DEFINITION OF TERMS

• DRUGS
− Any substance that brings about a change in biologic function through
its chemical actions
• PHARMACODYNAMICS
− Actions of a drug on the body
• Receptor interaction
• Dose-response phenomena
• Mechanisms of therapeutic and toxic actions
DEFINITION OF TERMS
• PHARMACOKINETICS
− Actions of the body on the drug
− Concerned with:
• Absorption
• Distribution
• Metabolism
• Elimination
DEFINITION OF TERMS
• PHARMACOKINETICS
− Actions of the body on the drug
− Concerned with:
• Absorption
• Distribution
• Metabolism
• Elimination
NATURE OF DRUGS
• SIZE AND MOLECULAR WEIGHT
− Vary from MW 7 (lithium) to over MW 50,000 (alteplase,
thrombolytic enzymes)
− Majority have MW 100 to 1000
− <100 – rarely sufficiently selective in their actions
− >1000 – poorly absorbed and poorly distributed
NATURE OF DRUGS
• SIZE AND MOLECULAR WEIGHT
− Vary from MW 7 (lithium) to over MW 50,000 (alteplase,
thrombolytic enzymes)
− Majority have MW 100 to 1000
− <100 – rarely sufficiently selective in their actions
− >1000 – poorly absorbed and poorly distributed
NATURE OF DRUGS
• DRUG-RECEPTOR BONDS
− Arranged according to decreasing order of strength
oCovalent bonds
oElectrostatic bonds
▪ Ionic bonds
▪ Hydrogen bonding
▪ van der Waals
oHydrophobic bonding
NATURE OF DRUGS
• DRUG-RECEPTOR BONDS
− Strength of bond formed by drugs determine reversibility of
effects
oPRALIDOXIME (cannot reverse insecticide poisoning if the bonds
formed by the poison have aged and become covalent)
MOVEMENT OF DRUGS IN THE BODY
• Drug molecules must travel from the site of administration to the
site of action
− Permeation
− Fick’s Law of Diffusion
− Water and Lipid solubility of Drugs
MOVEMENT OF DRUGS IN THE BODY
• PERMEATION
− is the movement of drug molecules into and within biologic
environments
oAqueous diffusion
oLipid diffusion
oTransport by special carriers
oEndocytosis, pinocytosis
MOVEMENT OF DRUGS IN THE BODY
• PERMEATION
− Aqueous Diffusion
oPassive movement of non-protein-bound drugs between the blood
and extravascular space through small water-filled pores
(exceptions: Brain, Testes, Eye and Placenta)
oAffected by drug concentration and charge
oGoverned by Fick’s Law of Diffusion
MOVEMENT OF DRUGS IN THE BODY
• PERMEATION
− Lipid Diffusion
oMovement of drugs through lipid membranes (i.e. BBB, Placenta)
separating body compartment, and from the ECF to the ICF
oMost important limiting factor for permeation
oGoverned by Fick’s Law of Diffusion
oVery important for the diffusion of weak acids and weak bases
MOVEMENT OF DRUGS IN THE BODY
• PERMEATION
− Transport by Special Carriers
oDrugs that do not readily cross through membranes may be transported
across barriers by mechanisms that carry similar endogenous
substances
▪ Ions through Na/K pump
▪ Neurotransmitter through reuptake transporters
▪ Metabolites such as glucose through GLUT
▪ Carriers for foreign molecules or xenobiotics
oNOT governed by Fick’s Law of Diffusion and is capacity-limited
MOVEMENT OF DRUGS IN THE BODY
• PERMEATION
− Endocytosis
olarge drugs bind to receptors, are internalized and released after
vesicle breakdown (exocytosis is the reverse process)
oSmall polar drugs combine with special proteins to form complexes
which undergo endocytosis
▪ Vitamin B12 bound to Intrinsic factor
▪ Iron bound to transferrin
MOVEMENT OF DRUGS IN THE BODY
• FICK’S LAW OF DIFFUSION
−Predicts the rate of movement of molecules across a barrier
MOVEMENT OF DRUGS IN THE BODY
• FICK’S LAW OF DIFFUSION
−Pharmacologic Implications:
oAbsorption is faster in organs with large SA
(intestine > stomach)
oAbsorption is faster in organs with thinner membranes
(lung > skin)
MOVEMENT OF DRUGS IN THE BODY
• WATER AND LIPID SOLUBILITY OF DRUGS
−Aqueous solubility is directly proportional to electrostatic
charge (ionization, polarity)
oIonized and polar drugs are more water-soluble
oIncreased aqueous solubility = increased clearance
MOVEMENT OF DRUGS IN THE BODY
• WATER AND LIPID SOLUBILITY OF DRUGS
−Lipid solubility is inversely proportional to electrostatic charge
(ionization, polarity)
oNon-ionized and non-polar drugs are more lipid-soluble
oIncrease lipid solubility = increased capacity to cross biological
membranes
ABSORPTION
• Transfer of a drug from its site of administration to the
bloodstream
−Affected by 3 major factors:
oRoute of administration
oBlood flow
oConcentration
ROUTES OF ADMINISTRATION
• Oral Route
− Offers maximum convenience
− Most common route of drug administration
− Absorption is slow and less complete
oGastric contents
oFirst-pass effect
− A significant amount of the drug is metabolized in the gut wall, portal
circulation and liver before it reaches the systemic circulation
ROUTES OF ADMINISTRATION
• Intravenous Route
−Instantaneous and complete absorption that bypasses first-pass
effect (100% bioavailability)
−Potentially more dangerous:
oHigh blood levels reached on rapid administration
oInadvertent systemic introduction of bacteria through the IV line
(line sepsis)
ROUTES OF ADMINISTRATION
• Intramuscular Route
−Absorption is faster and more complete than oral (higher
bioavailability)
oBypasses first-pass effect
−Large volumes may be delivered if drug is not too irritating
(i.e. 5g of MgSO4)
−Anticoagulant cannot be given by this route because they may
cause bleeding (hematomas)
ROUTES OF ADMINISTRATION
• Intramuscular Route
−Absorption is faster and more complete than oral (higher
bioavailability)
oBypasses first-pass effect
−Large volumes may be delivered if drug is not too irritating
(i.e. 5g of MgSO4)
−Anticoagulant cannot be given by this route because they may
cause bleeding (hematomas)
ROUTES OF ADMINISTRATION
• Subcutaneous Route
−Slower absorption than intramuscular route
oNO blood vessels in the subcutaneous space
−Large volume doses are less feasible
−Bypasses the first-pass effect
−Anticoagulants do NOT cause hematomas when administered
via this route
ROUTES OF ADMINISTRATION
• Buccal and Sublingual Route
−Buccal: pouch between the gums and cheek
−Sublingual: under the tongue
−Direct absorption into the systemic venous circulation
bypassing the first-pass effect
ROUTES OF ADMINISTRATION
• Buccal and Sublingual Route
−Buccal: pouch between the gums and cheek
−Sublingual: under the tongue
−Direct absorption into the systemic venous circulation
bypassing the first-pass effect
ROUTES OF ADMINISTRATION
• Rectal (Suppository) Route
−Partial avoidance of the first pass effect
−Useful for large amounts of drugs with unpleasant tastes
and for patients who are vomiting
ROUTES OF ADMINISTRATION
• Rectal (Suppository) Route
−Partial avoidance of the first pass effect
−Useful for large amounts of drugs with unpleasant tastes
and for patients who are vomiting
ROUTES OF ADMINISTRATION
• Inhalational Route
−Offers delivery closest to the target in respiratory diseases
−Rapid absorption with minimal systemic effects
−Convenient for drugs that are gases at room temperature
(nitrous oxide, nitric oxide) or easily volatilized (anesthetics)
ROUTES OF ADMINISTRATION
• Topical Route
− Application to skin, mucous membranes of the eye, ear, nose, throat,
airway, or vagina for local effect
− Absorption varies with the area of application and drug formulation
oIncreasing ability to retard evaporation
▪ (more evaporation) tinctures > wet dressings > lotions > gels >
aerosols > powders > pastes > creams > foams > ointments
(less evaporation)
− Slowest route of drug administration
ROUTES OF ADMINISTRATION
• Topical Route
− Application to skin, mucous membranes of the eye, ear, nose, throat,
airway, or vagina for local effect
− Absorption varies with the area of application and drug formulation
oIncreasing ability to retard evaporation
▪ (more evaporation) tinctures > wet dressings > lotions > gels >
aerosols > powders > pastes > creams > foams > ointments
(less evaporation)
− Slowest route of drug administration
ROUTES OF ADMINISTRATION
• Transdermal Route
−Application to the skin for systemic effect
−Absorption occurs very slowly but bypasses the first-pass
effect
DISTRIBUTION
• Drug reversibly leaves the bloodstream and enters the target
organ
• Depends upon 4 major factors:
−Size of the organ
−Blood flow
−Solubility
−Binding
SIZE OF THE ORGAN
• Determines concentration gradient between blood and the
organ
−Skeletal muscle is very large organ
oLarge doses are required to actually change the concentration
gradient
−The brain is a small and compact organ
oOnly a small amount of drugs is required to change concentration
gradients
BLOOD FLOW
• Important determinant of the rate of drug uptake
• Well-perfused organs will achieve high tissue
concentrations sooner than poorly perfused tissues
• Concentration of drugs with rapid elimination will not
significantly rise in poorly perfused tissues
SOLUBILITY
• Influences the concentration of the drug in the
extracellular fluid surrounding blood vessels
• Most barriers in the body (BBB, placenta, glomerulus) are
lipid-barriers
−Non-ionized, non-polar drugs are more lipid-soluble and
undergo more extensive distribution
BINDING
• Binding to macromolecules in the blood or tissue will tend to
increase the drug’s concentration in that compartment
−Acidic drugs are bound to albumin
−Basic drugs are bound to orosomucoid
• Bound drugs CANNOT cross membranes and exert their effect
• Only unbound drugs CAN cross membranes and exert their
effect
METABOLISM
• Drugs are chemically altered in the body
• Drugs may undergo 3 metabolic fates:
−Termination of drug action
−Drug activation
−Elimination without metabolism
TERMINATION OF DRUG ACTION
• Drugs are metabolized into biologically inactive
derivatives
• Conversion to a metabolite is a form of elimination
DRUG ACTIVATION
• Prodrugs are metabolized in the body to become active
• Some drugs are metabolically active but still have active
metabolites
ELIMINATION WITHOUT METABOLISM
• Some drugs are not modified by the body and continue to
act until they are excreted
ELIMINATION
• Elimination: termination of drug action
• Excretion: release of drugs or their metabolites in the urine,
stool, bile, exhaled air, etc.
• Duration of drug action is determined by:
−Dose administered
−Rate of elimination following the last dose
ELIMINATION AND DRUG METABOLITES
• Elimination of parent molecule does not terminate the
drug’s action for drugs with active metabolites
• Excretion is the mode of elimination for drugs that are not
metabolized
FIRST-ORDER ELIMINATION
• Rate of elimination is proportionate to the concentration
−Concentration decreases exponentially over time
• Characteristic half-life elimination
−Concentration decreases by 50% for every half-life
• Most common type of elimination
ZERO-ORDER ELIMINATION
• Rate of elimination is constant regardless of
concentration
−Concentration decreases linearly over time
• Occurs when drugs have saturated their elimination
mechanisms
ZERO-ORDER ELIMINATION
• Rate of elimination is constant regardless of
concentration
−Concentration decreases linearly over time
• Occurs when drugs have saturated their elimination
mechanisms
RECEPTORS
• Specific molecules in a biologic system with which drugs
interact to produce changes in the function of the system
• Must be selective in their ligand-binding characteristic
• Must be modified when they bind an agonist to bring
about functional change
• Most are proteins
RECEPTOR SITES OR RECOGNITION SITES
• Specific binding region of the macromolecule
• High and selective affinity for the drug molecule
EFFECTORS
• Translate the drug-receptor interaction into a change in
cellular activity
• Some receptors are also effectors
−A single molecule may incorporate both the drug binding
site and the effector mechanism
oTyrosine kinase receptor in insulin receptor molecule
oNa/K channel in nicotinic Ach receptor
GRADED DOSE-RESPONSE RELATIONSHIPS
• Dose-response curve
−Response of a particular receptor-effector system
measured against increasing drug concentrations
−Yields a sigmoid curve if plotted on a semilogarithmic axis
• Efficacy (Emax) and Potency (EC50) are derived from this
curve
BINDING AFFINITY
• Fraction of receptors bound by a drug plotted against
the log of the drug concentration
• Kd is the concentration required to bind 50% of the
receptors
−The smaller the Kd, the greater the affinity of a drug for
its receptor
BINDING AFFINITY
• Fraction of receptors bound by a drug plotted against
the log of the drug concentration
• Kd is the concentration required to bind 50% of the
receptors
−The smaller the Kd, the greater the affinity of a drug for
its receptor
QUANTAL DOSE-RESPONSE RELATIONSHIPS
• Minimum dose require to produce a specified response is
determined in each member of a population
• Quantal dose-response curve
−Fraction of the population that responds to each dose
against the log of the dose administered
• No attempt is made to determine maximal effect
QUANTAL DOSE-RESPONSE RELATIONSHIPS
• Minimum dose require to produce a specified response is
determined in each member of a population
• Quantal dose-response curve
−Fraction of the population that responds to each dose
against the log of the dose administered
• No attempt is made to determine maximal effect
EFFICACY
• Maximal efficacy or Emax
• Maximal effect an agonist can produce if the dose taken to very
high levels
• Determined mainly by the nature of the receptor and its associated
effector system
• Measured with graded dose-response curves NOT with quantal
dose-response curves
• Partial agonists have lower maximal efficacy than full agonists
POTENCY
• Denotes the amount of the drug needed to produce a given effect
• Determined mainly by the affinity of the receptor for the drug
• Measurement:
− In grade dose-response curves, it is the dose required to produce
50% of the maximal effect
− In quantal dose-response curves, three potency variables are
measurable (ED50, TD50, LD50)
FULL AGONISTS
• Capable of fully activating the effector system when
it binds to the receptor
• High affinity for the activated receptor conformation
• Sufficiently high concentrations result in all the
receptor achieving the activated state
PARTIAL AGONISTS
• Produce less than the full effect, even when it has
saturated the receptors
• In the presence of an agonist, a partial agonist acts
as an inhibitor
PARTIAL AGONISTS
• Produce less than the full effect, even when it has
saturated the receptors
• In the presence of an agonist, a partial agonist acts
as an inhibitor
ANTAGONISTS
• Do not provoke a biological response by themselves upon binding to
a receptor
• Blocks or dampens drug response in the presence of an agonist
• Classification:
− Competitive (reversible)
− Non-competitive (irreversible)
− Physiologic
− Chemical
COMPETITIVE OR REVERSIBLE ANTAGONISTS
• Bind to receptors in a reversible way without activating the effector
system
• Shift DRCs to the RIGHT (increase ED50) but same maximal effect is
reached
• Effects overcome by adding more agonist
• Examples:
− β-blockers (Propranolol)
− β-agonists (Isoproterenol)
NON-COMPETITIVE OR IRREVERSIBLE ANTAGONISTS
• Causes DOWNWARD shift of the DRC
• No horizontal shift of DRC (ED50 unchanged) unless spare
receptors are present
• Not overcome by adding more agonists
• Examples:
−Norepinephrine
−Phenoxybenzamine
PHYSIOLOGIC ANTAGONISTS
• Binds to a different receptor, producing an effect
opposite to that produced by the drug it is antagonizing
• Examples:
• Histamine & Epinephrine
• Propranolol & Thyroid hormone
CHEMICAL ANTAGONISTS
• Interact directly with the drug being antagonized to
remove it or to prevent it from reaching its target
• Does not depend on interaction with agonist receptors
• Examples:
−Dimercaprol for lead poisoning
−Pralidoxime for organophosphate poisoning
VARIATIONS IN DRUG RESPONSE
• Tachyphylaxis
−Responsiveness diminishes rapidly after
administration of drug
−Frequent or continuous exposure to agonists often
results in short-term diminution of the receptor
response
VARIATIONS IN DRUG RESPONSE
• Tachyphylaxis
−Responsiveness diminishes rapidly after
administration of drug
−Frequent or continuous exposure to agonists often
results in short-term diminution of the receptor
response
VARIATIONS IN DRUG RESPONSE
• Tolerance
−Continuous activation may lead to depletion of essential
substrates
−Reversed by repletion of missing substrates
−EXAMPLE: depletion of thiol cofactors in nitroglycerin
tolerance, reversible with administration of glutathione
VARIATIONS IN DRUG RESPONSE
• IDIOSYNCRATIC DRUG RESPONSE
−One that is infrequently observed in most patients
−EXAMPLES:
oAplastic anemia with chloramphenicol
oCataracts with allopurinol
APPARENT VOLUME OF DISTRIBUTION
• Volume at which drug would need to be uniformly distributed
to produce an observed blood concentration

• Purely pharmacokinetic parameter with no direct physical

equivalent
• Can be altered by liver and kidney disease
VOLUME OF DISTRIBUTION
Low Vd Distribute in blood
Medium Vd Distribute in
extracellular space or
body water
High Vd Distribute in tissues
VOLUME OF DISTRIBUTION
Low Vd Distribute in blood
Medium Vd Distribute in
extracellular space or
body water
High Vd Distribute in tissues
CLEARANCE
• Relates the rate of elimination to the plasma concentration

• Depends on the drug and the condition of the organs of

elimination
−For a drug that is very effectively extracted by an organ,
clearance is flow-limited
CLEARANCE
• For drugs eliminated with first-order kinetics,
clearance is a constant proportion
• For drugs eliminated with zero-order kinetics,
clearance is a constant amount
CLEARANCE
• Most important pharmacokinetic parameter to be
considered in defining a rational steady state
during dosage regimen
CLEARANCE
• Most important pharmacokinetic parameter to be
considered in defining a rational steady state
during dosage regimen
STEADY STATE
• Condition in which the average total amount of drug
in the body does not change over multiple dosing
intervals
• Rate of drug input equals the rate of elimination
• Reached in 4-5 half-lives of the drug
HALF-LIFE
• Constant for drugs following first-order kinetics
• Disease, age, and other variables usually alter
clearance of a drug much more then Vd
• Half-life may not change despite a decreased
clearance if the Vd decreases at the same time
HALF-LIFE
• Constant for drugs following first-order kinetics
• Disease, age, and other variables usually alter
clearance of a drug much more then Vd
• Half-life may not change despite a decreased
clearance if the Vd decreases at the same time
BIOAVAILABILITY
• Fraction of the administered dose that reaches the systemic
circulation
• Drugs administered intravenously have 100% bioavailability
• Reduced by incomplete absorption, first-pass metabolism, and
pre-systemic redistribution
• Determined by computing the area under the plasma
concentration curve (AUC)
BIOAVAILABILITY
• Fraction of the administered dose that reaches the systemic
circulation
• Drugs administered intravenously have 100% bioavailability
• Reduced by incomplete absorption, first-pass metabolism, and
pre-systemic redistribution
• Determined by computing the area under the plasma
concentration curve (AUC)
DOSAGE REGIMEN
• Plan for drug administration over a time period
• Results in the achievement of therapeutic levels of the drug in
the blood without exceeding the minimum toxic concentration
• Based on knowledge of both the minimum therapeutic and
minimum toxic concentrations for the drug, as well as its
clearance and Vd
MAINTENANCE DOSE
• Equal to the rate of elimination at steady state

• Vd is NOT involved in calculating MD

• Important to maintain concentration above minimum therapeutic level:
− Give large doses at long intervals
− Smaller doses at more frequent intervals
LOADING DOSE
• If the therapeutic concentration must be achieved rapidly and the
volume of distribution is large

• Clearance is NOT involved in calculating LD

• If the LD is very large, dose should be given slowly to prevent toxicity
− Due to excessively high plasma levels during the distribution phase
THERAPEUTIC WINDOW
• Safe range between the minimum therapeutic
concentration and the minimum toxic concentration of a
drug
−Minimum effective concentration usually determines the
desired trough levels of a drug given intermittently
−Minimum toxic concentration determines the permissible
peak plasma concentration
THERAPEUTIC WINDOW
• Safe range between the minimum therapeutic
concentration and the minimum toxic concentration of a
drug
−Minimum effective concentration usually determines the
desired trough levels of a drug given intermittently
−Minimum toxic concentration determines the permissible
peak plasma concentration
ADJUSTMENT OF DOSAGE
• 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
−EXAMPLES: heart failure, severe cirrhosis, other forms of
liver failure
ADJUSTMENT OF DOSAGE IN RENAL IMPAIRMENT

• If a drug is cleared partly by the kidney and partly by

other routes, apply the equation only to the part of the
dose that is eliminated by the kidney
COCKCROFT-GAULT EQUATION
• To calculate the patient’s creatinine clearance, use
the Cockcroft-Gault equation
DRUG METABOLISM
• All organs are exposed to foreign chemical
compounds (xenobiotics)
• Metabolic pathways alter drug activity and their
susceptibility to excretion
PHASE 1 REACTIONS
• Convert the parent drug to a more polar (water-
soluble) or more reactive product by unmasking or
inserting a polar functional group
• EXAMPLES: oxidation, reduction, deamination,
hydrolysis
PHASE 1 REACTIONS
• Convert the parent drug to a more polar (water-
soluble) or more reactive product by unmasking or
inserting a polar functional group
• EXAMPLES: oxidation, reduction, deamination,
hydrolysis
CYTOCHROME P450 ENZYMES
• Also called mixed-function oxidases
• High concentration in the smooth endoplasmic reticulum of the
liver
• Not highly selective in their substrates
• Of the drugs metabolized by phase I cytochrome P450s,
approximately 75% are metabolized by just two:
−CYP3A4 or CYP2D6
CYTOCHROME P450 ENZYMES
• Also called mixed-function oxidases
• High concentration in the smooth endoplasmic reticulum of the
liver
• Not highly selective in their substrates
• Of the drugs metabolized by phase I cytochrome P450s,
approximately 75% are metabolized by just two:
−CYP3A4 or CYP2D6
PHASE 2 REACTIONS
• Involve conjugation of subgroups to –OH, –NH2, and –SH functions
on the drug molecule
− Makes the drug more polar and less lipid-soluble than the original
drug molecule
− EXAMPLES: glucoronate, acetate, glutathione, glycine, sulfate, and
methyl group
• Phase II enzymes are NOT very selective
• Drugs may undergo phase II metabolism before or after phase I
PHASE 2 REACTIONS
• Involve conjugation of subgroups to –OH, –NH2, and –SH functions
on the drug molecule
− Makes the drug more polar and less lipid-soluble than the original
drug molecule
− EXAMPLES: glucoronate, acetate, glutathione, glycine, sulfate, and
methyl group
• Phase II enzymes are NOT very selective
• Drugs may undergo phase II metabolism before or after phase I
SITE OF DRUG METABOLISM
• LIVER
• Most important organ for drug metabolism
• KIDNEYS
• TISSUE COMPARTMENTS
• Few drugs (e.g., esters) are metabolized in many tissues (e.g.,
liver, blood, intestinal wall) because of the broad
distribution of their enzymes
DRUG BIOTRANSFORMATION
• Most often due to genetic or drug-induced differences
• Gender is important for only a few drugs
−First-pass metabolism of alcohol (M>F)
• Primary determinant of clearance
−Variations must be considered carefully when designing
or modifying a dosage regimen
GENETIC FACTORS
• Drug-metabolizing systems differ among families or
populations in genetically determined ways
• Recent advances in genomic techniques allow
screening for a huge variety of polymorphisms
(pharmacogenomics)
EXAMPLES IN PHARMACOGENOMICS
• HYDROLYSIS OF ESTERS
− Succinylcholine metabolism by pseudocholinesterase
• ACETYLATION OF AMINES
− Fast and slow acetylation of isoniazid, hydralazine and
procainamide
• OXIDATION
− Debrisoquin, Sparteine, Phenformin, Dextromethorphan,
Metoprolol, and Tricyclic antidepressants
ENZYME INDUCTION
• Results from increased synthesis of cytochrome P450
enzymes and heme
• Several days are usually required to reach maximum
induction
• Most common strong inducers are carbamazepine,
phenobarbital, phenytoin, and rifampin
ENZYME INDUCTION
• Results from increased synthesis of cytochrome P450
enzymes and heme
• Several days are usually required to reach maximum
induction
• Most common strong inducers are carbamazepine,
phenobarbital, phenytoin, and rifampin
ENZYME INHIBITION
• Most significant inhibitors are Amiodarone, Cimetidine,
Furanocoumarins present in grapefruit juice, azole
antifungals, and the HIV protease inhibitor (Ritonavir)
• Metabolism may be decreased by reduction in blood
flow to metabolizing organ
−EXAMPLE: Propranolol reduces hepatic blood flow
SUICIDE INHIBITORS
• Metabolized to products that irreversibly inhibit the
metabolizing enzyme
• EXAMPLES: Ethinyl estradiol, Norethindrone,
Spironolactone, Secobarbital, Allopurinol,
Fluroxene, PTU
SUICIDE INHIBITORS
• Metabolized to products that irreversibly inhibit the
metabolizing enzyme
• EXAMPLES: Ethinyl estradiol, Norethindrone,
Spironolactone, Secobarbital, Allopurinol,
Fluroxene, PTU
ANIMAL TESTING
• Required before human studies begin
• Function of the proposed use and the urgency of the application
• Drug proposed for non-systemic use requires less extensive
testing
• Anticancer drugs and drugs proposed for use in AIDS require
less evidence of safety
ACUTE TOXICITY
•Required for all new drugs
•Involve administration of single doses of the
agent up to the lethal level in at least 2 species
(e.g., 1 rodent and 1 nonrodent)
SUBACUTE AND CHRONIC TOXICITY
•Required for most agents, especially those
intended for chronic use
•Duration: 2 – 4 weeks (subacute) or 6 – 24
months (chronic), in at least 2 species
PHARMACOLOGIC PROFILE
•Description of all the pharmacologic effects
−Effects on cardiovascular function, gastrointestinal
activity, respiration, renal function, and endocrine
function, CNS
•Both graded and quantal dose-response data are
gathered
REPRODUCTIVE TOXICITY
•Involves the study of the fertility effects of the
candidate drug and its teratogenic and mutagenic
toxicity
•FDA uses a 5-level descriptive scale to summarize
information regarding the safety of drugs in
pregnancy
TERATOGENESIS
• Induction of developmental defects in the somatic tissues of the
fetus
• Studied by treating pregnant female animals of at least 2
species at selected times during early pregnancy when
organogenesis is known to take place
−EXAMPLES: thalidomide, isotretinoin, valproic acid,
ethanol, glucocorticoids, warfarin, lithium, and androgens
TERATOGENESIS
• Induction of developmental defects in the somatic tissues of the
fetus
• Studied by treating pregnant female animals of at least 2
species at selected times during early pregnancy when
organogenesis is known to take place
−EXAMPLES: thalidomide, isotretinoin, valproic acid,
ethanol, glucocorticoids, warfarin, lithium, and androgens
MUTAGENESIS
•Induction of changes in the genetic material of
animals of any age and therefore induction of
heritable abnormalities
−EXAMPLES: aflatoxin, cancer chemotherapeutic
drugs, and other agents that bind to DNA
AMES TEST
•Standard in vitro test for mutagenicity
•Uses a special strain of Salmonella that
naturally depends on specific nutrients
•Loss of this dependence signals a mutation
DOMINANT LETHAL TEST
•In vivo mutagenicity test carried out in mice
•Male animals are exposed to the test substance
before mating
•Abnormalities in the results for the subsequent
mating signal a mutation in the male’s germ cells
CARCINOGENESIS
• Induction of malignant characteristics in cells
• Difficult and expensive to study
• High degree of correlation between mutagenicity in the Ames
test and carcinogenicity in some animal tests
−EXAMPLES: coal tar, aflatoxin, nitrosamines, urethane, vinyl
chloride, polycyclic aromatic hydrocarbons in tobacco smoke
CLINICAL TRIAL
•Requires approval by institutional committees
that monitor the ethical (informed consent,
patient safety) and scientific aspects (study
design, statistical power) of the proposed tests
INVESTIGATIONAL NEW DRUG (IND)
•Includes all the preclinical data collected up to
the time of submission and the detailed
proposal for clinical trials
NEW DRUG APPLICATION (NDA)
•Constitutes the request for approval of general
marketing of the new agent for prescription
usage and includes all the results of preclinical
and clinical testing
PHASE 1 TRIAL
• Careful evaluation of the dose-response relationship and
pharmacokinetics among normal human volunteers (25-
50)
−EXCEPTION! In cancer and highly toxic agents (volunteer
patients with target disease)
• Acute effects of the agent are studied over a broad
range of dosages
PHASE 2 TRIAL
• Evaluation of a drug in a moderate number of patients (e.g., 100-
300) with the target disease
• Placebo or positive control drug is included in a single-blind or
double-blind design
• Under carefully controlled conditions with close monitoring usually in
hospital ward
• Determine whether the agent has the desired efficacy at doses that
are tolerated by sick patients
PHASE 3 TRIAL
• Large design involving many patients (1000-5000) and many
clinicians
• Include placebo and positive control in a double-blind crossover
design
• Explore further the spectrum of beneficial actions of the new drug to
compare it with older therapies, and to discover toxicities
• Large amounts of data are collected
• Usually very expensive
PHASE 4 TRIAL
•Post-marketing surveillance phase
•Detects toxicities that occur very infrequently
•Findings reported early enough to prevent
major therapeutic disasters
DRUG PATENTS
• Usually submitted around the time that a new drug enters animal
testing
• Right to market the drug without competition from other firms for a
period of 20 years
• After expiration of patent, any company may apply to the FDA for
permission to market a generic version of the same drug
− Must demonstrate that their generic drug molecule is bioequivalent
BIOEQUIVALENCE
•Two related drugs are bioequivalent if they
show comparable bioavailability and similar
times to achieve a peak blood concentrations
•Used in determining safety and efficacy of
generic drugs
BIOEQUIVALENCE
•Two related drugs are bioequivalent if they
show comparable bioavailability and similar
times to achieve a peak blood concentrations
•Used in determining safety and efficacy of
generic drugs
ORPHAN DRUG
•Drug for a rare disease (one affecting fewer
than 200,000 people)
•Often neglected because the sales of an
effective agent for an uncommon ailment might
not pay the costs of development