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Pharm Exam 1 > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

1
Q

three main phases of drug action

A

1) pharmaceutical phase: disintegration of dosage from dissolution of active substances
2) pharmacokinetic phase: ADME
3) Pharmacodynamic phase: drug-receptor interaction in target tissue
EFFECT

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2
Q

most drugs will likely interact with many other _____ within a given clinical dose range used therapeutically

A

receptors

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3
Q

the chemical forces that contribute to drug binding

A

electorstatic, hydrogen bonding, van der Waal’s forces (at closer distances), or hydrophobic forces (between lipophillic components)
- therefore most drug binding interactions are reversible and don’t form a covalent bond

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4
Q

all drugs interact only with ____ receptors

A

unoccupied

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5
Q

receptor binding is a ______ _____ process

A

dynamic equilibrium

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6
Q

binding sites vs receptors

A

-binding sites can bind a substance but are not themselves capable of initiating a susequent response while receptors can

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7
Q

for any receptor population, the percent occupied (fractional occupancy) is dependent only on the drug’s ____ and ____

A

affinity and concentration (dose)

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8
Q

drug affinity constant (Kd)

A

Kd = (k2/k1) = (koff/kon) = ([D][R] / [DR])
=equilibrium dissociation constant
-represents a measure of the propensity of a drug to bind to a given receptor
-drug affinity and Kd values are inversely related
-also represents the concentration of that drug required to occupy 50% of a receptor population

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9
Q

receptro fractional occupancy is dependent on _____ and _____

A

drug affinity and drug concentration

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10
Q

converting to Kd units

A
  • if the Kd of a drug is 1nM, then a conc of 1nM would = a conc of 1Kd and 2nM would be 2 Kd units
  • causes the conc vs receptor occupation curve to be representative of how receptor occupancy would increase for a drug
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11
Q

concentration as Kd units and the fractional occupancy

A
  • .01 Kd =1% occupancy
  • .1 Kd = 9%
  • 1 Kd =50%
  • 10 Kd = 91%
  • 100 Kd = 99%
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12
Q

mathematical response in the body to the drug

A
  • the magnitude of the response will be some function of the total number of receptors occupied
  • response = f[(fractional occupancy)(receptor density)] or f[total # of receptors occupied]
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13
Q

drug selectivity

A
  • dependent on the relative affinities of a drug for various receptors (comparative Kd values for various receptors) and for any drug
  • selectivity will decr as drug dose is incr
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14
Q

selectivity window for drugs

A
  • some drugs need a certain selectivity window where they will only activate the target receptors and not the other receptors
  • other drugs have such a small selectivity window that you have to plan for activating the other receptors (side effects)
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15
Q

dose-response relationship

A
  • this is the correspondence between the amount of drug and the magnitude of the effect
  • increasing the dose increases the effect in a graded manner
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16
Q

simple occupancy theory

A
  • one to one relationship between occupation and response

- not very representative of biology

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17
Q

modified occupancy theory

A

-depends on potency and maximal efficacy

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18
Q

potency

A
  • concentration or dose of drug needed to produce 50% of that drug’s maximal response
  • depends on the drug’s affinity for the receptor and the efficiency with which the receptor activation is coupled to the response
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19
Q 
maximal efficacy 
(=intrinsic activity)
A
  • maximal response produced by the drug
  • full agonist: intrinsic activity = 1
  • partial agonist: intrinsic activity
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20
Q

negative antagonist (inverse agonist)

A

-an antagonist that can reduce the constitutive activity of receptors

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21
Q

biological activity cannot be determined from …

A

fractional occupancy

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22
Q

the clinical effectiveness of a drug depends on its _____ and NOT _____

A
  • maximal efficacy

- potency

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23
Q

spare receptors

A
  • systems in which maximal response is achieved by doses of agonists that occupy only a small fraction of receptors are considered to have spare receptors
  • all receptors are considered to be equally functional, but its not required that all receptors be occupied to achieve a maximal response
  • can sometimes be identified from the steepness or dose-range required to achieve Emax in a D-R curve
  • need greater dose with fewer # of receptors to reach Emax
24
Q

how does competitive antagonism affect the dose-response curve?

A
  • shift curve to the right
  • increase ED50
  • no change in Emax
25
Q

how does non-competitive antagonism affect the D-R curve?

A
  • decrease in Emax

- no change in ED50

26
Q

chemical antagonism

A

via chemical inactivation of a drug

27
Q

physiological antagonism

A

the use of opposing paths to antagonize the effects of a drug

28
Q

biological antagonism

A

one drug may affect the metabolism or pharmacokinetics of another drug

29
Q

quantal dose response curve

A
  • relationship between drug dose and a specified effect in a population of individuals
  • obtained from the cumulative frequency distribution of doses of drug that produce a specified (quantal) effect in a patient or animal population
30
Q

how to get a dosal response curve?

A

1) specify your endpoint- must be yes or no categories
2) give a low dose of the drug and determine the number of individuals that exhibit the affect
3) give a higher dose of drug and again determine the number of individuals that exhibit the effect
4) continue increasing the dose until you obtain the effect in all individuals in the population

31
Q

what can we determine from quantal dose-response curve?

A
  • median effective dose (ED50)
  • an index of selectivity of a drugs actions by comparing the ED50 for different specified effects
  • estimate the degree of safety for a drug for a specified effect (ex therapeutic index = TD50/ED50 or LD50/ED50 where LD = lethal dose)
  • therapeutic window
32
Q

therapeutic window

A
  • more clinically relevant index of safety

- dosage range between the minimum effective therapeutic dose and the minimum toxic dose

33
Q

pharmacophore

A

-drug recognition site

34
Q

5 general receptor features

A

1) structural specificity
2) stereospecificity (one isomer will be more potent than the other or all activity will reside in one isomer)
3) saturability
4) there will be some quantitative relationship between the magnitude of the response and the total number of receptors occupied
5) subject to regulation

35
Q

The magnitude of the response and the total number of receptors occupied will depend on….

A

1) the amount of drug reaching its site of action
2) the specific drug-receptor interaction at that site (coupling efficiency)
3) the functional status of the receptor and/or target cell

36
Q

the binding of (lipid soluble) drugs to intracellular receptors may…

A

-stimulate an intracellular enzyme or regulate the cellular localization of the receptor and alter gene transcription

37
Q

what are the therapeutic consequences of gene active receptors

A
  • there is a lag period before the effects may be observed- time to synthesize proteins
  • the effects of gene active receptors may persist for hours or days after the agonist is gone - slow turnover of proteins
  • Therefore, activation of the gene and its effects may long outlast the presence of the drug in the body
38
Q

types of p-mb receptors

A
  • ligand regulated transmb enzymes including protein tyrosine kinase and cytokine receptor
  • ligand gated channel receptors
  • GPCRs
39
Q

the ligand regulated transmb enzyme receptors

A
  • receptor polypeptides that cross the mb once and consist of an extracellular binding domain and an intracellular enzymatic domain (may be tyrosine or serine kinase or guanylyl cyclase)
  • once activated, these receptors can p-late tyrosines or serines on various downstream proteins
  • autop-lation of tyrosines on the receptor’s cytoplasmic side can intesify or prolong the duration of receptor activation
  • subject to receptor down-regulation via endocytosis and degradation of receptors
  • ex. insulin, epidermal growth factor (EGF), and atrial naturitic factor (ANF)
40
Q

cytokine receptor mechanism

A
  • closely resembes the tyrosine kinase recptors but utilize a separate protein tyrosine kinase that binds non-covalently and isn’t intrinsic to the receptor
  • respond to a heterologous group of peptide ligands such as growth hormones and other regulators of growth and differentiation
41
Q

cytokine receptor activation steps

A

1) ligand binding induces a conformational change and receptor dimerization
2) dimerization allows JAKs to be activated and p-late tyrosine residues on the receptor
3) p-lation of tyrosine on the receptor facilitates the binding of Signal Transducers and Activators of Transcription (STAT proteins)
4) the bound STATs are then p-lated by the JAKs
5) 2 STATs dimerize and the dimer dissociates, travels to the nucleus and regulates gene transcription
- the receptor doesn’t have intrinsic enzymatic activity

42
Q

ligand gated channel receptors

A

1) pentamer consisting of 4 types of glycoprotein subunits that form a cylindrical structure containing the channel
2) Ach binding to the alpha subunits produce a conformational change and transient opening of the channel
3) the open channel allows Na+ ions to pass from the extracellular fluid into the cell
4) the time between binding and response is in ms which provides for rapid info transfer
- nts using this mechanism = Ach, GABA, and a.a.s

43
Q

GPCRs

A

1) a single polypeptide chain that transverses the p-mb 7 times
2) the amino terminus is in the extracellular side while the carboxy terminus resides on the intracellular side
3) the third inracellular loop regulates the ability to interact with specific G-proteins while the carboxy terminus contains sites (serine residues ) that are subject to p-lation and regulation of receptor function
4) activation conveys effects to second messanger enzymes
- DA, NE, 5-HT, and ACH

44
Q

hydrolysis half lives of Gs, Gq, and Gz

A

Gs - 10-20s
Gq- 50 s
Gz - 7 min

45
Q

steps in GPCR activation

A

1) By and a segments together with a linked to GDP.
2) receptor binds ligand and a switches GDP for GTP
3) two pieces come apart and a-GTP activates second messenger
4) GTP is hyrdolyzed to GDP and a-GDP binds By

46
Q

activation of adenylyl cyclase

A

1) multiple GPCRs activated
2) activation of multiple catalytic units of AC
3) conversion of ATP to cAMP
4) cAMP activates multiple cAMP dependent kinases (PKA)
5) PKA p-lates multiple downstream proteins
6) amplified final response

47
Q

activation of phosphoinositide hydrolysis path

A
  • greater signal amplification/diversity than AC
    1) multiple GPCRs activated
    2) activation of multiple catalytic units of PLC
    3) conversion of PIP2 to 2 second messengers: DAG and IP3
    4) DAG activates multiple PKC enzymes (>9 types)
    5) multiple PKCs p-late various downstream proteins
    6) IP3 release of large intracellular stores of Ca2+
    7) Ca2+ activates multiple calmodulin (CaM) dependent kinases (PKA)
    8) multiple PKAs p-late multiple downstream proteins
48
Q

3 types of beneficial vs toxic effects of drugs

A

1) extension of effects at the same receptor - manage dose
2) effects mediated by the same receptor in different tissues - add other drugs to lower dose of 1st drug, give lowest dose possible, or limit effects via route of adiministration
3) effects mediated by activation of different receptors – give drug with greater selectivity

49
Q

receptor desensitization occurs in response to ____ stimulation (and vice versa)

A

over

these reactions occur slowly over time as a cellular adaptation

50
Q

tachyphalaxis

A

rapid development of diminished responsiveness to a drug

51
Q

list of mechanisms involved in desensitization

A

1) agonist induce p-lation of the activated receptor and subsequent binding of B-arrestin (a readily reversibe phenomenon)
2) receptor down-regulation
3) post receptor adaptations

52
Q

post receptor adaptations and desensitization

A

-receptors become functionally uncoupled from post-receptor components due to modification of G proteins or second messenger enzymes

53
Q

which way does desensitization shift the agonist dose response curve

A

to the right (and usually without a reduction in Emax unless receptor reserve is exceeded)

54
Q

what might explain a desensitization induced reduction in Emax

A

1) receptor reduction exceeding receptor reserve

2) post-receptor defects (Changes in G proteins, enzyme activity, etc required to maintain orginal Emax)

55
Q

Homologous desensitization

A

desensitization is restricted to only the receptor population that was activated by the drug.
It will have the desensitized response to anything that activates it, not just the drug
-kinases p-late agonist occupied receptors only and then beta-arrestin binds to the receptor

56
Q

heterologous desensitization

A

desensitization is not restricted to only the receptor population activated by the drug

  • several protein kinases are capable of promoting p-lation of other, non-activated receptors, these are PKA and PKC
  • may be associated with functional modifications at post-receptor intermediates in the signal transduciton path (like G proteins)
57
Q

supersensitivity

A
  • compensatory receptor mechanism in which the loss of activity on receptors leads to an increase in receptor density and/or an enhanced receptor effector coupling
  • increased responsiveness to subsequent receptor activation and a shift to the left on the D-R curve

Pharm Exam 1 (10 decks)

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