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193 Cards in this Set

  • Front
  • Back
Drug
Any substance that brings about a change in biologic functions through its chemical actions.
(Could be small molecules, antisense RNA, proteins)
Pharmacology
The study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.
Pharmacokinetics
The Absorption, Distribution, Biotransformation, and Excretions (ADBE) of drugs.

"What the body does to the drug"
PharmacoDynamics
The mechanism of drug action and the relationship between drug concentration and effect. Usually governed by a receptor.

"What the drug does to the body"
Receptor
The component of a cell or organism that interacts with a drug and INITIATES the chain of biochemical events leading to the drug's observed effects.
Two Factors affecting Relationship between dose/Concentration of drug and pharmacologic effect:
1. Receptor-Drug binding affinity

2. Number of receptors on cell surfaces and intracellular
Toxicology
- The adverse effects on drugs and chemicals on living systems (includes drugs with narrow therapeutic index)

- The science of poisons, their effects, detection, and treatment
Pharmacotherapeutics
The use of drugs in the prevention and treatment of disease
Factors Influencing the ability of a drug to cross a biological membrane
1. Constitution of cell membrane (amphipathic)
2. Size of the Molecules (<200MW can use Passive Diffusion)
3. Concentration Gradient - Fick's Law
4. Influence of pH
Passive Transport
Diffusion down a concentration gradient.

Depends both on the magnitude of the concentration gradient & the lipid:water partition coefficient.
What Fick's Law does
Quantifies observations that drug absorption is FASTER across organs with Large Surface Areas (small intestines > stomach) and Thin Membrane Barriers (lung < skin)
Ficks Law Equation
Flux (molecules per unit time) = (C1 - C2)(Area)(Partition Coefficient) / Thickness
Henderson - Hasselbaich Equations
pH = pKa + log (B/A)
Ion Trapping
At steady state, an acidic drug will accumulate on the more Basic side of the membrane.
Carrier-Mediated Membrane Transport
Necessary for transport of endogenous compounds whose rate of movement across biological membranes by simple diffusion would be too slow.

Usually selective for specific drug conformations
MDR (Mulit-Drug Resistance) gene product
Reverses absorption of drugs by pumping them out (ex. chemotherapy)
Facilitated Diffusion
Carrier-mediated transport process in which there is No Input of Energy, thus transport CANNOT occur against an electrochemical gradient
Absorption
Describes the rate at which a drug leaves its site of administration and the extent to which this occurs
Bioavailability
Indicates extent to which a drug reaches its site of action or a biological fluid from which the drug has success to its site of action. Metabolism and excretion will reduce the bioavailability of a drug.
Enteral Route of Administration
-Most common, convenient, economical, safest

=Problems= Poor adsorption, emesis from irratation to GI muccosa, enzyme modification, interference by other drugs or food, patient cooperation

=Routes= oral ingestion, sublingual, rectal
Parenteral Rout of Administration
May be required from absorption, rapid and predictable availability, emergency situation, patient unconscious or uncooperative or can't keep down anything swallowed

=Problems= Sepsis, injection pain, hard to self-medicate, expensive

=Route=IV, SQ, IM, intrathecal, intraarterial, intraperitoneal
Initial distribution
durg is from bloodstream to well-perfused organs (heart, liver, kidney, brain)
Initial Distribution is dependent upon 4 things:
1.) Size of the Organ (determines concentration gradient b/n blood & organ)
2.) Blood Flow (determines rate of drug uptake)
3.) Solubility (influences drug concentation in extracellular fluid surrounding blood vessels)
4.) Drug Binding (blood or tissue)
Secondary Distribution
from drug to muscle, most viscera (internal organs), skin, and fat
Redistribution
Termination of drug effect by drug moving from the site of action to another tissue or site.
Drug Reservoirs, good & bad
Drug can accumulate in body parts and be subsequently released as plasma concentration falls.

=Good= time release is desired

=Bad= Reservoir capacity is large so that high levels to drug initially employed. If Narrow TI, need to overcompensate for reservoirs.
Plasma Proteins
Binding is usually reversible, but occasionally covalent alkylation
(albumin, a1-acid glycoprotein)
3 Types of Cellular reservoirs
1.) Fat - stable reservoir because of low blood flow, like lipophilic tissue

2.) Bone - A Slow-Release reservoir. Tetracycline and other divalent metal ion chelators may be absorbed by bone surface and be incorporated into crystal lattice.

3.) Transcellular (GI tract) - Weak bases may accumulate in stomach from blood due to pH differential.
The CNS & BBB has 2 Barriers to entry
- Astrocytes
- Tight Junctions
Astrocytes
Glial cells that surround the brain capillary, but these cells can mediate passage of certain substances.
Tight Junctions
Brain capillaries that lack intercellular pores or pinocytotic vesicles.
How to get into the BBB
- lipid-soluble and non-ionized drugs can pass through (water-soluble and ionized can enter via carrier-mediation)
- BBB works in both directions-hard to get in & out
Can the BBB be overwhelmed?
Yes, by diseases or high doses of certain drugs (ex. Meningitis, or high doses of PCN can causes seizures)
Are all drugs metabolized before elimination?
No, a minority of drugs like lithium, are not and therefore continue to act until they are excreted.
Metabolism (biotransformation)
Lipophilic drugs are not eliminated easily because they can be reabsorbed into circulation via the renal tubular membrane. The drug is therefore converted to a more hydrophilic metabolite (usually less potent), then excreted
Prodrugs
Sometimes administered in this inactive form and then becomes metabolized prior to activation (ex. levodopa --> dopamine)
Phase I Metabolism
"Functionaliziation reaction"
- introduces or exposes a functional group on the parent compound
- usually with loss of activity
Phase II Metabolism
"Biosynthetic (conjugation) reactions"
- covalent, Irreversable
- highly polar, excite rapidly
- Drug is covalently linked in vivo to glucuronic acid, sulfate, glutathione, amino acids or acetate.
Cytochrome P450
Major catalyst of drug biotransformation reactions (Phase I metabolism)
- Lowers the availability of the parent drug
Factors Affecting Biotransformation
1.) cP450 induction
2.) Inhibition of metabolic enzymes
3.) Genetic Polymorphism
4.) Disease
5.) Age
6.) Diet, Environment
7.) Metabolic Drug Interactions
Ways to Induse cP450
= Drugs (Barbituates, Benzo-L-pyrene, Carbamazepine)
= Environmental pollutants (smoking, drinking, genetics, cooking in charcoal, factory work)
= Several days are usually required to reach maximum induction.
Inhibition of metabolic enzymes
=Leads to reduced clearance, prolonged half-life, and drug accumulation that may potentially produce toxic effects in the individual
= includes Suicide Inhibitors, and Pharmacodynamic inhibitors
= ex. Cimetidine (Tagamet), Cyclosprine (Sandimmune), Ketoconazole (Nizoral), Erythromycin (E-Mycin), Grapefruit juice
Pharmacodynamic Inhibitors
metabolism decreases due to decreased pharmacodynamic factors (reduced blood flow to metabolizing organ)
Suicide Inhibitors
Drugs may be metabolized to prducts that irreversibly inhibit the metabolizing enzyme
= ex. AZT inhibits HIV-1 reverse transcriptase; 5-flurouracil inhibits thymidaylate synthase necessary for thymine synthesis
Genetic Polymorphism
Point mutation usually responsible, often in cP450 protein
Disease effect on Metabolism
Liver function imparired by hepatitis, cirrhosis, low liver blood flow, etc.
- Normal dose of diazepam (Valium) may cause coma if liver dysfunctional
Age effect on Metabolism
Very young and very old are typically more susceptible to a drug's pharm, tox
Diet & Environment effect on Metabolism
Charcoal- broiled foods: induce CYP-1A activity

Smokers, industrial workers: metabolize some drugs quicker
Metabolic drug interactions
Coadminstation of 2 drugs may affect the metabolism of 1 or both

Usually by competing for the same enzyme site
Excretion
Drugs are eliminated from the body either unchanged or as metabolites (polar compounds are eliminated more efficiently).
The kidney by far is the most important excretory organ for drugs

Renal, biliary fecal excretion are the major routes
Four Key Pharmacokinetic Parameters
1.) Clearance (Cl)- measure of the body's ability to eliminate the drug
2.) Volume of distribution (Vd): A measure of the apparent space in the body available to contain the drug (includes wt of pt)
3.) Elimination half-life (t1/2): A measure of the rate of removal of drug from the body
4.) Bioavailability (F): Fraction of drug absorbed as such into the circulation
Clearance
Most important when long-term drug administration regimen designed.

To maintain drug level, rate of elimination = rate of admission
Clearance Equations
Cl = (rate of elimination) / (Drug concentration)

Cl sys = Cl renal + Cl hepatic + Cl other
Volume of Distribution (L/kg) =
(Amount of Drug) / (Plasma Concentration of Drug)
or
D/Cp
Half Life (t1/2) defined
Time it takes for the plasma concentration of the drug in the body to be reduced by 50%
t 1/2 =
= (ln2)(Vd) / Cl
How long must you wait before adjusting a new dose?
4 half lives. Based on the approach of the accumulation curve to over 90% of the final steady state concentration.
If a drug is easily measured, how do you design and optimize a dosage regimen?
Trial and Error.

ex. Blood Pressure, temperature, pulse
Rules of thumb for Changing dosage
1.) Change by no more than 50%

2.) Change no more often than every 3 to 4 half-lives
When dosing drugs with little or no dose-elated toxicity, you should:
Use "Maximum dose" strategy, this maximizes Efficacy & Prolongs effect in compounds where toxicity is not a major concern
Two Concerns that must be Considered when Dosing Most Medication
1.) Narrow Therapeutic Window

2.) Ambiguous measurement of effects
Target Dose (Css) or (Cp)
Desired plasma concentration

Varies between patients greatly
Therapeutic Window
Desirable range for Css
Lower end
Concentration that produces measurable therapeutic effect
Higher end
Fixed by toxicity

< 5-10% of patients experience toxic effect
Maintenance dose
Amount of drug needed to maintain target level
Dosing Rate (DR) =
= T x Cl / F

or

= (Target Cp)(Clearance) / (Bioavailability)
Maintenence Dose =
= dosing rate x dosing interval
Which is more effective:

Larger doses once a day

Smaller doses more frequently
Smaller doses are better to reduces spikes close to toxicity levels, and to maintain more consistent Cp.
Leading Dose (LD) =
Target Cp x Vd / F
Leading dose defined
Initial dose(s) that seek to achieve target concentration rapidly

Used when time required to attain steady -state drug conc (4-half lives) is too long given the pt's condition.

ex. situations of arrhythmia
Problems with Loading Doses
1.) If unusually sensitive to a drug, you're exposing them to a toxic situation.

2.) If drug has a long half-life, it takes a long time for concentration to fall if overdosed.
List of drugs with half-lives over 24 hours
Diazepam - 43 horus

Fluoxetine - 53 hours

Phenobarbital - 100 hrs

Mefloquine - 20 days

Amiodarone - 25 days
Why would you want to individualize dosage?
There's variability in all drugs and patients, and sensitivity (even people of similar physique - one could be and ex-Narc Addict)
How to therapeutically monitor drug dosing
- Must measure Cp and then adjust if necessary.
When do you sample during the dosing interval??
1.) Measure JUST before next dose (testing soon after adminsitration can be misleading if the distribution rate is slow)

2.) Measure after 2 half-lives (Although you should wait till after 4 before adjusting, it could be dangerous if it's toxic, so measure but do not CHANGE)
Dose (new) =
= Dose (previous) x Cp(desired) / Cp (measured)
What did Ehrlich historically note?
That toxic and therapeutic effects of synthetic organic chemicals were dependent on subtle differences between agents.

- one chemical had an antiparasitic effect, but a close structural analog did not - denoting Chemical Structure Specificity
What did Langely historically note
Postulated existence of "receptors" after noticing that some agents elicited highly specific and potent biological responses

- saw that curare (poison dart frog poison & nicotinic acetylcholine receptor antagonist) could inhibit nicotine-mediated skeletal muscle contraction but could not block electrical stimulation of muscle contraction (b/c electrical stimulation bypassed receptor-mediated activation)
What did Dale historically note:
Suggested that acetylcholine interacted with 2 types of receptors, coined them "nicotinic" and "muscarinic" based on their observed selectivity or the plant alkaloids nicotine and muscarine.
What did Ahlquist historically note?
Proposed that adrenergic receptors be divided into "alpha" and "beta" subtypes based on pharmacologic profiles.
Affinity
How tightly the receptor binds the drug, usually expressed as a dissociation constant (Kd)
Dissociation constant (Kd) defined
Concentration of free drug at which half-maximal binding is observed (half of Bmax)

therefore: A hight Kd means more drug wants to be separated (D + R)
Efficacy
relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level
Kd =
K2/ K1 or D + R / DR

when
K1 = D + R --> DR
K2 = D + R <-- DR
Agonist
A drug that binds to and ACTIVATES a physiological receptor, mimicking the effects of the endogenous regulatory compound
Antagonist
A drug that binds to a physiological receptor and BLOCKS the action of an agonist.

Has equal affinity for active & inactive receptor conformations.
Full Agonist
Binds and activates a receptor with full efficacy
Partial Agonist
Bind and activates a receptor, but has only partial efficacy compared to the full agonist.

In the presence of a full agonist, a partial agonist acts as an Inhibitor.

Binds to both active and inactive receptor conformations, but prefers active.
Inverse Agonist
Binds to the same receptor site as an agonist and reverses the activity of the receptor.

These have the opposite pharmacological effect as a receptor agonist.

Prefers inactive conformation of receptor, and produces effects opposite to that of agonist by Stabilizing receptor against agonist action.

Ex. Famotidine (Pepcid), metoprolol, risperidone (Risperdal)
Noncopetitive Antagonist
Binds to a distinctly separate (allosteric) binding site from the agonist, and eliminates the systems ability to respond.

High concentrations do not overcome this effect - These will always win.

Irreversibly binds (Covalent bonds) to inhibit agonist action.
Competitive Antagonist
Reversibly bind to a receptor at the same binding site as the endogenous ligand or agonist, without activating the receptor.

The effects of this can be overcome by increasing the concentration.

Efficacy is unaltered, just harder to get there, therefore potency decreases.
Allosteric Antagonist
when ligand I binds to a different site on the receptor to either inhibit response or potentiate response.

This effect is saturable, inhibition reaches a limiting value when the allosteric site is fully occupied.

Antagonist causes a receptor to Conformationally Change, that depresses the agonist-mediated response
Irreversibly or Pseudo-Irreversible Antagonist
Slow dissociation but just strongly ionic (NOT a covalent bond)

Affinity for the receptor is so hight that the agonist cannot compete.

Causes a shift of the dose-response curve to the right, with further depression of the maximal response.
Potentiation Antagonist
Binding of an "antagonist" causes a receptor conformational change that Increases agonist potency.
5 Types of Pharmacologic Antagonism
1.) Competitive
2.) Non Competitive
3.)Pseudo-Irreversible
4.) Allosteric
5.) Potentiation
Constitutive Activity
Activation of receptor in the absence of an agonist, often due to a receptor mutation
What is the only detectable agonist for a CA receptor?
Inverse agonist
Intrinsic Activity defined
Describes the relationship between the effect (E) elicited by a drug (D) and the concentration of drug-receptor complex
Effect (E) =
= (intrinsic activity)x(Drug-Receptor complex)

= 1.00 for a full agonist
Efficacy (e) =
= Stimulus / occupancy

= y / S
Potency
The concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect
Clinical effectiveness of a drug depends less on potency, and more on :
1.) Efficacy

2.) Ability of drug to reach relevant receptor
Spare Receptors
The maximal response of drug that can be elicited by an agonist at a concentration that does not result in full receptor occupancy.

The increased receptor to drug ratio enhances the sensitivity of a given drug agonist.
Effect of spare receptors on Kd
They can Compensate for agonist concentrations well below the Kd value.

They increase the sensitivity of a tissue to a drug
What are the majority of drug receptors?
Mostly proteins, but occasionally it could be a nucleic acid (usually anti-tumor agents)
What happens when the agonist binds to a typical receptor?
It drives a Receptor Conformational Change that transduces a signal.
Why is chirality important?
Some isomers appear identical, but only 1 fits into the receptor.

Most drugs are racemic mixtures (50-50 of each stereoisomer)

(+)-Ketamine is a better anesthetic and less toxic then (-) isomer

Nexium is supposed to have more active enantiomers in it then Prilosec.
Rational Drug Design
= must map, crystallize drug receptors

= molecular modeling of drug docking to receptor

= Data from drug structure-activity series allows crude model of receptor binding sites.
5 Types of Drug-Receptor Interactions
1.) Covalen
2.) Ionic
3.) Hydrogen
4.) van der Waals
5.) Hydrophobic
Covalent D-R interactions
Strongest,

Often Irreversible under biological conditions

Unless an enzyme can reverse it, the receptor type is inactivated until new receptors are synthesized.

Drug affect may last long after free drug is cleared form bloodstream (alkylating agents and other carcinogens)
Ionic D-R interactions
Strongest type of electrostatic interaction

Often the primary tether between a drug and a signal-transducing receptor

ex. G-protein coupled receptor's primary bond is ionic
Hydrogen bonding D-R interactions
Relatively weak electrostaic interaction, but extremely important for drug receptors

Several H-bonds typically combine to form drug-binding site.
van der Waals D-R interactions
Extremely weak electrostatic interactions - hard to detect

Electrons accumulate on 1 side of the molecule, which will weaken over time and distort neighboring molecules

The higher the specificity the weaker the bond strength, therefore the more symmetry needed to hold the D-R in place snuggly and highly compatible chains.
Hydrophobic interactions
Often weak, but increasingly important structure for specificity
Pharmacogenetics
the study of the genetic variation in drug response
Pharmacogenomics
Using bioinformatic and pharmacologic tools to find correlations between therapeutic drug responses and genetic profiles.
Reverse genetics
Genotype-to phenotype approach is now possible.

"where is the variation?"
What is a fun fact about Isoniazid??
First drug for which metabolic variations were linked to a specific genetic variation

it's an antibiotic used to treat TB

(polymorhpism of NAT2 gene, responsible for N-acetylation)
What is the "weapon of choice" for pharmacogenetic studies?
Twin studies:

identical vs. fraternal vs heterozygotic sibling vs. unrelated
3 types of SNPs
single nucleotide polymorphism substitutes

Most common genetic variant

1.) Coding, non-synonymous
Polypeptide Sequence Altered ("missense") or truncated ("nonsense")
2.) Coding, synonymous
3.) Noncoding
Coding, nonsynonymous SNPs
Changes aa codon, which could change protein structure, stability, substrate affinities, or introduce a stop codon.
Coding, synonymous SNPs
do not change the amino acid codon, but may have expression and functional consequences (transcript stability, splicing) .

Lease harmful
Noncoding SNPs
(promoter, intronic)

may be promoters, introns, or other regulatory regions that may affect transcription factor binding, enhancers, transcript stability or splicing.

Usually affects metabolism
Molecular mechanisms of genetic polymorphism
1.) SNPs

2.) Indels

3.) CNVs
Indels
(insertion/deletions)

Alters or eliminates the protein expression

Can have any of the same effects as SNP substitutions: short repeats in the promoter (which can affect transcript amount), or insertions/deletions that add or subtract amino acids
3 types of CNVs
Copy Number Variations

Most detrimental & potential form harm

Involve large segments of genomic DNA that may involve:

1.) Copy Number Variations
2.) Gene Duplications
3.) Large Deletions
Gene duplications
Stably transmitted inherited germline gene replication that causes increased protein expression and activity.
Gene deletions
complete lack of protein production, or inversions of genes that may disrupt gene function.
How much variation of drug half-life is genetically mediated??
75-85% from one of the types of mutation variations.
Polymorphism
Variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population
Haplotype
Series of alleles found at a linked locus of chromosome

The linked-set of variants that occur together for the gene
What are the most common DNA mutation associated with human disease??
1)Nonsense & Missense


2.) Deletion
3.) Splicing
etc.
Ethnic Diversity of Polymorphism
Ethnic and race-specific polymorphic profiles follow human migration patterns.

ex. N. Europeans = "slow acetylators"

"Asian Flush" = aldehyde dehydrogenase SNP

Sickle cell anemia SNP
3 Types of Pharmacogenetic Phenotypes
1.) Pharmacokinetic
- Usually effects metabolism, or concentrations of the drug in questions. cP450 genes usually responsible.
2.) Receptor/Target
- Alter binding site or availability of drug's primary target/receptor. Make more or less sensitive to drug.
3.) Disease-modifying
- gene does not directly interact with the drug, but is involved in manifestation of the disease.
Advantages of Pharmacogenomics
1.) Avoids ADRs that are often fatal (especially with chemotherapy.

2.) Avoids waisting time and money on doomed therapies.
4 Limitations of Control Groups
1.) Patients are usually selected to eliminate coexisting diseases/therapies.

2.) The effect of 1 or 2 drugs is assessed, not the many that might be given to a patient.

3.) Trials usually involve a small number of pts, and are of shorter duration that what would probably be employed in an actual drug regimen.

4.) Compliance is better controlled than in practice
"Blinding"
The masking of investigators and/or subjects in a clinical trial

Critical to a successful trial!!
Double-blind study
1.) Removes investigator interpretations bias

2.) Removes selective clinician enthusiasm

3.) Good when the primary endpoint is subjective (pain relief, depression)
3 Caveats Regarding Clinical Trials
1.) Results of a valid clinical trial allow physician only to develop a Hypothesis about how the pt will respond to the drug
**>50% of drug effects are discovered by physicians in practice, not in the clinical trial**

2.) If an anticipated effect of a drug has not occurred in a patient, this does not mean that the effect cannot occur in others.

3.) Even when the drug regimen appears to be efficacious and innocuous, the physician should not attribute improvement solely to the regimen (or vice versa in deteriorating conditions)
When do you measure drug levels??
1.) There is a demonstrated relationship between plasma drug concentration & an eventual therapeutic/toxic effect.

2.) There is substantial inter-patient variability in the disposition of the drug.

3.) The intended or unintended effects of the drug are difficult to monitor.

4.) The concentration of drug required for the therapeutic effect is close to that for toxicity.
4 Characteristic variables in the drug concentration-effect relationship
1.) Potency - clinically not as important, as long as the required dose can be conveniently given. (EXCEPT transdermal drugs)

2.) Maximal efficacy - Max drug effect produced in vivo. Reflected by upper plateau of C-E curve.
*May not be clinically achieved because of Toxicity*
*More important clinically then potency*

3.) Slope - indicates # of drug receptor binding sites & Mechanism of Action. Steepness of curve dictates range of clinically-useful doses.
*Clinically, the Least important*

4.) Biological Variability - interindivitual differences in magnitude of drug response. A single patient may not always respond in the same way to the same concentration of a given drug.
Cumulative frequencey distribution
Total respondents at that concentration or lower
ED50
Dose of drug required to produce a specific effect in 50% of the population
LD50
Dose of drug resulting in death for 50% of the population (found in Preclinical)
Other Factors that affect therapeutic Outcome
1.) Age
2.) Drug-Drug Interactions
3.) Placebo Effect
4.) Pharmacogenetic Factors
How Age affects therapeutic outcomes
=Children
-Most drugs are developed in adult to middle aged & scaling down doses do not account for limitation in RENAL & HEPATIC clearance.
- "Gray Baby" syndrome - drug used for treating meningitis accumulates.
- Pathways are quite variable in 1st year of life.

= Adults
- More interindividual variation with respect to dosage
- Cleareance is often reduced (renal may be down 50%)
- Changes in drug distribution (reduced lean body mass & total body water, increased body fat %)
Unexpected outcomes in children vs. adults for some drugs
Antihistamines & Barbituates - makes adults sleepy and children hyper

Valproic Acid Hepatoxicity - Much worse in Kids

Isoniazid hepatoxicity - Much worse in adults
How Drug-Drug Interactions affect therapeutic outcomes
2nd Drug may:

1.) Enhance effect of 1st drug

2.) Diminish effect of 1st drug

3.) Create new effect not seen with either drug alone.

Drug "cocktails" are used in many chemo, and infectious disease treatments.
Factors affecting Placebo effects
1.) Physician-patient relationship

2.) Significance of the therapeutic effort to the patient

3.) The mental set imparted by therapeutic setting + physician
1914 Harrison Narcotic Act
Established regulations for the use of opium, opiate, and cocaine.

(so they can't put heroin in cough suppressant)
1962 Kefaufer-Harris amendment
Required proof of efficacy as well as Safety for new drugs.

Established guidelines for reporting ADRS, clinical testing and advertising new drugs.

Due to Thalidomide disaster
Preclinical Testing
- Trial and error with structure activity series of compounds

- More promising compounds are tested in animals

- Those that pass must have a 30 day safety review by the FDA.

- 1-5 years (ave=2.6)
Clinical Testing
3 Phases

- Lasts 2-10 years (ave=5.6)
Phase 1 Clinical Testing
- Small number

- Normal volunteers

- Broad range of doses

- Want doses with no detectable effect progressing to one that produces significant physiological effects and/or slight toxicological effects.

- Safety, Biological effects, Metabolism, Kinetics, Drug interactions.
Phase 2 Clinical Testing
- Moderate number of patients

- Patients with target disease

- Placebo or positive control, single or double blinded.

- Determines if the agent has the desired therapeutic effects at doses that are tolerated by sick patients

- Therapeutic efficacy, Dose Range, Kinetics, Metabolism
Phase 3 Clinical Testing
- Large design

- Patients using the drug in manner proposed for its ultimate general use.

- Includes place and positive controls in a double blind study

- Explores spectrum of beneficial actions of new drug

- Compares with older therapies

- Discovers toxicities

- Safety & Efficacy
NDA
New Drug Application

- Submitted if drug approved through all 3 Clinical phases

- Takes ~1 year unless exceptional circumstances
Phase 4 Clinical Testing
- Post Marketing Surveillance

- Not as rigidly regulated by FDA

- more ADRs are discovered, Patterns of drug utilization, additional indications discovered.
Probit
(probability unit)

- deviation from the mean
Toxicity
Ability of a chemical agent to cause injury
Hazad
The likelihood that injury will occur in a given situation or setting.
Risk
The expected frequency of the occurrence of an undesirable effect (arising from exposure to a chemical or physical agent)
FDA has 3 approaches to Potential Carcinogens
1.) Food Additives
= FDA very cautious
- Many people exposed vs. Not likely to beneficial effect to humans.

2.) Drugs
= FDA weighs relative risks and benefits for patients

3.) Environmental Carcinogens (herbicides, pesticides, etc)
= Attempts to limit lifetime exposure such that the cancer incidence due to the chemical would be no more than 1 in a million (drug dose = 10-20% incidence of tumors in animals)
Bioaccumulation
The intake of a long-lasting chemical contaminant by an organism leads to accumulation of the contaminant
Biomagnification
An undetectable amount of contaminant is magnified (possibly 100,000 X or more) as the contaminant passes up the food chain.
Chemical Forms of Drugs that Produce Toxicity
1.) Toxic Metabolites

2.) Phototoxic & Photoallergic reactions.

3.) Reactive Oxygen Species (ROS)
Toxic Metabolites
Most organophosphate insecticides are cP450-biotranformed to produce their toxicities.

a.) Stabole metabolites - The PARATHION metabolite PARAOXON binds to and inactivates acetylcholinesterase (this metabolizes actylcholine, which acts on muscles, causing salivation, tears, deification)

b.) Reactive Intermediates
cP450 activate APAP electrophile
Phototoxic & Photoallergic Reactions
Photosensitivity - induced by some drugs so that the skin is damaged upon exposure to sunlight
(ex. Tetracycline)

Photoallergy - Radiation is absorbed by a drug which converts it into a product that is a more potent allergen than the parent drug
(ex. Sulfonamide)
Reactive Oxygen Species (ROS)
ex. Paraquat - Herbicide that causes severe lung injury and can cause cancer later on in life.
APAP Pathway
APAP --> NAPQI (toxic intermediate) ===>

either

+ Glutathione --> Mercapturic Acid

+ Nucleophilic Macromolecule --> CELL DEATH!!!!!!!!!
Pharmacological Toxicity
Effects usually disappear when drug concentration falls.

Ex Excessive CNS depression by barbiturates
Pathological Toxicity
Organ specific

Less reversible, but some healing - depends on organ (liver vs. brain)

ex. Hepatic injury produced by APAP,
3 Deleterious Toxic Effects
1.) Pharmacological

2.) Pahtological

3.) Genotoxic
Genotoxicity
Alteration of DNA
As long as concentration of the chemical in the tissue doesn't exceed critical level, the effect is usually reversible.

Usually nonreactive themselves (procarcinogens) but converted to primary or ultimate carcinogens in the body.

Ex. Neoplasm produced by nitrogen mustard, chemotherapeutics
Nongenotoxic
Doesn't produce tumors alone, but Potentiates effect of genotoxins.

Facilitate growth, development of dormont (latent) tumor cells

Promoters determine whether latency is 15 or 45 years.

"Promoters"
Chemical allergy
Adverse reaction that results from previous sensitization to a particular chemical or one that is structurlly similar.

"hypersensitivity reaction"
Idiosyncratic reactions
Extreme sensitivity to low doses of chemicals

Ex. For some people "statins" are hepatoxic.
Interactions between chemicals can produce 2 effects
1.) Additive effect - equals sum of each

2.) Synergistic effect - Greater than the sum of each (Barbiturates + Alcohol)
Potentiation
Increased effect of toxic agent in the presence of a nontoxic one.

Ex Isopropanol is not hepatoxic, but increases carbon tet's tox.
4 Types of Chemical Antagonism
Interference of one chemical with the action of another

1.) Functional (Physiological)

2.) Chemical (Inactivation)

3.) Dispositional

4.) Receptor
Functional Chemical Antagonism
(Physiological)

Two chemicals produce opposite effects on the same physiological function

Ex. IV dopamine maintains perfusion of vital organs during certain severe intoxications characterized by marked hypotension
Chemical Antagonism
(Inactivation)

Reaction between 2 chemicals that neutralizes their effects

Ex. Dimercaprol chelates various metals to decrease their toxicity
Dispositional Chemical Antagonism
Alteration of the disposition (its ADME) of a substance so that less reaches target organ, or its persistence there is reduced.
Receptor Chemical Antagonism
Blockade of agonist effect

Ex Naloxone antagonizes morphine at opioid receptors
7 Ways to Prevent Further Poison Absorption
1.) Emesis

2.) Gastric Lavage

3.) Chemical Adsorption

4.) Chemical Inactivation

5.) Purgation

6.) Enhanced Elimination

7.) Hemodyalysis
Emesis
Triggers vomiting response

Good for oral poison ingestion

Ex. Ipecac or Apomorphine

Contraindicated if
- Corrosive ingested (Drano)
- Comatose, stupor, delirious - risk of aspiration of Gastric contents
- CNS stimulant ingested - vomiting may cause convulsions
- Gasoline ingested (HC pneumonia) - lungs inflamed, bleeding
Gastric lavage
Tube inserted in stomach, wash stomach with water or saline to remove unabsorbed poison.

Reserved for patients who have ingested a potentially life-threatening amount of poison, and when the procedure can be undertaken withing 60 MINUTES of ingestion

"stomach pumping"
Chemical Adsorption
Activated charcoal absorbs many chemicals and drugs

Exceptions: Alcohols, metals, corrosive, hydrocarbons
Chemical Inactivation
Antidote may alter the toxin, or prevent its absorption.

Seldom used today because not as fast as charcoal, emetics, lavage.

Past: Neutralize with Acid/Base
Now: Dilute with water or milk
Purgation
Used when ingestion occured >1 hour ago, or for Hydrocarbons.

Cathartics (sorbitol, MgSO4) - used to accelerate passage of toxin through GI tract

Sometimes this can cause or aggravate renal problems.
Enhanced Elimination
Ex. Alkalinization of during with NaHCO3 to trap acidic drugs in urine
Hemodialysis
Usually extreme and not efficient but works well for methanol, ethylene glycol, salicylate poisoning

"heroic measure"