Pharmacology Introduction

Drugs
Chemicals that act on livings systems at the molecular level.

Receptors
Specific molecules in a biological system that mediate drug effects.

Pharmacology
Study of the action of drugs and effects on a living system.

Medical Pharmacology
Study of drugs used for the diagnosis, prevention, and treatment of disease.

Toxicology
Branch of pharmacology that deals with the untoward effects of drugs on living systems.

History of Pharmacology
Prehistoric methods were ineffective/toxic.
Relied on “serendipity” — the idea that if it worked we do it. Based only on effectiveness.
Eventually replaced by observation and experiment, however, molecular level of knowledge was lacking.
*Chemistry and *Physiology lead us to know how drugs work on the organ level.

History of Pharmacology (Continued)
In last 50 years: Advent of the controlled clinical trial.
-Accurate evaluation of therapeutic claims.
Research allowed us to:
-Gain info of drug action and receptor
-Improve understanding of molecular basis of drug action

Pharmacogenetics
The relation of a person’s specific genetic makeup to his or her response to specific drugs.

Therapeutic effects
Effects of a drug that help cure or prevent the disease.

Toxic effects
Effects of a drug that cause secondary toxic effects.

ADME
Absorption, Distribution, Metabolism, Elimination

Drug properties
Gas, solid, liquid, gel, suspension, solution.

Factors in Aqueous Solution
Ionization, solubility, stability.

Factors for Acting on Membranes
Lipid solubility, Diffusion, Receptor binding, Partitioning, Blood flow.

Drug Size
Commonly between 100-1000MW.
-100MW to achieve selectivity (sufficient binding).
-1000MW to allow for proper distribution.
-If greater than 1000MW, needs to be administered at site.

Drug Receptor Interactions
Dependent on:
-Size, shape, charge, atomic makeup
-Structure + specificity
-3 point attachment
-Specific, mimic endogenous

Affinity
Strength of the bond that a drug has to receptor. Affects potency. High affinity = high potency.

Selectivity
Also known as specificity. Determined by type of bond. High specificity = few effects in body. Low specificity = side effects all over.

Covalent Bonds
Covalent / Strong bond = less selectivity (but more reactivity)
-commonly irreversible
Noncovalent = most common = more selectivity (less reactivity)
-Hydrogen, Van der Waals’, ionic.
-Commonly reversible

Drug Shape
Should complement receptor site.
Many exist as chiral molecules, thus have enantiomers.
Dextro = Right = D
Levo = Left = S

Enantiomers
Dextro and Levo. D and S.
E.G. Prilosec Vs. Nexium
Prilosec: Omeprazole, racemic, S has activity.
Nexium: Esomeprazole, S isomer, absorption/ half life +,
Extended patent life = + money for company.

Most start racemic but eventually produced as single isomer

Pharmacodynamics
Actions of drug on body:
-Determines classification
-Determines appropriate therapy

Pharmacokinetics Definition
Actions of body on drug:
-ADME
-Choice and administration of drug to specific patient

PharmacoD. Conc./Resp.
Pharmacodynamics studies the relationship between concentration and response. The concentration of the drug at the site of action, and the beneficial and toxic effects.
-Depends on: CONCENTRATION

Concentration-response curve
Plots concentration of drug versus % of maximum effect whether therapeutic or toxic.

Drug receptors
Most are proteins.
-Selective, and change function upon binding.
-Drugs typically look like endogenous molecule.

Agonist
Activate receptor

Antagonist
Prevents action at a receptor

Pharmacokinetics Imp. stuff
ADME.
Bile = feces
Kidneys = urine

Absorption
The measure of how quickly a drug gets into the bloodstream

Common routes of absorption
PO/PR (oral/anal)
Inhaled, topical, transdermal,sublingual
Intramuscular, intravenous, subcutaneous

Drug formulations
Affect absorption.
Depends on:
-Barriers drug is capable of passing (B/b. B/t)
-Setting in which drug will be used (Hospital vs. home)
-Urgency of situation
-Drug stability
-First pass effect

Distribution
Movement of drug from site of administration to other parts of the body.
Depends on:
-Vascularity. Higher = higher uptake (EG Brain/kidneys)
-Drug solubility in certain tissue
-Binding of drug to macromolecules in blood IE. Albumin
-Ability to cross special barriers IE Blood brain Blood testes

Elimination
2 major routes.
Metabolism: Enzymatic conversion of drugs to inactive derivatives, more polar, more water soluble, enzymes in GI and liver.
Excretion: Follows metabolism or unchanged
Kidneys = urine
Liver/bile = feces

Drug legislation prior to 1906
No regulation on sale of drugs.
-Outrageous claims of benefit and safety
-Unregulated use of addictive substances

Federal Pure Food and Drug Act
1906: Active ingredients placed on label, purity levels maintained.
-not for efficacy, just purity.
1912: Amended to stop false advertising claims

Food Drug and Cosmetic Act
1937: Diethylene gloycol in sulfanilamide elixir kills hundreds
1938: FDCA: Label with direction for safe use / Preapproval for safety

Durham-Humphrey Act
1952: Prescription vs. OTC defined and federally regulated (FDA)

Kefauver-Harris Amendment
1962: Thalidomide babies in non USA.
Required efficacy in addition to safety.

Controlled Substances Act
1970: Scheduled drugs

FDA Modernization Act
1997: Recognized changes needed to be made for 21st century.

Pediatric Research Equity Act
2003: Requires tests in pediatrics for certain drugs for certain circumstances

Dietary Supplement and Non-Script Drug Consumer Protection Act
2006: Requires serious adverse event reporting for dietary or nutrition supplements. Non regulated so far.

FDA
Responsible for approval of new drugs, and oversight of marketing/sale of drugs on market.
Prescription and OTC included

DEA
Drug enforcement agency:
Classifies drug schedules on basis of abuse potential.

Who can write scipts?
Depends on states.

Stages of Drug Approval
0-4 years: Preclinical: In-vitro animal testing
4-8 years: Human clinical trials
8-20 years: Exclusive marketing rights
20+ years: generics form

Human Clinical Testing Phase 1
25-50 HEALTHY volunteers, look for toleration, check for safe clinical dosing range. Evaluate pharmacokinetics

Human Clinical Testing Phase 2
100-200 SICK volunteers are tested. Assess dose-efficacy relationship.
Dose to pharmacological/therapeutic effect.

Human Clinical Testing Phase 3
1000s of people. Randomized controls in actual conditions.
Establish safety in patients with disease, and efficacy compared to other treatments.

Human Clinical Testing Phase 4
Post marketing surveillance. Safety under actual life conditions.

Proprietary Drug
Drug with trade name, protected under patent.
Patent life = 20 years. Drugs are frequently patented 5 years before marketing. After patents expire other companies can create bioequivalent generic drugs. More familiar to outpatient settings.

Generic Drug
Drug made from a once-patented formula. Cheaper, less “development” cost. Must have same pharmacokinetic properties as original. Promoted in hospitals, cheaper.

Chemical name
Not used in practice, but in lab. Long ass. Ridic.

Drug Naming Example
Nexium.
Esomeprazole magnesium
(S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)
methylsulfinyl]-3H-benzoimidazole

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