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Medical
Toxicology
Pharmacology
Medical Pharmacology: the area of pharmacology concerned with the use of chemicals in the prevention,
diagnosis, and treatment of disease, especially in humans.
Toxicology: is the area of pharmacology concerned with the undesirable effects of chemicals on biologic
systems.
What is the difference between
pharmacokinetics &
pharmacodynamics?
Pharmacokinetics
• Describes the effects of the body on drugs
• Example: absorption, excretion
Pharmacodynamics
• Denotes the actions of the drug on the body
• Example: mechanism of action, toxic effects
The Nature of Drugs
Composition:
➢inorganic ions
➢nonpeptide organic molecules
➢small peptides and proteins
➢nucleic acids
➢lipids
➢carbohydrates
➢ Larger than MW 1000 → often poorly absorbed & poorly distributed in the
body
Pharmacodynamics
High-Yield Terms
Receptor A molecule to which a drug binds to bring about a
change in function of the biologic system
Inert binding molecule A molecule to which a drug may bind without
or site changing any function
Receptor site Specific region of the receptor molecule to which
the drug binds
Effector Component of a system that accomplishes the
biologic effect after the receptor is activated by an
agonist; often a channel or enzyme molecule, may
be part of the receptor molecule
Agonist A drug that activates its receptor upon binding
High-Yield Terms
Pharmacologic A drug that binds without activating its receptor
antagonist and thereby prevents activation by an agonist
Competitive A pharmacologic antagonist that can be overcome
antagonist by increasing the concentration of agonist
Irreversible antagonist A pharmacologic antagonist that cannot be
overcome by increasing agonist concentration
Physiologic antagonist A drug that counters the effects of another by
binding to a different receptor and causing
opposing effects
Chemical antagonist A drug that counters the effects of another by
binding the agonist drug (not the receptor)
High-Yield Terms
Allosteric agonist, A drug that binds to a receptor molecule without
antagonist interfering with normal agonist binding but alters the
response to the normal agonist
Partial agonist A drug that binds to its receptor but produces a smaller
effect at full dosage than a full agonist
Graded dose-response A graph of increasing response to increasing drug
curve concentration or dose
Quantal dose-response A graph of the fraction of a population that shows a
curve specified response at progressively increasing doses. The
median effective (ED50), median toxic (TD50), and (in
animals) median lethal (LD50) doses are derived from
experiments carried out in this manner.
High-Yield Terms
Efficacy, maximal The maximal effect that can be achieved with a
efficacy particular drug, regardless of dose
Potency The amount of drug needed to produce a given
effect.
Therapeutic Index Is the ratio of the TD50 (or LD50) to the ED50.
Represents an estimate of the safety of a drug. A
very safe drug might be expected to have a very
large toxic dose and a much smaller effective dose.
Therapeutic Window A more clinically useful index of safety. Describes
the dosage range between the minimum effective
therapeutic concentration or dose, and the
minimum toxic concentration or dose.
Drug-receptor Activation of
AGONIST
binding receptor
Drug-receptor Inhibition of
ANTAGONIST
binding receptor
Sugammadex is a new drug that reverses the action of
rocuronium and certain other skeletal muscle-relaxing agents. It
appears to interact directly with the rocuronium molecule and
not at all with the rocuronium receptor. Which of thefollowing
terms best describes sugammadex?
A. 8 am: 100 mg
B. 10 am: 75 mg
C. 12 pm: 50 mg
D. 2 pm: 25 mg
Half-life: 4 hours
High-Yield Terms
Minimum effective The plasma drug concentration below which a patient’s
concentration response is too small for clinical benefit
(MEC)
First-pass effect, The elimination of drug that occurs after administration
presystemic but before it enters the systemic circulation (eg, during
elimination passage through the gut wall, portal circulation, or liver
for an orally administered drug)
Steady state In pharmacokinetics, the condition in which the average
total amount of drug in the body does not change over
multiple dosing cycles (ie, the condition in which the
rate
of drug elimination equals the rate of administration)
The Movement of Drugs in the
Body
A. PERMEATION
Permeation
1. Aqueous diffusion
2. Lipid diffusion
4. Endocytosis, pinocytosis
Aqueous Diffusion
Movement of molecules through the watery extracellular & intracellular
spaces
Passive process
The capillaries in the brain, testes, and some other organs lack aqueous
pores
→ less exposed to some drugs
Lipid Diffusion
Endocytosis
Molecule binds to receptor on cell membrane →infolding of that
area of the membrane → internalization → intracellular vesicle →
contents of vesicle released into cytoplasm of cell
Endocytosis
Example:
Exocytosis
is the reverse process, that is, the expulsion of material that is
membrane-encapsulated inside the cell from the cell.
• Drug absorption is faster from organs with large surface areas, such
as the small intestine, than from organs with smaller absorbing areas
(the stomach).
• Weak bases are ionized—and therefore more polar and more water-
soluble—when
• If a patient takes an overdose of a weak acid drug, for example, aspirin, the
excretion
2. Blood flow
IM & SC sites, & in shock, the GIT as well
3. Concentration
• The first-pass effect is usually, but not always, due to metabolism in the gut, the
portal blood, or the liver.
Distribution of Drugs
Determinants of Distribution
2. Blood flow
3. Solubility
•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.
•Example: brain has a high lipid content → dissolve a high concentration
of lipid-soluble agents rapidly
4. Binding
• A few drugs are metabolized in many tissues (eg, liver, blood, intestinal wall)
because of the wide distribution of their enzymes.
Determinants of Biotransformation Rate
A. Genetic Factors
- e.g., abnormal plasma cholinesterase, slow acetylators
- coadministration
1. Enzyme Induction
2. Enzyme Inhibition
Enzyme Induction
• Induction: increased rate and extent of metabolism
• usually results from increased synthesis of cytochrome P450-
dependent drug-oxidizing enzymes in the liver as well as the cofactor,
heme.
• Several days are usually required to reach maximum induction; a
similar amount of time is required to regress after withdrawal of the
inducer.
• The most common strong inducers of drug metabolism are:
• carbamazepine, phenobarbital, phenytoin, and rifampin.
Drugs that significantly induce P450-mediated drug metabolism in humans
CYP Family Important Inducers Drugs whose metabolism is Induced
Induced
1A2 Benzo[a]pyrene (from tobacco smoke), Acetaminophen, clozapine, haloperidol, theophylline, tricyclic
carbamazepine, phenobarbital, rifampin, antidepressants, (R)-warfarin
omeprazole
2C9 Barbiturates, especially phenobarbital, Barbiturates, celecoxib, chloramphenicol, doxorubicin,
phenytoin, primidone, rifampin ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide,
(S)-warfarin
2C19 Carbamazepine, phenobarbital, phenytoin, Diazepam, phenytoin, topiramate, tricyclic antidepressants,
rifampin (R)-warfarin
• Along with the dosage, the rate of elimination following the last dose
(disappearance of the active molecules from the site of action, the
bloodstream, and the body) determines the duration of action for most
drugs.
Example:
action lasts for 48 h, the time required for turnover of the receptors
Elimination of Drugs
A. First-Order Elimination
B. Zero-Order Elimination
First-Order Elimination
• Implies that the rate of elimination is proportional to the concentration (ie, the
higher the concentration, the greater the amount of drug eliminated per unit
time).
with time.
A Controlled studies in women fail to demonstrate a risk to the fetus in the first
trimester (and there is no evidence of a risk in
later trimesters), and the possibility of fetal harm appears remote
B Either animal reproduction studies have not demonstrated a fetal risk but there are
no controlled studies in pregnant women,
or animal reproduction studies have shown an adverse effect (other than a decrease
in fertility) that was not confirmed in
controlled studies in women in the first trimester (and there is no evidence of a risk in
later trimesters)
C Either studies in animals have revealed adverse effects on the fetus (teratogenic or
embryocidal or other) and there are no
controlled studies in women, or studies in women and animals are not available.
Drugs should be given only when the
potential benefit justifies the potential risk to the fetus
FDA ratings of drug safety in pregnancy.
Category Description
D There is positive evidence of human fetal risk, but the benefits from use in pregnant
women may be acceptable despite the
risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for
which safer drugs cannot be used or
are ineffective)
X Studies in animals or human beings have demonstrated fetal abnormalities or there is
evidence of fetal risk based on human
experience or both, and the risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is
contraindicated in women who are or may become pregnant
Further Readings
A. Phases of clinical trials (Phase 1 to Phase 4)
B. Drug patents
C. Generic drugs
D. Orphan drugs