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PHRM 246

Mr Thabiso Tlaila
MSc Pharmacology
Department of Pharmacology
Discipline of Pharmaceutical Sciences
University of KwaZulu-Natal
tlailat@ukzn.ac.za
INTRODUCTION TO PHARMACOLOGY

■ Basic Principles of Pharmacology


■ Drug Metabolism
■ Pharmacokinetics
■ Pharmacodynamics
■ Drug Evaluation and Regulation
Basic Principles of Pharmacology
Basic Principles of Pharmacology cont…
Pharmacology:
Concerned with the action of chemicals on biologic
systems
Medical Pharmacology:
The use of chemicals in the prevention, diagnosis and
treatment of disease
Toxicology:
The area of pharmacology concerned with the
undesirable effects of chemicals on biologic systems
Basic Principles of Pharmacology cont…
Drugs:
■ Substances that act on living systems at a molecular
level
■ Some found in plants and animals while others are
partial or completely synthetic
Drug names
■ Chemical name
■ Nonproprietary (generic) name
■ Proprietary (trade/brand) name
Basic Principles of Pharmacology cont…
Case study:
■ E.J. is a 27 year old man who previously presented at your clinic with complaints of
fever, night sweats, weight loss and a white exudate in his mouth. His symptoms
were present for the past 4-6 weeks by the time he visited the clinic. On physical
examination, it was concluded that E.J. had thrush due to Candida albicans. He
admitted to intravenous drug use during his younger years but was clean for 3 years
at the time of his visit. HIV was suspected and E.J. was tested after providing
consent. He was subsequently diagnosed HIV+ and initiated antiretroviral therapy.
The 1st line regimen is a Fixed Dose Combination (FDC) of oral efavirenz,
emtricitabine, and tenofovir.
■ Rx:
EFV (600mg) + FTC (200mg) + TDF (300mg) PO 1 tablet once daily on an empty
stomach.
Basic Principles of Pharmacology cont…
Basic Principles of Pharmacology cont…

Drug receptors:
■ Molecular components of the body with which a drug
interacts to bring about its effect
Drug Metabolism
In order to reach its receptor and bring about a
biological effect, a drug molecule must travel from the
site of administration to the site of action.
a) Absorption of drugs
■ Drugs usually enter the body at sites remote from
the target tissue or organ and thus require transport
by the circulation to the intended site of action. To
enter the blood stream, a drug must be absorbed
from its site of administration (unless if its
administered IV)
Drug Metabolism cont…
b) Transport of a drug from the GIT
■ Depending on their chemical properties, drugs may
be absorbed from the GIT by either passive diffusion
or active transport.
c) Distribution of drugs
■ Following absorption or systemic administration into
the bloodstream, a drug distributes into interstitial
and intracellular fluids
Drug Metabolism cont…
CNS Distribution
■ Distribution of drugs into the CNS from the blood is
unique, brain capillary endothelial cells have
continuous tight junctions- this is called the blood
brain barrier (BBB). Thus, drug penetration into the
brain depends on transcellular transport.
■ Lipid solubility of a drug is an important determinant
of its uptake by the brain
■ The more lipophilic a drug: the more likely it is to
cross BBB
Drug Metabolism cont…
CNS Distribution
Drug Metabolism cont…
Distribution to the Placenta
■ The transfer of drugs across the placenta is of critical
importance because drugs may cause anomalities in
the developing fetus.
■ Lipid solubility, extent of plasma binding and degree of
ionization of weak acids and bases are important
general determinants in drug transfer across the
placenta
■ The placenta is not an absolute barrier to all drugs as a
number of influx transporters are present- the fetus is
thus to some extent exposed to all drugs taken by the
mother
Drug Metabolism cont…
d) Metabolism of drugs
■ The lipophilic characteristics of drugs that promote
their passage through biological membranes and
subsequent access to their site of action also serve
to hinder their excretion from the body
■ The metabolism of drugs into more hydrophilic
metabolites is essential for their elimination from
the body, as well as for termination of their biological
and pharmacological activity
Drug Metabolism cont…
d) Metabolism of drugs
■ Metabolism of a drug sometimes terminates its
action – metabolized to biologically inactive
derivatives
■ Orally administered drugs are metabolized before
they enter systemic circulation – first-pass effect
Drug Metabolism cont…
d) Metabolism of drugs
Drug Metabolism cont…
Pro-drugs
■ are inactive when administered and must be
metabolized in the body to become active
■ Many drugs are active when administered and also
have active metabolites.
■ Some drugs are not modified by the body and
continue to act until they are excreted.
Drug Metabolism cont…
Drug Metabolism cont…
e) Elimination of drugs
■ Drugs are eliminated either unchanged by the process of
excretion or converted to metabolites
■ Excretory organs eliminate polar compounds (more
hydrophilic) efficiently than lipophilic compounds
■ Lipophilic drugs are not readily eliminated until they are
metabolized to more polar compounds
■ The kidney is the most important organ for excreting drugs
and their metabolites
■ Substances excreted in the feces are principally unabsorbed
orally ingested drugs or drug metabolites excreted either in the
bile or secreted directly into the intestinal tract and not
reabsorbed
Drug Metabolism cont…
e) Elimination of drugs
■ Excretion of drugs in breast milk is important as
drugs are potential sources of unwanted
pharmacological effects on the baby.
■ Excretion from the lung is important for the
elimination of anesthetic gases.
■ Excretion of drugs into sweat, saliva, and tears is
quantitatively unimportant
Pharmacokinetics
Pharmacokinetics is the effect of biological systems on drugs. It
deals with the processes of absorption, distribution and
elimination.
a) Dosage regimens
■ A dosage regimen is a plan for drug administration over a
period of time.
■ An appropriate dosage regimen results in the achievement of
therapeutic levels of the drug in the blood without exceeding
the minimum toxic concentration
■ Ideally, the dosing plan is based on knowledge of both the
minimum therapeutic and minimum toxic concentrations of
the drug as well as the clearance and volume of distribution
Pharmacokinetics cont…
Loading dose:
■ If the therapeutic concentration must be achieved
rapidly and the volume of distribution is large, a loading
dose may be needed at onset of therapy
Maintenance dose:
■ If it is important to maintain a concentration above the
minimum therapeutic level at all times, either a larger
dose may be given at long intervals or smaller doses at
more frequent intervals.
■ If the difference between the toxic and the therapeutic
concentration is small, then smaller doses should be
administered more frequently
Pharmacokinetics cont…
b) Adjustment of dosage when elimination is altered by disease
■ Renal disease or reduced cardiac output often reduces the
clearance of drugs that depend on renal function
■ Impairment of hepatic clearance occurs when liver blood flow is
reduced as in heart failure.

■ If it is important to maintain a concentration above the minimum


therapeutic level at all times, either a larger dose may be given at
long intervals or smaller doses at more frequent intervals.
■ The dose in a patient with renal impairment may be corrected by
multiplying the average dose for a normal person times the ratio of
the patient’s altered creatinine clearance to normal creatinine
clearance
Pharmacodynamics
Pharmacodynamics deals with the effects of drugs on
biologic systems.

■ The effects of most drugs result from their


interaction with macromolecular components of the
organism
■ The interaction results in biochemical and
physiological changes that are characteristic of the
response to the drug
Drug + Receptor ↔ Drug-Receptor complex → Biologic effect
Pharmacodynamics cont…
a) Drug-receptor interaction
Pharmacodynamics cont…
a) Drug-receptor interaction
■ Receptors are specific molecules in a biological system
with which drugs interact to produce changes in the
function of the system
■ The interaction of a drug with its receptors is the
fundamental event that initiates the action of the drug
■ Drugs that bind to the physiological receptors and
mimic the regulatory effects of the endogenous
signalling compounds are agonists
■ Other drugs bind to receptors without regulatory effect,
but their binding blocks the binding of the endogenous
agonist. These drugs are called antagonists
Pharmacodynamics cont…
b) Therapeutic Index and
therapeutic window
■ The therapeutic index is the
ratio of the dose that produces
toxicity (LD50) to the dose that
produces a clinically desired or
effective dose (ED50)
■ The therapeutic index represents
an estimate of the safety of a drug
■ Therapeutic window describes the
dosage range between minimum
effective dose and the minimum
toxic dose
Drug evaluation and regulation
a) Safety and Efficacy
■ Government regulates the development and marketing
of new drugs to ensure safety and efficacy
■ South African Health Products Regulatory Authority
(SAHPRA), formerly known as Medicines Control Council
(MCC) is the regulatory body in SA
■ SAHPRA requires evidence of safety (derived from
toxicity testing on animals) and probable therapeutic
action (from pharmacologic profile in animals) before
human testing is permitted.
Drug evaluation and regulation cont…
Drug evaluation and regulation cont…
a) Safety and Efficacy
Animal testing
■ The amount of animal testing required before
human studies begin is a function of the proposed
use and the urgency of the application
■ Thus, a drug proposed for occasional non-systemic
use requires less extensive testing than one
destined for chronic systemic administration.
Drug evaluation and regulation cont…
a) Safety and Efficacy
Acute toxicity
■ Acute toxicity studies are required for all drugs
■ Involve administration of single doses of the agent up to the
lethal level in at least 2 species, one rodent and one non-
rodent.
Subacute and chronic toxicity
■ Subacute and chronic toxicity testing are required for most
agents, especially those intended for chronic use.
■ Tests are usually conducted for at least the amount of time
proposed for human application, i.e. 2-4 weeks (subacute) or
6-24 weeks (chronic) in at least 2 species.
Drug evaluation and regulation cont…
Types of animal tests
■ General screening tests for pharmacologic effects
■ Hepatic function monitoring
■ Renal function monitoring
■ Blood tests
■ Urine tests
■ Gross and histopathologic examination of tissues
■ Tests of reproductive effects
■ Carcinogenecity
Drug evaluation and regulation cont…
Types of animal tests
■ Teratogenesis: induction of developmental defects in
the fetus
■ Mutagenesis: induction of changes in the genetic
material of animals
■ Carcinogenesis: induction of malignant
characteristics in a cell
Drug evaluation and regulation cont…
Clinical Trials
Phase Description No. of participants Tests conducted/ Outcome/Objective
study design
Phase I Evaluation of dose- Small number of Acute effects of the Dose that produces
response relationship normal human agent are studied no detectable effect
volunteers (e.g. 20- over a broad range of and one that
30) dosages produces either a
significant
physiological
response or very
minor toxic effect is
established
Phase II Evaluation of a drug Moderate number of Placebo or positive To determine
in patients with the patients (e.g. 100- control drug is whether the agent
target disease. 300) included in a single- has desired
blind or double-blind therapeutic effects at
design. doses that are
tolerated by sick
patients
Drug evaluation and regulation cont…
Clinical Trials
Phase Description No. of participants Tests conducted/ Outcome/Objective
study design
Phase III Consists of a very Involves many Usually include To explore further the
large design and patients (e.g. 1000- placebo and positive spectrum of
many clinicians who 5000 or more in controls in a double- beneficial actions of
are using the drug in many centres) blind crossover the new drug, to
the manner proposed design. compare it with older
for its ultimate therapies, and to
general use, e.g. in discover toxicities
outpatients.
Phase IV Post-marketing Drug is used by the None To detect toxicities
surveillance phase of general public, that occur very
evaluation anyone can report infrequently early
toxicities enough to prevent
major therapeutic
disasters.
Drug evaluation and regulation cont…
b) Adverse drug reactions (ADRs)
■ An adverse drug reaction is any response to a drug that
is noxious and unintended and occurs at doses normally
used in humans for prophylaxis, diagnosis or therapy of
diseases, or for modification of physiological function.
■ A toxic effect differs from an ADR because it is caused
by an exaggeration of the desired therapeutic effect and
thus is dose related.
■ An ADR may thus be a toxic effect.
■ Toxicology itself is the study of deleterious effects of
physical, chemical, or biological substances and covers
much more than pharmacological drugs
Drug evaluation and regulation cont…
■ An adverse drug event is an undesirable event that
occurs during treatment with a medicine but is not
necessarily caused by the medicine itself.
■ A side effect is related to the pharmacological activities
of a drug and may be beneficial as well as harmful.
■ ADRs are important since it is estimated that 6% of all
hospital admissions are due to ADRs.
■ There are no generally accepted classifications for
ADRs. However, one major classification is 1. related
(Type A) and 2. unrelated (Type B) to the
pharmacological action of the drug.
Drug evaluation and regulation cont…
■ Type A reactions are due to the augmented or
exaggerated effect of the drug. This effect can be
derived from the pharmacological activity.
■ Type B reactions are not related to the
pharmacological mechanism and involve
idiosyncratic and allergic reactions These reactions
are unpredictable, relatively rare, but often serious,
only occurring in susceptible patients.