Drug –
WHO scientific group definition
Any substance or product that is used/
intended to be used to modify or
explore physiological systems or
pathological systems or pathological
states for the benefit of the recipient
 Drugs

“ Poisons in small doses are the best

medicines; and useful medicines in too
large doses are poisonous”

Willam Withering (1741 – 1799) MD, FRS

 Pharmacology
Pharmacodynamics
- Biological and therapeutic effects of
drugs

pharmacokinetics

- Absorption, Distribution, Metabolism &

Excretion of drugs
 The Relationship between Pharmacokinetic
and Pharmacodynamic processes
Drug is absorbed into the blood
Drug is taken Stream & is available for circulation

Pharmaco
Drug is Drug is concentrated Drug is kinetics
excreted at the site of action metabolised

Pharmacological effect

Pharmaco
Clinical response dynamics

Side effects Efficacy

Effect of Drugs on Organs and Tissues
Drugs only modify cellular function – do not create effects

DRUG RECEPTOR RESPONSE

Drug receptors
• The molecular components of the body with which a
drug interacts to bring about its effects.
Pharmacokinetics

AbsorptionDistribution
Biological Effect
Drug
Pharmacodynamics
MetabolismElimination
Pharmacokinetics and Pharmacodynamics

ADME:
- Absorption
- Distribution
- Metabolism
- Elimination

Katzung: page 36
Definitions
once thought that the biological response to a drug was due to its pharmacologic
activity
– it is now apparent that this is NOT the case
Absorption: movement of a drug FROM the site of administration → the
circulation
Distribution: movement of drug FROM circulation → tissues (e.g. plasma →
receptor)
Metabolism: biotransformation of drugs into metabolites
Elimination: removal of unchanged drug and metabolites from the body
Introduction
in order for a drug → biological activity, it MUST be present at its target site in
the body
ADME processes occur simultaneously and determine the time course of [drug]
at its target

in combination with the affinity of the drug for its target site:
– ADME processes serve to regulate the pharmacological activity of a drug
ADME processes play an important role in the overall drug effect:
– drugs are rarely administered directly to the site of action (e.g. topical
administration)

an understanding of cell membrane

properties and structure is required
Transport of Drugs:
drug transport = movement of a drug molecule across a series of membranes and spaces

most often: drug is given into one body compartment and must move to its site of action in
another
– requires that the drug be absorbed into the blood and distributed to its site of action

drug action (time of onset and duration) depends on ALL of the rates of ADME processes

elimination can occur by metabolism and/or directly excreted

– should occur at a reasonable rate so length of drug effect is appropriate for therapy

the rate of uptake/release by a tissue is a function of:

– blood flow to that tissue
– affinity (partition coefficient) of tissue for drug

rates of absorption can depend upon the rate of blood perfusion at the site of absorption
Permeation:
Is the movement of drug molecules into
and within the biologic environment.

It involves

Aqueous diffusion
Lipid diffusion
Transport by special carriers
Endocytosis, pinocytosis
Aqueous diffusion:

Aqueous diffusion is the movement of

molecules through the watery extracellular and
intracellular spaces.

The membranes of most capillaries have small

water-filled pores that permit the aqueous
diffusion of molecules up to the size of small
proteins between the blood and the extravascular
space.

This is a passive process governed by Fick's law

Lipid diffusion

Lipid diffusion is the movement of

molecules through membranes and other
lipid structures.

Like aqueous diffusion, this is a passive

process governed by Fick's law
Fick's law of diffusion:

Fick's law predicts the rate of movement of

molecules across a barrier; the concentration
gradient (C l - C2) and permeability coefficient for
the drug and the area and thickness of the barrier
membrane are used to compute the rate, as
follows:
Rate = (C 1 - C2) x Permeability coefficient x
Area Thickness
Transport by special carriers:

Drugs may be transported across barriers by

mechanisms that carry similar endogenous
substances, e.g. the amino acid carriers in the blood-
brain barrier and the weak acid carriers in the renal
tubule.

Unlike aqueous and lipid diffusion, carrier

transport is NOT governed by Fick's law and is
capacity-limited.
Transport by special carriers:

Selective inhibitors for these carriers may have

clinical value; e.g. probenecid, which inhibits
transport of uric acid, and other weak acids, is used
to increase the excretion of uric acid in gout.

Probenecid is sometimes used along with penicillin

antibiotics to increase antibiotic blood levels. This
increase makes the antibiotic work better at treating
certain infections. Probenecid works by decreasing
the kidneys' ability to remove the antibiotic from the
body.
Endocytosis:

Occurs through binding to receptors on cell membranes,

with subsequent internalization by infolding of that area of
the membrane.

The contents of the resulting vesicle are subsequently

released into the cytoplasm of the cell.

Permits very large or very lipid- insoluble chemicals to

enter cells. e.g. peptides

Smaller, polar substances such as vitamin Bl2 and iron

combine with special proteins (B12 with intrinsic factor and
iron with transferrin), and the complexes enter cells by
Endocytosis.
Pinocytosis

is a mode of endocytosis in which

small particles are brought into the
cell, forming an invagination, and
then suspended within
small vesicles. These pinocytotic
vesicles subsequently fuse
with lysosomes to hydrolyze the
particles. This process requires
energy in the form of adenosine
triphosphate (ATP)
Many drugs are weak bases or weak acids.

For such molecules, the pH of the medium

determines the fraction of molecules charged
(ionized) versus un-charged (nonionized).

If the pKa of the drug and the pH of the

medium are known, the fraction of molecules
in the ionized state can be predicted by means
of the Henderson-Hasselbalch equation
Ionization of weak acids and bases
Weak bases are ionized, and therefore more polar
and more water-soluble, when they are protonated;
Weak acids are not ionized, and so are less water-
soluble, when they are protonated.
Clinical importance of Henderson- Hasselbalch
relationship

When it is necessary to accelerate the excretion of drugs by

the kidney, e.g. in the case of an overdose.

Most drugs are freely filtered at the glomerulus, but

lipid-soluble drugs can be rapidly reabsorbed from the
tubular urine.
Clinical importance of Henderson- Hasselbalch
relationship

When a patient takes an overdose of a weak acid drug, its

excretion may be accelerated by alkalinizing the urine, e.g. by
giving bicarbonate.

This is because a drug that is a weak acid dissociates to its

charged, polar form in alkaline solution and this form cannot
readily diffuse from the renal tubule back into the blood.

Conversely, excretion of a weak base may be accelerated

by acidifying the urine, e.g. by administering ammonium
chloride.
Drug Absorption:

Routes of
Administration
Drug Absorption
for most routes of administration, drugs must cross epithelial membranes in
order to reach the blood
– e.g. GI, oral
– but NOT injection (sc, im, or iv)
therefore, (except for injection) drugs must go through the cells in the membrane
– cannot go between cells by bulk flow
drug absorption is usually limited by:
– the rate the drug can cross cell membranes by drug transport mechanisms:
(diffusion, filtration, ion-pairing, endocytosis, facilitated transport, or active
transport)
– perfusion (i.e. circulation at the site of absorption) and concentration
gradient
– surface area
Routes of Administration
choice will have a profound effect upon the rate and efficiency with which the
drug acts
– enteral = drug placed directly in the GI tract (epithelial barriers – stomach)

» oral – swallowing
» rectal – absorption through the rectum
» sublingual – placed under the tongue
– parenteral - BYPASS GI system (endothelial barriers)

» injection - sc, im, iv

– topical - (epithelial barriers - skin)

– inhalation - (epithelial barriers - lung)

remember: no single method of drug administration is ideal for all drugs in all
situations
Bulk Flow (cont.)
Absorption Distribution
Environment Plasma

+
+ -
GI +
ORAL
Skin
- +
Lung o
- o
o
-

SC, IM o
epithelium capillary endothelium
(tight junctions) (loose junctions)
Enteral Absorption
formulation: controls the ability of the active ingredients to dissolve and go into
solution
– essential 1st step for absorption
– especially important at gastric pH (very low)
– achieve delayed release into small intestine with pH sensitive coatings – avoid
stomach

microbial metabolism:
– proteolytic and hydrolytic enzymes of intestinal microflora may metabolize
drugs →
– altered rate of absorption OR
– altered biological activity (metabolites)
Enteral Absorption (cont.)
FOOD (generally decreases absorption)

– delays gastric emptying

– increases hydrolysis by gastric enzymes

– increases intestinal blood flow and subsequent absorption

– complexes with drugs to retard absorption

» e.g. tetracycline: complexes with Ca2+ in food and milk products

Effect is considerable → can reduce absorption of tetracyclines by

80%

Solution: leave a 2 hour gap between eating and taking tetracycline

Routes of Administration: Oral
Advantages:
– convenient: can be self-administered, pain-free, easy to take
– absorption: takes place along the entire GI tract
– cheap: compared to parenteral routes

Disadvantages:
– sometimes inefficient: only part of the drug may be absorbed
– 1st pass effect: drugs absorbed orally are initially transported to the liver via
the
portal vein
– irritation to gastric mucosa → nausea and vomiting
– destruction of drugs by gastric acid and digestive juices
– effect too slow for emergencies
– unpleasant taste of some drugs
– unable to use in an unconscious patient (patient compliance is a problem)
1st Pass Effect

drug is absorbed from the gut and delivered to the liver by the portal circulation

enzymes in the liver metabolize the drug to an inactive species before it reaches
the systemic circulation
– inactive product = metabolite that does not possess the desired
pharmacological activity

the greater the 1st pass effect:

– the less the drug will reach the systemic circulation
when administered orally
Routes of Administration: Sublingual

barrier is oral mucosa (epithelial cells)

surface area is limited (< 1 m2), but well perfused
cell layer is relatively thin
absorption is rapid if lipid/water partition coefficient is high

pKa is the major rate limiting factor - saliva pH is 7.0

absorption direct to general circulation - thus bypasses 1st pass metabolism
limiting factors: dissolution and transit time in oral cavity
– some drugs are taken as smaller tablets which are held in the mouth or under
the tongue
» advantages: rapid absorption, drug stability, avoid 1st pass effect
» disadvantages: incovenient, small doses, unpleasant taste of some drugs
GI Absorption
size of the absorptive surface of the various parts of the GI tract (in m2):

– oral cavity: 0.02

– stomach: 0.1-0.2
– small intestine 100
– large intestine 0.5-l .0
– rectum 0.04-0.07
Other Routes of Administration:
Advantages
Rectal:
– Bypasses:
» low pH of GI, hydrolytic enzymes in GI, first-pass metabolism
» good for drugs affecting the bowel (laxatives)
– useful for unconscious or vomiting patients or uncooperative patients
(children)
Topical:
– generally produces only local effects e.g. dermatology: antibacterial,
antifungal, sunscreens, antiviral agents
Lung:
– very highly vascularized and absorption RATE in the lungs is considerably
higher than that in the small intestine
Parenteral Administration
barrier is endothelial cells
can bypass epithelial barriers via injection

subcutaneous (sc): bypass epidermis - only barrier is dermis

intramuscular (im): bypass epidermis and dermis – injected into skeletal
muscle
– faster absorption than s.c. due to better perfusion and lateral diffusion
transdermal: diffusion through intact skin
intravenous (iv): bypass ALL barriers (membranes) to absorption
– drug injected directly into the blood stream
– produces essentially immediate response
Advantages of Intravenous
Administration
absorption phase is bypassed (drug is 100% bioavailable)

almost immediate onset of action

obtain precise plasma levels; excellent compliance; fairly pain free

large quantities can be given

good for drugs with narrow therapeutic index (accurate route of administration)

useful for rapidly metabolized or labile drugs – bypass 1st pass and absorption
phase

especially good for drugs which are poorly absorbed by other mechanisms

especially good for very large drug molecules (macromolecules that can’t cross
membranes)
Disadvantages of Intravenous
Administration
very rapid response → potential for overdose (OOPS! factor is high)

non-recoverable – can’t “suck out the poison”

requires skilled administration (costly)

potential for tissue necrosis

potential for embolism – drug or particulate in formulation blocks the flow of

blood

potential for microbial or viral contamination in preparation

IV vs Oral Administration
Bioavailability (F) Calculation:

– Amount of drug available after oral administration

compared to:
– Amount of drug available after IV administration (F = 100%)

– Tells you:
» amount of first pass metabolism
» if there were absorption problems → new formulation?
» etc.
 Intramuscular route:
• Absorption from an intramuscular
injection site is often (not always) faster
and more complete (higher
bioavailability) than with oral
administration.

•Large volumes (e.g. > 5 mL into each

buttock) may be given.

•First-pass metabolism is avoided.

Subcutaneous route:

• Offers slower absorption than the

intramuscular route.

•Large volume bolus doses are not

suitable.

•First-pass metabolism is avoided.

 Sublingual route

# Abundant blood supply

# Quick effect
# No degradation by digestive juices
# No first pass metabolism
# Irritation of mucous membranes
Distribution of Drugs: Determinants of
distribution:

Size of the organ

Blood flow
Solubility
Binding
Size of the organ

a. The size of the organ determines the concentration gradient

between blood and the organ.

b. For example, skeletal muscle can take up a large amount of

drug because the concentration in the muscle tissue remains
low (and the blood-tissue gradient high) even after relatively
large amounts of drug have been transferred

c. In contrast, because the brain is smaller, distribution of a

smaller amount of drug into it will raise the tissue concentration
and reduce the blood-tissue concentration gradient to zero,
preventing further uptake of drug.
Blood flow:

• Blood flow to the tissue is an important determinant

of the rate of up-take.

• Well-perfused tissues (e.g. brain, heart, kidneys)

will often achieve high tissue concentrations sooner
than poorly-perfused tissues (e.g. fat, bone).

• If the drug is rapidly eliminated, the concentration

in poorly-perfused tissues may never rise
significantly
Solubility:

• The solubility of a drug in tissue influences the concentration of

the drug in the extracellular fluid surrounding the blood vessels.

• If the drug is very soluble in the cells, the concentration in the

perivascular extracellular space will be lower and diffusion from
the vessel into the extravascular tissue space will be facilitated.

• For example, some organs (including the brain) have a high lipid
content and thus dissolve a high concentration of lipid-soluble
agents.

• As a result, a very lipid-soluble anesthetic will transfer out of the

blood and into the brain tissue to a greater extent than a drug with
low lipid solubility.
Binding:

• Binding of a drug to macromolecules in the blood or a

tissue compartment will tend to increase the drug's
concentration in that compartment.

• For example, warfarin is strongly bound to plasma

albumin, which restricts warfarin's diffusion out of the
vascular compartment.

• Conversely, chloroquine is strongly bound to tissue

proteins, which results in a marked reduction in the
plasma concentration of chloroquine.
General Scheme of Drug Metabolism
Lipophilic Hydrophilic

Metabolism
increase elimination
decrease biological activity

Parent compound

Phase I Phase II
Metabolites (synthetic)
Conjugated
(oxidative)
Metabolites
polarity
functionality ionization
water solubility
Human P450 Isoforms

major drug metabolizing P450s % of drugs metabolized by P450s

Foye’s pages 178-179

 Clinical Considerations of CYP450 Metabolism

Loss of Drug Effect

No Toxicities
Substrate Oxidation
Drug
CYP450 CYP450 + Metabolite Elimination

CYP450 + Drug + electrons → Activated CYP450 → CYP450 + Metabolite

(capable of oxidations)
Clinical Considerations of Cytochrome P450 Inhibition
Prolonged or Enhanced Effect
Competitive Inhibition Undesirable Toxicities
(Drug-Drug Interaction)

Drug A Drug B
(Inhibitor) (Substrate)
P450 Inhibited P450 Drug B

slow release of inhibitor Drug-Drug Interaction (DDI)

 • H2 receptor antagonist (anti-ulcer agent)
Drug-Drug Interactions • general inhibitor of human P450s
• inhibits hepatic elimination of many drugs:
Cimetidine (Tagamet) warfarin alprazolam
H acenocoumarol triazolam
CN
N phenadion
N
theophylline
S phenytoin
MeHN N N
imipramine
H carbamazepine caffeine
N chlormethiazole
Fe N
N propanolol
N diazepam labetalol
chlordiazepoxide metoprolol
• imidazole ring able to coordinate to the lidocaine ethanol
heme iron atom of several different P450s

undesirable toxicities
 elimination

DRUG Phase II Reactions

Glucuronosyl Transferases
P450 Sulfotransferases
Phase I FMO Glutathione Transferases elimination
Reactions ADH
esterases Amino Acid Transferases
Acetyltransferases
amidases
Methyltransferases

Metabolite

elimination
Drug Elimination
Pharmacological activity of drug can be reduced by:

– metabolism

– plasma protein binding

– redistribution to other compartments (i.e. fat)

Elimination:

– required to remove the chemical from the body and terminate biological
activity

» especially if drug is minimally metabolized

– necessary to prevent accumulation of xenobiotics in the body

Major Routes of Drug Elimination:
are highly dependent on metabolism:

– KIDNEYS (renal)
» represent approx. 1% of of total body weight,
» but receive 25% of cardiac output
» blood flow rate is approx. 8X more that exercising muscle
– Liver
– Intestines
– Lungs
– Sweat, Saliva, Milk – not really significant

same physiological mechanisms govern drug elimination as absorption

– i.e. cell membranes are the barriers.
 References
• Basic and Clinical Pharmacology, 12th Edition.
Bertram G. Katzung, McGraw-Hill Inc., 2012.

• Rang and Dale’s Pharmacology, 6th Edition. H.P.

Rang, M.M. Dale, J.M. Ritter, and RJ Flower,
Churchill Livimistone, 2015.

• Lippincott Illustrated Reviews: Pharmacology, 6th

Edition. Karen Whalen, Richard Finkel, Thomas
A. Panavelil , Wolters Kluwer, 2015.