Principles of drug action

1
Principles of drug action

• Pharmacokinetics
• Pharmacodynamics
• Neuropharmacology
• Psychopharmacology

2
Pharmacodynamics

• Drug-receptor interactions
• Receptor complexes and the action of ligands
• Transmembrane potential changes via receptor
  complex
• Change is proportional to receptors occupied or
  by rate of reversible binding (attachment) of
  ligand
• Effects are agonistic or antagonistic

3
Receptor types

• These membrane-spanning proteins are coils of 7
  or 12 transmembrane loops, called alpha-helical
  coils. There are four types
• Ion channel receptor complexes respond to
  neurotransmitters from outside or G proteins from
  inside the cell. Drugs can affect either.
• Carrier/transporter proteins, especially for
  reuptake
• G-protein-coupled receptors and enzyme cascades
• G is for guanine, a cellular nucleotide affected
  by these receptors
• Enzymes

4
Ways a drug may act on a neuron or synapse

• Manufacture Increase or block
• Packaging Make vesicles leaky
• Transport Block or facilitate vesicle movement
• In the synapse
• Mimic
• Block
• Post-synaptic receptors and autoreceptors
• After reversible binding Enzymes or reuptake

5
Pharmacodynamics

• Drug-receptor affinity
• Governed by stereochemical fit
• Effects on brain determined by location of
  receptor types

6
The dose-response relationship

• Dose
• Potency
• Efficacy or maximum effect
• Slope

7
The dose-response curve

• The dose-response curve relates the amount
  administered to the response.
• Response may be measured as responding or as
  intensity of response

8
The dose-response curve Effectiveness and safety
9
Drug variability and toxicity assessment

• ED50 Effective dose for 50 of subjects
• TD50 Toxic dose for 50 of subjects
• Both ED50 and TD50 are different for each effect
• The therapeutic index
• TI TD50 / ED50
• No drug is 100 safe
• Placebo effects
• The FDA and drug development

10
FDA rules

• Pure Food and Drug Act, 1906 Labeling accuracy
  to eliminate adulteration
• Cuforhedake Brane-Fude, labeled 30 alcohol
• Sherley Amendment, 1912 No false and
  fraudulent therapeutic claims on the label
• Harrison Narcotics Act, 1914 Trade controls and
  taxation (Dr. Hamilton Wright)
• Marijuana Tax Act (1937) Harry Anslinger
• Agriculture Department vs. Treasury Dept.
• Enforcement concerns merged under Department of
  Justice, 1968? DEA, 1973

11
Expansion of FDA concerns

• Purity (1906)
• Safety (1938) The Food, Drug, and Cosmetics Act
• Toxicity assessment before marketing
• Instructions for use on the label
• Effectiveness (1962) Kefauver-Harris amendments
• Carters Little Liver Pills

12
The Australian approach

• The Therapeutic Goods Administration (TGA)
• Drug Safety and Evaluation Branch
• Adverse Drugs Reaction Unit (ADRU)
• Manufacturers and suppliers (importers) are known
  as sponsors, and are responsible for both entry
  into the Australian Register of Therapeutic Goods
  and reporting of postmarketing adverse reactions
  to the ADRU.
• Only the ADRU reports must be based on Australian
  populations.
• Uses a partnership approach.

13
The TGA

• Established by the Therapeutic Goods Act of 1989
• A unit of the federal department of Health and
  Ageing.
• Covers assessment and monitoring activities
• Focuses on Quality, Safety, and Effectiveness
• Defines therapeutic goods
• Website www.tga.gov.au/about/about.htm

14
Current FDA Approval Process

• Safety Pre-clinical testing of several dosages
  over relevant time periods on at least two
  species
• Carefully planned clinical trials with signed
  informed consent and annual reports
• Phase 1 clinical trials Small doses on healthy
  volunteers Pharmacokinetics and side effects
• Phase 2 Small sample of hospital patients
• Phase 3 Broader clinical trials on patients

15
The Controlled Substances Act, 1970

• Schedule system Based on abuse potential,
  medical usefulness, and risk of dependence
• Schedule I Hi-no-hi. Heroin, marijuana, LSD
• Schedule II Hi-yes-hi. Morphine, Marinol,
  cocaine, methamphetamine
• Schedule III Moderate-yes-moderate.
  Amphetamine, barbiturates, PCP
• Schedule IV Low-yes-less than III. Chloral
  hydrate
• Schedule V Low-yes-less than IV. Cocaine
  mixtures

16
More recent legislation

• The Orphan Drug Act, 1983
• Analogue (Designer Drug) Act, 1986
• Prescription Drug Marketing Act, 1987
• Anti-Drug Abuse Act, 1988 (established ONDCP)
• aka Omnibus Drug Act
• Anabolic Steroids Control Act, 1990
• http//www.druglibrary.org/schaffer/History/drug_l
  aw_timeline.htm

17
Harry J. Anslinger
Marijuana is smoked by musicians. And Im not
speaking about good musicians, but the
jazz type. -Commissioner of the U.S. Bureau of
Narcotics, 1930-1962