Pharm Flashcards
Drug
Chemical capable of reacting w/ biological systems
Can be endogenous or foreign
Toxin
Chemical that produces undesirable effects
Synthesized by plants, microorganisms, animals, insects
Poison
Chemical that produces undesirable effects
Synthetic or inorganic compound
Pharmacodynamics
Drug’s effect on body
Pharmacokinetics
Body’s effect on drug
ADME
Imantinib
Anti-cancer drug that interacts w/ BCR-Abl kinase A (rearrangement of 9 and 22 that causes tyrosine kinase to be always “on”, phosphorylates a target important in cell proliferation)
Inhibits phosphorylation of activation group
Not toxic to any other cells
Ligand-gated transmembrane ion channel receptor
Activated by binding of ligand
Ex. Nicotinic receptor (ACh binds to 2 alpha subunits and opens Na+ gate)
Voltage-gated transmembrane ion channel receptor
Activated by change in transmembrane voltage gradient
Ex. tetrodotoxin in puffer fish inactivates fast Na+ channel
Second-messenger gated transmembrane ion channel receptor
Activated by binding of ligand to G protein-coupled receptor w/ cytosolic domain, which activates a second messenger
Ex. cAMP –> PKA
G protein-coupled receptor
Ligand binds to receptor –> receptor changes conformation –> alpha subunit dissociates and diffuses to nearby effector
Ex. activation of adenylyl cyclase to form cAMP –> PKA and PLC
Transmembrane receptors w/ catalytic intracellular domain
Receptor tyrosine kinases Receptor tyrosine phosphatases Receptor serine/threonine kinases Non-receptor tyrosine kinases Receptor guanylyl cyclases
Cytoplasmic/nuclear receptor
Receptor AND/OR transcription factor
Ex. hormone receptors
Tachyphlaxis
Repeated administration of the same dose of a drug results in a reduced effect of the drug over time
Desensitization
Decreased ability of a receptor to respond to stimulation by a drug or ligand
Homologous desensitization
Decreased response at a single type of receptor
Heterologous desensitization
Decreased response at 2+ types of receptor
Inactivation
Loss of ability of a receptor to respond to stimulation by a drug or ligand
Refractory
After a receptor is stimulated, a period of time is required before the next drug-receptor interaction can produce an effect
Down-regulation
Repeated or persistent drug-receptor interaction results in removal of the receptor from sites where subsequent drug-receptor interactions could take place
Receptor
Site on cell or organism that binds w/ endogenous substance or drug that initiates a chain of biochemical events that leads to a response
Number limits response to drug
Inert binding sites
Proteins that bind and sequester drug and prevent it from performing its intended function
After withdrawn, the drug can come off and produce an effect
Ex. serum albumin
Agonist
Produces maximal response when receptors are fully occupied
Partial agonist
Produces lower than maximal response at full receptor occupancy
Can act as antagonist if coupled w/ full agonist
Antagonist
Prevents action of agonist (doesn’t do anything on its own)
Doesn’t change binding site
Ligand
Molecule that binds to a receptor
Drug-receptor interaction (equation)
[D][R]/[DR] = k2/k1 = Kd
Low Kd
High affinity, very potent
Administered in small amounts
High Kd
Low affinity, less potent
Administered in larger amounts
Ligand-receptor binding curve (equation)
[DR]/[Rt] = [D]/(Kd + [D])
Plots as rectangular hyperbola
Kd
Concentration of ligand at which half of the receptors are occupied
Occupancy-response curve (equation)
E/Emax = [D]/(Ke + [D])
Maximal effect
Ke = value of DR that exhibits half-maximal response
Drug potency
Concentration at which the drug elicits 50% of its maximal response (EC50)
Drug efficacy
Maximal response produced by the drug (how strong the reaction is) (Emax)
State at which receptor-mediated signaling is maximal and any additional drug will produce no additional response
Comparatively, doesn’t depend on how much drug you give
Effective Dose (ED50)
Dose at which50% of the population experiences a therapeutic effect
Toxic Dose (TD50)
Dose at which 50% of the population experiences a toxic effect
Lethal Dose (LD50)
Dose at which 50% of the population experiences a lethal effect
Therapeutic Index
TI = TD50/ED50
High TI- large separation between effective dose and toxic dose, drug will be very effective w/o adverse effects
Low TI- small separation between effective dose and toxic dose, have to be careful!
Margin of Safety
MS = LD1/ED99
Compares concentration of drug that is lethal to first 1% of population to concentration that is effective in 99% of population
Low MS- not safe, will cause some deaths, even at concentration that is therapeutic in most patients
High MS- safe, will affect most patients in therapeutic way w/o causing death
Inverse agonist
Binds receptor in inactive state and reduces fraction of receptors in active state
Causes opposite effect of agonist
Active site antagonist
Antagonist binds to same site as ligand
Can be reversible (competitive) or irreversible (noncompetitive)
Allosteric site antagonist
Antagonist binds to different site than ligand
Can be reversible or irreversible (both noncompetitive)
A “ceiling” to the effect exists (once all sites are occupied, no further effect is observed)
Chemical antagonist
Receptors are not involved
Activity is based on chemical interactions
Ex. Heparin (negatively charged) binds protamine (positively charged) to inactivate it
Physiologic antagonist
Opposing pathways must be activated to produce antagonism
Ex. glucagon increases blood glucose, insulin decreases blood glucose
Competitive antagonist effect on D-R curve
Reduces potency of agonist and increases Kd (curve shifts to right)
Does NOT affect efficacy
Noncompetitive antagonist effect on D-R curve
Reduces efficacy of agonist and lowers response/decreases Emax (curve height decreased)
Does NOT change Kd or potency
Spare receptors
Full response doesn’t require occupancy of all receptors
More receptors are present than are needed to produce Emax
System is more sensitive to drugs (b/c low concentration of drug occupies same number of receptors)
Spare receptor effect on D-R curve
Lower concentration of drug gives half maximal effect (curve is shifted left wrt drug-receptor curve)
Noncompetitive antagonist effect on D-R curve in presence of spare receptor
Antagonist destroys spare receptors (curve shifts to right)
Agonist action is reduced (curve shifts down)
Hydroxyurea
Sickle cell anemia
Increases HbF
Sulfonylurea
T2DM
Increases insulin release by permanently closing K+ channel in B-cells in pancreas
Metformin
T2DM
Suppresses gluconeogenesis in liver
SGLT2 inhibitors
T2DM
Decreases reabsorption/ncreases excretion of glucose in kidneys
Pioglitazone
T2DM
Reduces insulin resistance/improves peripheral tissue sensitivity to insulin
Acarbose/miglitol
T2DM
Impairs absorption of glucose in small intestine
GLP-1 analogues
T2DM
Slow transit of nutrients through stomach (makes you feel full longer, decreases appetite)
Increases insulin
Ends in “tide”
DPP-4 inhibitors
T2DM
Inhibits enzyme that breaks down GLP-1
Ends in “liptin”
Insulin
Long-acting- basal insulin, lasts all day
Short-acting- bolus insulin, taken w/ meals
