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Patho 2023 > Pharmacodynamics (EXAM 2) > Flashcards

Pharmacodynamics (EXAM 2) Flashcards

1
Q

what is pharmacology?

A

science of interactions of chemical compounds with biological systems

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2
Q

what is pharmacodynamics?

A

the study of biochemical and physiological effects of drugs and the mechanisms of their actions

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3
Q

what is pharmacokinetics?

A

the study of absorption, distribution, biotransformation, and elimination of xenobiotics

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4
Q

what are the many characteristics of drugs?

A
  • Defined by actions
  • Most act on receptors
  • Endogenous drugs or xenobiotics
  • Includes poison/toxin
    solids/liquids/gasses
  • Covalent, electrostatic, and hydrophobic interactions
  • Ions to larger proteins/antibodies/vaccines, majority are small molecules
  • Drug shape and rational drug design for receptor specificity
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5
Q

what are the sites of drug action?

A

extracellular, intracellular, on the cell target

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6
Q

describe the extracellular site?

A
  • Neutralization of excessive gastric acid by antacids
  • Ex: cholestyramine resin in reducing cholesterol absorption
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7
Q

describe the intracellular site?

A
  • Drugs used to treat infections
  • Drugs used for cancer therapy
  • Ex: hormones such as estrogen
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8
Q

describe the on cell target site?

A
  • Comprises cell-membrane receptors
  • Many drugs act by combining with receptors on the surface of the cell
  • Examples
    — Acetylcholine and muscarinic or nicotinic receptors
    — Growth factors (EGF/FGF) and GF receptors
    — Monoclonal antibodies (mABs)
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9
Q

how can we relay affinity to the law of mass action and receptor occupancy?

A
  • Effect of a drug is directly proportional to the amount of drug-receptor complex formed
  • Lower Kd (d*r/dr) → higher affinity
  • Higher affinity → more drug receptor complex and receptor occupancy → more intense drug effect
  • Based on koff and kon rates of drugs
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10
Q

what are the components in a receptor binding assay?

A
  • orthosteric: agonist/antagonist, partial agonist, inverse agonist
  • allosteric: PAMS, NAMS
  • each receptor has one orthosteric site and can have many other allosteric sites
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11
Q

what are the principles of receptor bindng assays that measure affinity?

A
  • affinity is the ability to interact with the receptor
  • kD is a measure of affinity
    – low= tight
    – high= loose
  • affinites can differ from drug to drug
  • affinity = potency
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12
Q

what is pharmacologic profiling?

A

heterologous competition testing several unlabeled compounds simultaneously

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13
Q

how can we use the graphical data for pharmacologic profiling?

A
  • cheng-prusoff equation
    – has IC50 value and from that we can determine the Ki
  • Ki is a measure of kD
  • Ki for each can be computed and compared and affinity rank can be calculated
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14
Q

how can we apply affinity to receptor selectivity?

A
  • the log 3 rule
    – 10%, 50%, 90%
    —> one log above and one log below
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15
Q

what is Bmax?

A

total number of receptors on a given cell or tissue

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16
Q

how can we use bmax with drug action?

A

it is the max affect of a drug
– it is the concentration of all receptors where they are all occupied and reach max conc.

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17
Q

how can we identify and compare dose response curves for each type of ligand in the spectrum?

A
  • Super agonist is > 100% response
  • Agonist is 100% response
  • Partial agonist is 50% response
  • Silent antagonist is 0% response or opposite
  • Partial inverse agonist is -50% response or negative effect
  • Full inverse agonist is -100% response
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18
Q

what is the difference between agonist and antagonist receptor binding?

A
  • Agonist binding: binding of an agonist results in an induced fit that activates the receptor
  • Antagonist binding: binding of an antagonist results in a different induced fit that does not activate the receptor
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19
Q

how can we use graphical data to compare potency and efficacy for active ligands?

A

efficacy: goes toward max response or up
potency: goes to the left for increasing potency

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20
Q

what is a partial agonist?

A
  • Produces a reduced response even at full receptor occupancy
  • Cannot produce the same max effect as a full
  • Partial agonist may inhibit competitively the response to a full agonist
  • Mechanisms complex but probably related to drug binding to inactive form of receptor
    EXAMPLES: abilify, buspar, buprenorphine
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21
Q

how can we apply the concept of partial agonist theory to managing drug therapy?

A

We know an agonist can open an ion channel immediately, so when we have a partial agonist we can see that there is a complex in between the open and closed state. It can also take longer with both a complex and a flip state before closing or opening the channel

Also we can use this theory to determine the total response between full agonists and partial agonist and produce a dose response curve to compare the two

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22
Q

what are the features of inverse agonists?

A
  • Requires constitutive activity
  • Produces the opposite response of an agonist
  • Can have full and partial inverse agonists
  • Response can be altered by agonist, partial agonist, and antagonist
  • Stabilize inactive form of receptor
    —- Ex: rimonobant
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23
Q

what is reversible competitive inhibition?

A
  • Antagonist combines with the same site on the receptor as the agonist
  • Antagonism can be reversed by increasing the dose of the agonist
  • competitive goes to the right and is same as regular in size
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24
Q

what is irreversible non-competitve inhibition?

A
  • Usually bind to the same site as an agonist, but will not be readily displaced
  • Irreversible inhibition is generally caused by covalent reaction between antagonist and receptor
  • Inhibition persists even after an irreversible antagonist is removed. Duration of action dependent of receptor turnover
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25
Q

how can we use spare receptor to explain drug action?

A
  • When max response can be elicited by an agonist at a conc. That does not result in 100% occupancy of available receptors
    —> Ex: response of heart muscle to catecholamines can still be obtained when 90% of beta receptors are occupied by an irreversible antagonist
  • Important in the action of irreversible antagonists
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26
Q

what is chemical antagonism?

A
  • occurs between an agonist and an antagonist to form an inactive product
  • Agonist is inactivated in direct proportion to the extent of the chemical reaction with the antagonist
    –> Ex: calcium antacids and tetra. Antibiotics, cyanide and sodium nitrite
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27
Q

what are the mechanisms of allosteric modulators?

A

PAMS
NAMS
Signaling texture

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28
Q

what are allosteric modulators potential benefit in drug therapy?

A
  • Bind at sites unique from agonist or antagonist
  • Increased specificity for receptors that have similar orthosteric binding site
  • Increased safety due to ceiling effect
  • Provide more physiological/ temporal signaling
    —> EX: PAMS of dopamine receptors for parkinsons
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29
Q

what is efficacy?

A

biological response resulting from receptor interaction

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30
Q

what is potency?

A

does of drug required to produce a particular effect of given intensity

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31
Q

what is a non-competitive antagonist

A
  • produces its effect at a site of the receptor other than the site used by the agonist
  • Agonist and noncompetitive do not compete with one another for a single binding site
  • Cannot be completely reversed by increasing the conc. Of agonist
  • Increasing antagonist conc. Increase the KD and dec. Emax of agonist
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32
Q

spare receptors are:

A

system/tissue dependent
- some cells have no reserve
- coupling efficiency is a determinant
- may differ for responses with same receptor

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33
Q

what is functional antagonism?

A
  • 2 drugs influence a physiological system but in opposite directions
  • Each drug is unhindered in the ability to elicit its own characteristic
    –> Ex: effect of histamine on BP can be offset by epinephrine
  • Can lead to contraction or relaxation based on path
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34
Q

what are the 5 classes of receptors

A

intracellular receptors
cytokine receptors
protein kinase receptors
ion channels
GPCRs

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35
Q

what are intracellular receptors

A
  • Intracellular receptors (regulate gene expression) (steroids)
    — Stimulate the transcription of genes in the nucleus by binding to specific DNA sequences near the gene whose expression is regulated
    – Additional non receptor receptors
    ——– Effector enzymes that regulate cellular function include membrane potential, protein phosphorylation, translation, transcription, etc.
    ———–> Kinase, cyclase, phosphatases, ubquitinases
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36
Q

what are cytokine receptors

A

simplest
- JAK-STAT pathway
- mechanism: binds, activation leads to JAK, phosphorylation to STAT, dimerizes and travels to regulate transcription
–> Examples: GHs, erythropoietin, interferons

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37
Q

what are protein kinase receptors

A
  • Mechanism: ligands dimerize,conformational change, phosphorylation happens and recruits GRAB, leads to activation of RAS, RAS leads to transcription
    —> Examples, EGF, PDGF, insulin
  • Kinases add a phosphate group
  • This pathway can be turned off by blocking
  • RTKs as drug targets
    —> Lots of ways to target an receptor
38
Q

what are the two types of ion channels

A

voltage gated and ligand gated

39
Q

what do voltage gated ion channels do

A
  • No ligand just membrane potential
  • Bind at allosteric sites
  • In order to block we have to activate
    –> Ex: na, ca,k
  • Involved in pain, epilepsy, arrhythmias, vascular tone, neurotransmitter release
  • Channels can be regulated by phosphorylation and G proteins
40
Q

what do ligand gated ion channels do

A
  • Many drugs act by mimicking or blocking endogenous ligands that regulate flow of ions through channels
    –> Ex: acetylcholine, gamma-aminobutyric acid, glutamate, etc.
  • When bind the signal is transmitted across membrane and alters electrical potential
  • Very fast (milliseconds)
    –> Important in rapid transfer of signals across synapses
41
Q

what are g couples protein receptors

A
  • Very popular in human genome and largest family
  • 40% of drugs target GPCRs
  • 3 classes (A,B,C)
  • Ligands act by modulating effectors and concentrations of second messengers
42
Q

who invented cyclic AMP in 1971

A

earl sutherland

43
Q

what are the affects of allosteric modulators on ion channels

A

Allosteric modulators that activate or inhibit ion channels by binding to domains other than the pore are more favorable than channel blockers because they have the capability to target channels more specifically and regulate their activities more precisel

44
Q

what are the affects of allosteric modulators on GPCRS

A

Allosteric modulators may stabilize, disrupt, or induce structural conformations that preferentially (biased) signal via one or multiple pathways, at magnitudes unlike the endogenous ligand. C. Many GPCRs are targeted by large endogenous ligands, such as peptides and proteins

45
Q

what are the features of G protein activation

A
  • effectors: channels, enzymes, regulatory proteins
  • second messengers: cAMP, CA2+, phosphoinositides
46
Q

what are the components of the signaling process for gpcrs

A

R
- extracellular ligand is detected by cell surface receptor
G
- this receptor in turn trigger activation of G protein located on cytoplasmic face of the plasma membrane
E
- activation of Galpha and Gamma/beta then changes the activity of the effector
– enzyme or ion channel
- this effector often changes the concentration of the intracellular second messengers which produce an effect
– greatly amplified response

47
Q

what are the subtypes of G proteins

A

Gas, Gai, Gas/11, Ga12/13, Gby

48
Q

what is Gas effector

A

inc. adenylyl cyclase

49
Q

what is Gas isoforms

A

gas, golf

50
Q

what is Gai effectors

A

dec. adenylyl cyclase

51
Q

what is Gai isoforms

A

Gai1, Gai2, Gai3

52
Q

what is Gaq/11 effectors

A

inc. phospholipase C

53
Q

what is Gaq/11 isoforms

A

Gaq

54
Q

what is Ga12/13 effectors

A

recruit Rho guanine exchange factors

55
Q

what is Ga12/13 isoforms

A

Ga12, Ga13

56
Q

what is Gby effectors

A

dec. adenylyl cyclase
inc. ion channels (Ca and K)

57
Q

what is Gby isoforms

A

B (1-5)
y (1-13)

58
Q

what are the second messengers

A

cAMP
cGMP
calcium and phosphoinositides

59
Q

what does the second messenger cAMP do

A
  • Effector enzyme is adenylyl cyclase and enzyme that converts ATP to cAMP
  • cAMP stimulates PKA
  • Specificity of cMAP is defined by compartmentalization of signaling complexes
    — Ex: B1 adrenergic receptors for asthma
60
Q

what does the second messenger cGMP do

A
  • Effector enzyme is guanylyl cyclase
  • cGMP activates cGMP-dependent protein kinase
    — PKG
  • Regulated by nitric oxide
  • Much more specific than other messenger systems
61
Q

what do the second messengers calcium and phosphoinositides do

A
  • PLC results in release of phosphoinositides and diacylglycerol
  • Phosphoinositides result in release of calcium
  • Diacylglycerol active protein kinase C
    –> Ex: muscarinic receptors in alzheimers
62
Q

what are kinases

A

phosphorylation
- 800 genes in genome
- unique specificity
- inhibitors as drugs:
–> imantinib, trastuzumab

63
Q

what are phosphatases

A

dephosphorylation
- 250 genes in genome
- very few drugs targets
—> ex: diabetes, PD, AD, allergy and asthma

64
Q

what is the mechanism and consequence for homologous desensitization

A
  • Does it to itself
  • Rapid desensitization
    – GRKs aka B-ARK
    – Less responsive
  • Receptor uncoupling-arrestin binding
  • Sequestration and fate (arrestin involvement)
    — Recycling (dephosphorylation)
    — Degradation (lysosomal degradation)
65
Q

what’s the mechanism and consequence for heterologous desensitization

A
  • Can do this to another receptor with kinases
  • non-agonist/receptor-specific
  • Involve signaling cascades from other receptors
    — PKA or PKC phosphorylate receptor of interest
  • Blunt receptor response or alter G protein coupling
66
Q

how can we use functional selectivity to design better drugs

A

we can use them to enhance therapeutic pathway
- TRV027-AT1 biased agonist that promotes B arrestin
– Blocks vasoconstriction in HF
– Beneficial in COVID
- Opioid therapy for analgesia
– B arrestin linked to tolerance and maybe respiratory depression
– Avoid this pathway
– we want the G protein pathway here

67
Q

what is functional selectivity and its purpose in concentration response curves

A
  • AKA agonist trafficking, biased agonism, ligand bias, differential engagement, and protein agonism
  • Requires the receptor couple to multiple signal transduction pathways
    – G protein and B arrestin
  • Display selectivity for one or more pathways when compared to another pathway
  • Receptor binding to other pathways
68
Q

what is the GPCR effector pathway for norepinephrine (receptor, effector, second messenger, later effectors, response)

A

Gas, adenylyl cyclase, cAMP, protein Kinase A, inc. protein phosphorylation

69
Q

what is the GPCR effector pathway for dopamine (receptor, effector, second messenger, later effectors, response)

A

Gai, adenylyl cyclase, cAMP, protein kinase A, inc. protein phosphorylation

70
Q

what is the GPCR effector pathway for glutamate (receptor, effector, second messenger, later effectors, response)

A

Gas, phospholipase C, Dag and IP3, protein kinase A, and Ca release, inc. protein phosphorylation, and activate Ca binding proteins

71
Q

what is the GPCR effector pathway for LPA (receptor, effector, second messenger, later effectors, response)

A

Ga12, RhoGEF, Rho GTPase, effector, inc. endocytosis, motility, transcription

72
Q

tell me about the Diversity of Gs-AC-cAMP system for cAMP

A

Gs-linked receptors
– 100s
Gs variants
– 3+
AC isoforms
– 10
PDE isoforms
– 11
PKA, EPAC, CNGC

73
Q

tell me about the Diversity of Gq-PLCAC-IP3/DAG system for calcium and phosphoinostides

A

Gq-linked receptors
- Multiple types
PLC isoforms
- Cleaves PIP2, DAG, IP3
- 13
PKC isoforms
- 15
CaM targets
- 300

74
Q

what are the significances of intracellular receptors

A

— Significances:
———– Has lag period and slow
———– Cannot be altered in minutes, takes hours
———– Effects can persist after conc. Is reduced to zero
———– Slow turnover
—————-> May be due to high affinity

75
Q

what is the mechanism for intracellular receptors

A

— Mechanism: steroid, ligand binding domain, dna binding domain, altered transcription of gene

76
Q

how can we measure the second messenger cAMP

A

Measure by:
- Protein-based biosensors
- Fluorescent approaches
- Radioactive assays are not popular anymore

77
Q

Identify and define the key means by which drug effect is quantified and compared.

A
  • Onset: when it hits the desired response for the first time
  • Intensity: rate of energy expenditure
  • Duration: the time it takes for the action to take plac
78
Q

know the differences between quantal and graded drug responses

A
  • Graded: maximal efficacy (progressive increase)
  • Quantal: potential variability of response (all or none)
79
Q

how to compare and calculate therapeutic index between drugs

A
  • Relative safety of a drug expressed as LD50/ED50 or TD50/ED50
  • The larger the ratio presumably the greater the relative safety
    – Unfavorable (toxic and close together)
    – Favorable (spread out and safer drug)
80
Q

what are the factors that can modify the effects of drugs

A
  • Drug tolerance
  • Physiological
    – Age
    – Gender
    – Pregnancy
    – Food
    – Circadian clock
  • Pathological
    – Liver disease
    – Renal disease
    – Malnutrition
  • Genetic
    – Pseudocholinesterase deficiency
    – Malignant hyperthermia
    – Oxidation polymorphism
  • Interaction with other drugs
    – Pharmacokinetic
    – Pharmacodynamic
    – placebo
81
Q

what is drug disposition tolerance

A
  • Decrease in effective concentration of the agonist at the site of action
  • Drug disposition/ metabolic tolerance
    — I.e. phenytoin increases rate of biotransformation of a number of drugs which are metabolized by liver enzymes
    — End result is decreased effect on drug
82
Q

what is pharmacologic tolerance

A
  • Decrease in normal reactivity of receptor
  • Cellular or pharmacologic tolerance
    — Downregulation of receptors
    — Change in receptor affinity
    — Most often seen with CNS drugs such as narcotics, depressants, and stimulants
83
Q

how can we apply cross tolerance to disease management

A

bases to opioid receptors and tachyphylaxis

84
Q

what are the opioid receptors doing

A
  • Tolerance develops to one drug that is also seen with drugs belonging to the same class
    —– For example, an individual tolerant to morphine develops some level of tolerance to morphine develops some level of tolerance to opioids that act on same receptor (e.g. heroin, methadone, codeine)
    –> not always complete
85
Q

what is the tachyphylaxis doing

A
  • Acute development of tolerance following rapid and/or repeated administration of a drug
    – The first administration of drug produces a much larger response than subsequent doses, when given after a brief interval
    – Can NOT overcome this type of tolerance with increasing dose
    —> Ex: amphetamine, ephedrine (norepinephrine release) and LSD
86
Q

what are the on and off target adverse effects for intended tissue

A

on-dose too high and chronic activation or inhibition effects
off- incorrect receptor is activated or inhibited

87
Q

what are the on and off target adverse effects for unintended tissue

A

on- correct receptor but incorrect tissue, dose too high, chronic activation or inhibition effects
off- incorrect receptor is activated or inhibited

88
Q

what are the physiological response in multicellular/multi receptor context.

A

altered gene expression, relaxation, contraction

89
Q

what causes gene expression changes

A

all pathways

90
Q

what causes relaxation changes

A

epinephrine and acetylcholine and BNP from cAMP and cGMP

91
Q

what causes contraction changes

A

angiotensin 2 from calcium, IP3, and adrenergic nerves

Patho 2023 (37 decks)

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