L5 Drug Action and Toxicity

Principle of Drug action, Drug
Toxicity and Adverse Drug effect

Connie Woo PhD RPh
Department of Pharmacology and Pharmacy
[email protected]
Mechanisms of Drug Action
The effects of most drugs result form their interactions with macromolecular
components of the organism
These interactions alter the function of the pertinent component and thereby
initiate the biochemical and physiological changes that are characteristic of
the response to the drug
Macromolecules > Commonly: PROTEINS
Enzymes
Ion channels
Transporters
Receptors
Enzymes
Major drug target, can be stimulate/inhibit or increase/decrease
Drugs usually as enzyme inhibitor, less common as stimulating enzyme
Can be provided as endogenous substrate
Examples:
◦ Pyridoxine – cofactor for decarboxylase
◦ Adrenaline – stimulate hepatic glycogen phosphorylase
Chemical in excess can be corrected by inhibiting an enzyme that produces the molecule
Examples:
Gout results from excess uric acid

◦ Xanthine oxidase converts xanthine to uric acid
◦ Inhibitors of xanthine oxidase reduce levels of uric acid
◦ E.g. Allopurinol
Enzyme inhibition
Specific vs. Non-specific
Reversible vs. Non-reversible
Competitive vs. Non-competitive

Non-specific:
◦ A nonspecific inhibition affects all enzymes in the same way. Non-specific methods of inhibition
include any physical or chemical changes which ultimately denature the protein portion of the
enzyme and are therefore irreversible
Specific
◦ Specific Inhibitors exert their effects upon a single enzyme. Most poisons work by specific
inhibition of enzymes. Many drugs also work by inhibiting enzymes in bacteria, viruses, or
cancerous cells
Non-reversible inhibitor
◦ dissociates very slowly from its target enzyme because it has become tightly bound to the
enzyme, either covalently or noncovalently.
Reversible
◦ is characterized by a rapid dissociation of the enzyme-inhibitor complex
Competitive
◦ An enzyme can bind substrate (ES) or inhibitor (EI) but not both (ESI).
◦ Drug resembles the substrate and binds to the active site of the enzyme, thereby preventing
from binding to the same active site.
◦ Inhibition can be relieved by increasing the substrate concentration, i.e. the substrate
“outcompetes” the inhibitor for the active site.
Noncompetitive
◦ Inhibitor (drug) and substrate can bind simultaneously to an enzyme at different binding sites
◦ Acts by decreasing the turnover number rather than by diminishing the proportion of enzyme
molecules that are bound to substrate.
◦ Cannot be overcome by increasing the substrate concentration
Competitive Non-competitive
Adding different
concentrations
of inhibitor/drug
Receptors
Drugs usually do not bind directly to channel, enzyme or structural proteins but
through receptor as mediator
Originally known as “specific receptive substance”
There are receptors for many endogenous compounds, including hormones
(endocrine and local), neurotransmitters, and growth factors.
Usually specific for one endogenous compound, also known as the endogenous
regulatory ligand (ligand meaning a naturally occurring substance that binds to
receptor).
Agonists vs. antagonists: agonists usually mimic the effect of the endogenous
ligand, whereas, antagonists usually prevent the effect of the endogenous ligand.
Agonism/Antagonism
Drugs that act at receptors can be either agonists or antagonists
Agonist: An agent that activates a receptor to produce an effect that similar
to that of the physiological signal molecule (e.g. Muscarine and Nicotine)
Antagonist: An agent that prevent the action of a agonist on a receptor or
the subsequent response, but dose not have effect on its own (e.g. Atropine)
Inverse agonist: An agent that activates a receptor to produce an effect in an
opposite direction to that of the agonist (e.g. DMCM)
Partial agonist: An agent that activates a receptor to produce submaximal
effect but antagonize the action of a full agonist (e.g. Pentazocine)
Affinity and Efficacy
Affinity is the attraction of the drug for the receptor. The best drugs are
the ones that have high affinity for their target receptor to initiate a
beneficial effect, and little or no affinity for other receptors, so that they
have as few unwanted effects as possible. Both agonist and antagonist
have affinity.
Efficacy is also known as intrinsic activity or effect. If a drug binds to

receptor and has no effect, it has an efficacy of zero. If a drug binds to
receptor and, at the higher concentrations, can have the same maximum
effect as the endogenous compound, it has an efficacy equal to one.
Agonists have efficacy, antagonists do not.
Receptor Regulation
Covalent modification
Association with other regulatory proteins
Can be relocalized within the cell (“Recycling”)
Downregulation vs. Upregulation
◦ Decrease/Increase affinity
◦ Decrease/Increase number
◦ Receptor synthesis
◦ Degradation
◦ Activation/Inactivation
Desensitization
◦ Also called refractoriness
◦ Continued stimulation of cells with agonist results in the effect that follows continued or
subsequent exposure to the same concentration of drug is diminished.
◦ Example: -adrenergic agonist as bronchodilator for asthma
Quantitation of Drug-Receptor
Interactions and Elicited effect
Dose response curve
◦ A depiction of the observed effect of a drug as a function of its
concentration in the receptor compartment
Therapeutic Index and
Quantal dose response curves
The therapeutic index of a drug is the ratio of the dose that produces
toxicity to the dose that produces a clinically desired or effective response
in a population of individuals.
Therapeutic index equation
◦ where: TD50 is the dose of drug that causes a toxic response in 50% of the population
and ED50 is the dose of drug that is therapeutically effective in 50% of the
population.
Both ED50 and TD50 are calculated from quantal dose response curves, which represent the
frequency with which each dose of drug elicits the desired response or toxic effect in the
population.
1. Dose of drug in plasma is plotted in the horizontal axis while the
percentage of individuals (animals or humans) that responds or
shows a toxic effect is represented in the vertical axis.
2. These curves measure all or none (positive or negative) responses.
Some examples of positive responses include: relief of headache
for an antimigraine drug, increase in heart rate of at least 20 bpm
for a cardiac stimulant, or 10 mmHg fall in diastolic blood pressure
for an antihypertensive.
3. Data is obtained from a population. Unlike graded dose-response
graphs, data for quantal dose-response curves is obtained from
many individuals.
Example of drugs with narrow TI:

•Warfarin
•Lithium
•Digoxin
•Phenytoin
•Gentamycin
•Amphotericin B
•5-fluorouracil
•AZT (zidovudine)
Drug Toxicity
When plasma concentration of drug exceed the TD50, patients may
experience drug toxicity
Related to metabolism and elimination
Factors affecting drug metabolism
◦ Genetic variation
◦ Allelic variants with different catalytic activities
◦ Can be lack of activity, a reduction of activity, enhance activity (e.g. gene
duplication)
◦ Leads to variation in drug response
◦ Example in metabolism
◦ CYP2D6 > about 70 SNPs (single nucleotide polymorphisms)
Environmental determinants
◦ Drug-drug interactions
◦ Drug-diet interactions
Inhibition of drug metabolism

◦ Increase plasma concentration of parent drug >> may increase toxicity
◦ Because of competition between 2 or more substrates for the same active site of the
enzyme
◦ The extent depends on the relative concentrations of the substrates and their affinities for
the enzyme
◦ May be irreversible if forming a tight complex with the heme iron of P450 (e.g. cimetidine,
ketoconazole) or destroy the heme group (e.g. norethindrone, ethinylestradiol)
◦ Phase II enzymes > commonly due to depletion of cofactors
Induction of drug metabolism (decrease efficacy rather than increase toxicity)
▪ Decrease plasma concentration of drug, reduce bioavailability, enhance oral first pass
metabolism
▪ Usually by enhanced gene transcription following prolonged exposure to an inducing
agent,
▪ CYP2E1 stabilization of protein against degradation is the major mechanism
▪ Need time to fully exhibit induction
▪ Autoinduction: a drug can induce both the metabolism of other compounds and its own
(e.g. carbamazepine)
▪ Example: rifampin therapy induce metabolism of oral contraceptive
▪ Inducers generally are selective for certain CYP subfamilies and isoforms
Disease Factors
▪ Dysfunction of metabolic organs can impair drug metabolism
▪ Liver: hepatitis, alcoholic liver disease, biliary cirrhosis, hepatocarcinomas
▪ Heart: cardiac failure, shock
▪ Severity of liver damage determines the extent of reduced metabolism

▪ Oral bioavailability may be increased 2 to 4-fold in liver disease
▪ Liver disease affects CYP450 (Phase I) to a greater extent than Phase II reactions
▪ E.g. Lidocaine metabolism reduced 2 folds in cardiac failure > adjust dosing for cardiac
arrhythmias in such case
Age and Gender

▪ CYP450 develop early in fetal development
▪ Both Phase I and II enzymes begin to mature gradually following the first 2-4 wks postpartum
▪ Newborns and infants are able to metabolize drugs relatively efficiently but still slower than
adults
▪ Impairment of bilirubin glucuronidation at birth > contribute to hyperbilirubinemia of newborn
▪ Gender differences in drug metabolic activity > e.g. CYP3A
▪ Pregnancy: certain drug metabolizing enzyme induced during 2nd or 3rd trimesters
Side Effect of Drugs
an unwanted pharmacological response that cannot be separated from the
main action of a drug
e.g. anti-anxiety drug usually can cause drowsiness
May be predictable
people may vary greatly in their sensitivity to drugs (idiosyncrasy)
may be a transient pharmacological change or a permanent pathological lesion

Adverse drug reactions (ADRs)
unwanted drug effects occurring at therapeutic doses
occur in 10-20% of hospitalized patients
skin and GI tract are commonly involved, but mostly relatively mild and
short-lasting
higher incidence at extremes of life
susceptibility depends on genetic differences and disease states
e.g. G6PD deficient people cannot use menthol-containing drug
preparation.
Prevention of adverse drug reactions
o never use any drug unless there is good indication
o if the patient is pregnant do not use the drug unless the need is imperative
o allergy and idiosyncrasy are important causes of ADRs
o ask if the patient had previous reactions
o ask if the patient is already taking other drugs including self medication
o age, hepatic and renal disease may impair clearance of drugs so smaller
doses may be needed
o genetic factors may also predispose to certain ADRs
o prescribe as few drugs as possible and give clear instructions
o where possible use familiar drugs; with new drugs be particularly alert for
ADRs and unexpected event
o if serious ADRs are liable to occur, warn the patient
Drug Tolerance vs.
Drug Dependence
Drug Tolerance refers to a diminished response to a drug taken in the
same dose
an increase in dose is required to maintain the same response
Drug Dependence is a condition in which the drug user has a

compelling desire to continue taking the drug
either to experience its effect or to avoid discomfort of its absence
Learning objectives
Understand the classification of enzyme action (inhibition): reversible
vs. non-reversible, competitive vs. non-competitive
Understand antagonism and antagonism in receptor dynamics
Define therapeutic index
Understand drug toxicity due to drug interaction
Define adverse drug reactions
Understand the differences between drug tolerance and drug
dependence

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Principle of Drug action, Drug

Toxicity and Adverse Drug effect

Gout results from excess uric acid

Specific vs. Non-specific

Reversible vs. Non-reversible

Competitive vs. Non-competitive

Efficacy is also known as intrinsic activity or effect. If a drug binds to

Example of drugs with narrow TI:

Inhibition of drug metabolism

▪ Severity of liver damage determines the extent of reduced metabolism

Age and Gender

may be a transient pharmacological change or a permanent pathological lesion

Drug Dependence is a condition in which the drug user has a

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