pharmacodynamics 2

Question 1

receptor theory

Answer 1

1) drugs are not magical entities
2) require direct interaction with tissue
3) wont work unless bound
- paul erlich

Question 2

term receptor used in various ways

Answer 2

1) generically equivalent to a drug target
2) describes a protein or complex of proteins that recognize and respond to endogenous chemical signals
3) other molecules defined as drug targets

Question 3

define drug specificity by

Answer 3

1) high structural conservation and thus ligand specificity
2) site specificity of expression
3) some therapeutic concentrations have side effects
- tricyclic antidepressants also bind ACh receptors leading to xerostomia

Question 4

drug targets primarily include

Answer 4

1) membrane receptors
2) ion channels
3) carrier/transporter molecules
4) enzymes
*exceptions, gene therapy

Question 5

drug-receptor binding

Answer 5

1) occupation governed by affinity
- may not result in activation and tissue response
- powerful drugs have high affinity
2) activation governed by efficacy

Question 6

agonist

Answer 6

1) both affinity and efficacy

Question 7

antagonists

Answer 7

1) affinity but not efficacy
2) blocks agonist ligands from binding receptor site
- no response as a result

Question 8

most therapeutic drugs

Answer 8

1) occupation of receptor is reversible
2) association rate constant and dissociation rate constant are k+1 and k-1

Question 9

drug-receptor interactions

Answer 9

1) to compare drug effects we use an arbitrary but defined value
- equilibrium dissociation constant Kd
- concentration of drug required to occupy 50% receptors
- units of nmol/L (nM) etc.
2) the dissociation constant is an inverse measure of affinity

Question 10

logarithmic x-axis

Answer 10

1) makes the active range easier to interpret compared to the linear plot

Question 11

law of mass action

Answer 11

1) binding reaction follows the law of mass action
2) k+1[A][R] = k-1[AR]
2) rate of reaction is proportional to the product of the concentration of reactants
- if no more drug is added, the reaction reached equilibrium when association = dissociation

Question 12

dissociation constant

Answer 12

1) k-1/k+1 = [A][R] / [AR] = Kd

Question 13

Hill langmuir equation

Answer 13

1) pA = [AR]/[Rtot] = [A] / Kd+[A]

Question 14

dose response relationships

Answer 14

1) need to know true receptor binding capacities of drugs
2) drug bound to receptor may not be equivalent to percentage of real tissue response
ex. epinephrine
3) Kd is functional replaced by ED50 (50% effective dost) or EC50 (50% effective concentration) as a comparator for drug effect
- measures 50% maximal biological response
- describes potency

Question 15

potency

Answer 15

1)ED50 or EC50
2) shape of curve is similar to the receptor occupancy curve, and a log scale is used
3) potency should not be confused with efficacy
- potency: measuring dose and maximal effect
- efficacy: agonist has ability to stimulate signal response from a receptor (intrinsic activity)

Question 16

reversible antagonist

Answer 16

1) reversible antagonist
- decrease potency of an agonist
- competing for binding sites
- can be described by hill langmuir
- administering it will shift the binding curve and dose response curve to the RIGHT

Question 17

irreversible antagonist

Answer 17

1) remains due to covalent binding
2) Reduce the potency of agonist drug, but primary influence is on efficacy
3) reduces the total number of receptors available, permanently reducing maximal tissue response
- usually toxins

Question 18

partial agonists

Answer 18

1) have lower efficacy due to lower ability to elicit signaling response while binding same number of receptors
2) may not cause optimal conformational changes in the receptor and thus will not provide max response
3) ex. synthetic butyrylcholine is less potent than ACh

Question 19

inverse agonists

Answer 19

1) drug that binds to a constitutively active receptor and causes reduction in activity
- negative efficacy
- can be inhibited in the same way a normal agonist can

Question 20

spare receptors

Answer 20

1)both receptor occupancy and dose response curves increase with increase drug concentration but are rarely equivalent
- 50% binding =/= 50% biological response
2) many full agonists can elicit maximal response with low levels of binding
3) unbound receptors are “spare receptors”

Question 21

non competitive antagonism

Answer 21

1) allosteric antagonism
2) pharmacokinetic antagonism
3) signaling blockade
4) physiological antagonism
5) chemical antagonism

Question 22

additive effect

Answer 22

overall effect is direct sum of individual drug

Question 23

synergistic or potentiating

Answer 23

1) overall effect is greater than the sum of individual effects
2) many variations of combined drug targeting
3) one drug preventing metabolism of second
ex. ampicillin and sulbactam
4) two drugs targeting diff molecules on the same pathway, enhancing downstream effect

Question 24

gradual diminishing of response to drug

Answer 24

1) tolerance to drug

Question 25

changes in receptors

Answer 25

1) altered conformation
2) uncoupling of associated signaling molecules

Question 26

other desensitization

Answer 26

1) translocation of receptors
- beta adrenoreceptor = destroyed
2) exhaustion of mediators
3) altered drug metabolism
- barbiturates and ethanol
- in alcohols
4) physiological adaptation
- body systems try to compensate where imbalance is detected
- reduce or abrogate effect of the drug

Question 27

population response curves

Answer 27

1) quantal response
- all or nothing response
2) ED50 can be calculated by plotting cumulative dose response in a population of patients
- the dose that produces the desired effect in 50% of treated population

Question 28

therapeutic index

Answer 28

1) drugs tested to lethality in vitro and in vivo
- most new drugs are tested to toxicity
- limiting dose is the point where adverse reactions are too great to support usage
2) therapeutic index is 50% lethal dose / ED50
- dont want an overlap between therapeutic and toxic doses!
- higher TI is better

Question 29

certain safety factor

Answer 29

1) dividing the LD1 by ED99
2) a value greater than 1 means the dose effective in 99% of population is lower than the dose that is toxic in 1% of the population
3) a value lower than 1 means the therapeutic dose may be toxic in more than 1% of the population
- ex barbiturate phenobarbital which has TI of 10 and CSF of 2

Question 30

summary

Answer 30

1) drug receptor interactions are governed by laws of mass transfer
2) rates of binding and unbinding define the dissociation constant at equilibrium
3) drug activity may be defined