Singh - Pharmacodynamics

Question 1

2 key principles of pharmacodynamics

Answer 1

1. dose of the drug is linked to the bodies response

2. drugs act through receptors (rely on kinetics)

Question 2

drug receptor leading to response

Answer 2

can have response immediately (short lasting) or can have response that takes longer (longer lasting)

• drug + receptor –> response
• drug + receptor –> effector –> response
• drug + receptor –> cell signaling –> response
• drug inhibiting enzymes that metabolize compounds

Question 3

how does interaction lead to biological response?

Answer 3

bind to more receptors –> more response and effect of drug

-linear up to 50% of response then becomes saturated

Question 4

Kd - dissociation constant

Answer 4

[] of drug that occupies 50% of receptors

• high affinity drug –> low Kd –> high potency
• low affinity drug –> high Kd –> low potency
• drug receptor interaction does not make product like enzyme/substrate complex

Question 5

how does drug amount affect drug receptor binding curve?

Answer 5

helps determine the dose needed to have max response & help determine affinity

Question 6

2 state model for receptor activation

Answer 6

receptor can be in active or inactive state - depends on the type of drug you give
-increase or decrease endogenous chemicals

Question 7

agonist

Answer 7

binding to receptor making receptor active

-intrinsic activity of 1 - max response

Question 8

antagonist

Answer 8

binds to inactive conformation of receptor –> no response

-intrinsic activity is 0

Question 9

partial agonist

Answer 9

binds to active or inactive conformation equally

• can have response but not to extent of agonist
• used in treating addiction - prevent withdrawal
• agonist on its own, antagonist when other drug is present
• intrinsic activity <1

Question 10

potency

Answer 10

dose of drug needed to produce 50% of response bc 50% of receptors are bound
-high potency –> less [] needed to bind those receptors

Question 11

efficacy

Answer 11

max effect drug produces, not potency

• clinical effectiveness deals with efficacy
• want drug to have max efficacy

Question 12

inverse agonist

Answer 12

drugs that act on constitutively active receptors bringing response to 0
-lower dose response curve - decrease basal activity of drugs

Question 13

agonist vs. antagonist

Answer 13

1. agonist - binding activates receptors either increasing or decreasing endogenous chemicals
2. antagonist - no response when bound; receptor stays in inactive form; can lower agonist binding

Question 14

competitive/reversible antagonist

Answer 14

max response possible when increasing dose of agonist (curve shifts to right when present)

• still achieve max response, but with higher dose
• Kd increases bc potency decreases
• get response if agonist dose exceeds competitive antagonist

Question 15

noncompetitive/irreversible antagonist

Answer 15

• max response limited bc drug stays bound to receptor
• lower response bc there is no receptor to occupy (lowers # of available receptors)
• no change in Kd –> does not affect drug/receptor interaction
• CAN get same response only if # of receptors needed for max response are available
• dose needed to produce 50% of response dose not change

Question 16

drug receptor interaction

Answer 16

drug binds to receptor then comes off due to non covalent interaction
-stays bound with covalent

Question 17

chemical antagonism

Answer 17

binding of one drug to another making it unavailable to bind to receptor
-protamine sulfate (+ charge) neutralizes heparin excess

Question 18

physiological antagonism

Answer 18

2 drugs have opposite effects

• want to stop drug response but cannot interfere with drug/receptor interaction
• activate a receptor that produces opposite effects
• ex. increase insulin with high glucose

Question 19

allosteric modulation

Answer 19

drug binds to receptor at different site than agonist binds

-benzodiazopine does not activate, but increases likelihood of GABA binding

Question 20

graded vs. quantal dose response curve

Answer 20

1. graded - may not work due to studying only single patient (everyone is different)
2. quantal - study dose response by looking at population
   - determine how many responded to different doses (ED50)

Question 21

therapeutic index/window

Answer 21

range at of doses at which it was effective but did not produce toxic effects

• range of minimum effective dose to minimum toxic dose
• LD or TD50 divided by ED50

Question 22

ED50

Answer 22

dose where half the population will respond to drug

Question 23

LD50

Answer 23

dose tested where half the animals will not survive

Question 24

CSF (certain safety factor)

Answer 24

estimate of safety of drug

Question 25

specificity vs. selectivity

Answer 25

1. specificity - drug has one effect only 2. selectivity - acting on more than one receptor when reaching high [] - stay within therapeutic index to bind to specific receptors

Question 26

narrow therapeutic index (NTI)

Answer 26

small differences in dose may lead to toxic effects --> side effect when exceeding therapeutic window - ED50 is high, LD50 is low - need more drug to reach effect but is close to toxic dose - higher TI --> safer the drug

Question 27

intracellular receptors

Answer 27

nuclear receptors - ex. corticosteroids, lipid soluble - receptors exist in cytosol - can stimulate intracellular enzyme or alter gene transcription - no effect of drug if body metabolizes proteins - slower response for gene transcription but longer lasting

Question 28

plasma membrane bound receptors

Answer 28

ligand regulated transmembrane enzymes - ex. RTK - receptors in inactive state - need ligand binding for activation, dimerization, autophosphorylation, protein docking, and signaling to occur - another ex. GPCR

Question 29

cytokine receptors

Answer 29

- no cytokine function without (ex. interleukins) - cytokine binding --> recruit JAK for phosphorylation --> docking and phosphorylation of STAT --> STAT dissociates, dimerizes, and goes to nucleus - response lasts long time even if you stop taking drug

Question 30

Ligand gates channel

Answer 30

drug binds to receptor opening it --> influx of Na+ and Ca++ depolarizing the cell --> signal by AP - fast response - rapid transmission - regulated by phosphorylation and endocytosis - synaptic plasticity --> learning and memory

Question 31

GABA and glycine

Answer 31

hyper polarize receptor by Cl- influx --> inhibition | -GABA in brain, glycine in spinal cord

Question 32

ACh, glutamate, serotonin 3

Answer 32

depolarize receptor through Na+ and Ca++ influx and K+ efflux --> excitatory

Question 33

GPCR

Answer 33

contain G protein --> multiple subunits - stimulate or inhibit effects of adenylate cyclase or PLC - GDP --> GTP to start signaling cascade --> activate adenylate cyclase, cAMP, PKA --> phosphorylation - GTP hydrolyzed back to GDP to stop signal - do NOT have to activate all receptors to get desired response

Question 34

cholera

Answer 34

bacteria cause continued activation of G protein by binding to GTP --> open Cl- channel through phosphorylation --> water follows Cl- --> diarrhea

Question 35

cannabinoids and opioids

Answer 35

stops pain signal to brain by inhibiting GPCR --> analgesia

Question 36

increased responsiveness

Answer 36

- chronic disuse of receptor from antagonist can increase response when reexposed to agonist --> get rid of receptors then upregulate them - cutting neural signal --> denervation supersensitivity by up regulating receptors

Question 37

tolerance

Answer 37

decreased response to drug or hormone over time by downregulating receptors --> adaptation - increase dose to maintain response - ex. B-adrenergic bronchodilators and alpha-adrenergic vasoconstrictors

Question 38

mechanism of tolerance

Answer 38

1. phosphorylation of receptor 2. post receptor adaptation - desensitization --> uncouple G protein from receptor 3. receptor down regulation - remove receptor on membrane

Question 39

therapeutic vs. side effect

Answer 39

deals with dose and how receptor signals - benefits and toxicity arise downstream of of separate receptors, which are both activated by the same drug due to low specificity - ex. 3 types of histamine receptors coupled to G protein --> produces different responses - ex. drug increasing ACh level activating autonomic and skeletal muscle

Question 40

receptor regulation

Answer 40

make receptor nonfunctional by removing G protein or another cytosolic protein, or by removing receptor from membrane - too much agonist --> can internalize receptor avoiding response - stop taking drug --> dephosphorylate receptor and travel back to membrane