Module A-1 Flashcards
Signal Transduction
Process by which a cell converts one kind of signal into another, think signal cascade or second messenger pathway
Types of signal Transduction:
Ion Channel- think acetylcholine as ligand for receptor vs voltage gated
G-coupled protein receptor-spans 7 times, w/ three subunits-conformational change with GDP-GTP
Enzyme linked-Ex. tyrosine kinase-signal molecule triggers dimerization/phosphorylation of residues with starts cascade
GPCR Ex.
Drug receptor Sensitivity
Drug response occurs from a low concentration
Drug receptor selectivity
Structurally similar chemicals illicit drug response
Drug receptor Specificity
Measure of a receptors ability to respond to a single ligand
Affinity VS. Potency
Affinity-strength of attraction
Potency-magnitude of drug effect (dose dependent)
Agonist
Binds specific receptor and triggers a response in a cell-mimics an endogenous ligand
Agonist
Binds specific receptor and triggers a response in a cell-mimics an endogenous ligand
Antagonist
Affinity for receptor but no efficacy
Partial agonist
Activates receptor but cannot produce maximum response- may also block full effect of true agonist
Inverse Agonist
Binds receptor-results in opposite action of agonist
Non competitive antagonism
Binds allosteric site- cannot be displaced
Allosteric modulators
Binding site adjacent/separate from receptor- can be agonist or antagonist!!
Two state model
Constant flux in equilibrium between resting and active states that are conformationally distinct- active state has a higher affinity for an agonist
Upregulation
An increase in number/sensitivity of receptors
In response to:
-less stimulation from ligands
-chronic antagonist exposure
Ex. Chronic use of beta adrenergic antagonists (Beta blockers)- rebound hypertension if stopped due to upregulation
Down regulation
Decrease in number/sensitivity of receptors due to:
-Repeated agonist exposure
Ex. Chronic beta-agonist use for asthma
-increase dose (side affects) or swap drugs
Tolerance
Chronic exposure- increased drug clearance. increasing dose is usually an option
Tachyphylaxis
Short term- stepwise reduction in physiological response due to down regulation of receptors-which means increasing the dose will not work
Therapeutic response variation with pharmacogenetics and population variation
-age, sex, BSA, weight, metabolic rate, pathological state and genetic profile will all impact therapeutic response
Pharmacogenetics can alter receptor sensitivity and drug metabolism between individuals
Mean
Average dose to elicit a response
Median
Dose on either side of which half the responses occur
Mode
Dose with greatest percentage of responses
Standard deviation
Variability of a response within a population
Standard error of the mean
SD of the mean
Obtaining the mean on different populations with same dose response measurements….
ED-50
Median effective dose
ED95
95% effective dose
Emax
Maximal drug effect
LD50
Lethal dose 50%
Therapeutic index
LD50/ED50
Therapeutic Saftey margin
Larger the index the safer the drug (how far apart are the ED and LD)
Therapeutic window
The range of therapeutically effective concentrations, most of the efficacy curve and less than 10% of toxicity curve
Addition
1+1=2
Drugs act in same pathway
Sulfamethoxazole+trimethoprim
Synergism
1+1=4
One drug allows the other to perform its function
Ex. Carbidopa+levodopa (keeps levodopa from being degraded in peripheral tissue)
Antagonism example:
Phentolamine displaces Norepinephrine
What increases the tendency to form the drug-receptor complex?
Higher concentration of free drug
Presence of unoccupied receptor
Law of mass action
Rate of a reaction is proportional to the product of the concentrations of each reactant
Second messengers and response to:
Catecholamines, caffeine and milrinone
(cAMP)
Response: kinase release, beta receptor stimulation, inotropic and chronotropic cardiac effects, production of adrenal and sex steroids, etc…
Second messengers and response to Lithium
Phosphoinositides and Calcium
Activates calmodulin
Nitroglycerin and Nitroprusside second messengers
cGMP
Activates protein kinases
Fig 5.1-major modes of signal transduction
Potentiation
Effect of a drug is enhanced by a drug with no effect of its own 1+0=3
Chiral
Not superimposable on its mirror image, optically active
Stereoisomer
Isomers that differ in the 3-D dimensional arrangement of atoms
Enantiomer
Stereoisomers that are non-superimposable
Racemic mixture
A mixture containing two enantiomers in equal proportions will be optically inactive,
Enantiomers can differ in dosages/efficacy/side effects but are sometimes given in racemic form
Specificity vs selectivity phrase
Select chemicals illicit a specific response
Describe GPCR second messenger system
Describe GPCR second messenger system
