antifebrin
- first synthetic drug for fevers on the market
- made of acetanilide (chemical from coal-tar waste found to be effective in reducing fevers)
- lead to synthesis of Aspirin
What was the impact of WWI and WWII on pharmacology?
- effects of chemical warfare transformed chemotherapy for blood cancers (ie leukaemia, lymphoma)
- mass scale production of penicillin and antibiotics
racemic mixture
50/50 mixture of both enantiomers of a drug
Why did thalidomide (medication for treating morning sickness) result in birth defects?
- morning sickness was just the off target effect
- true target was the protein responsible for proper limb development
- as a result, the body did not secrete hormones for limb development and did not experience sickness caused by these hormones
process of drug discovery
- identify the problem
- study the physiology
- select a target and screen a library OR design a compound
- test in vitro
- choose lead compound
- clinical trials
order of drug screen assays
- in vitro (artificial)
- in vitro (cell based)
- ex vivo (tissue outside body)
- in vivo
- clinical trials
HTS (high throughput screening)
- testing (screening) thousands of molecules with unknown functions to observe biological effect
- leads to HIT compound (compound with the desired effect)
no effect dose
- max dose w/o toxic effect
- initial dose for human testing is 1-10% of this dose
minimum lethal dose
- min dose with lethal effects
LD50 (median lethal dose)
- dose that causes 50% of animals to die
acute toxicity testing
- short term exposure drugs
- NED and max tolerated dose
chronic toxicity testing
- long term exposure drugs
phases of clinical trials
- phase I: healthy volunteers
- phase II: patients with target disease (75% fail this stage)
- phase III: best method of administration (~50% pass)
- phase IV: released to general population
- phase V: research
describe the nitric oxide pathway
- eNOS turns L-arginine into NO
- NO diffuses across smooth muscle cell membrane and binds to and activates guanylate cyclase
- guanylate cyclase turns GTP into cGMP which sends the cell signal for muscle relaxation (vasodilation)
- PDE5 turns cGMP back into GTP, leading to muscle contraction
orphan drugs
drugs for rare diseases
Why can’t you have grapefruit juice with some medications?
- grapefruit juice increases absorption by inhibiting enzyme that has to do with drug metabolism, leading to overdose
- can also inhibit drug transporter, leading to too little drug in the body
agonists I
- similar to endogenous ligand
- activates target pathway
- can be full, inverse (binds to agonist target but opposes activity stimulated by it) or partial
agonists II
- do not mimic endogenous ligand
- activates pathway by inhibiting negative regulators
antagonists
- prevents the activity of the endogenous ligand
- inhibits the target pathway
- competitive inhibitors: bind to same target as endogenous ligand
allosteric regulators
- binds to another alternative pocket
- does not compete with ligand
- allosteric agonists enhance target activity
- allosteric antagonists inhibit target activity
IC50
- 1/2 maximum inhibitory concentration
difference between Ka, Kd and Ki
Ka - equilibrium rate of association between drug and target
Kd - equilibrium rate of dissociation
Ki - equilibrium rate of dissociation in the presence of a ligand
EC50
1/2 max effect (response) concentration
schild equation
C’/C = 1 + [l}/Ki
- C’: EC50 in presence of ligand
- C: EC50 not in presence of ligand
