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Boards: Pharmacology > Pharmacology/Receptor Physiology > Flashcards

Pharmacology/Receptor Physiology Flashcards

1
Q

Receptor

A

protein or glycoprotein which interacts with signaling messenger substance

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2
Q

Ligand

A

Signaling messenger substance

Ex hormone or drug

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3
Q

‘Initial effect’

A

Action of drug

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4
Q

‘Succeeding effects’

A

Drug effects

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5
Q

Law of Mass Action

A

[L] + [R] <–> [LR]

where formation of L+R is via Ka, separation of L/R into individual components is Kd

[L]=concentration unbound ligand
[R]=concentration unbound R
[LR] = concentration bound R

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6
Q

Ka

A

rate of constant assoc of L with R

Ka=1/Kd=[LR]/([L]*[R])

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7
Q

Kd

A

Rate of constant of dissociation of L with R

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8
Q

Affinity

A

Relationship btw particular R, its L

If amt of ligand administered is just enough to occupy 50% of R then, Ka = 1/[L]

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9
Q

Can a ligand have a strong affinity for the R without producing effect?

A

Yes

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10
Q

Activity

A

Ability of ligand to induce an action’

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11
Q

Higher Ka

A

At equilibrium, number of unbound molecules is low so have high affinity of L for R

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12
Q

Lower Ka

A

At equilibrium, number of unbound molecules high so have low affinity of L for R

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13
Q

Selectivity of a ligand

A

determines capacity to produce a particular effect

Highly selective = produce only 1 effect through activity (at only one class/subclass of R

Ex: dopamine vs Dobutamine –> Dobutamine more selective bc only effects at B R, no alpha

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14
Q

Specificity of ligand

A

capacity to associate with only one specific type of R
o Effects of ligands of highly specific ligand = can be numerous but DT only one type of R-L interaction

Ex: atropine - associates with one specific type of R even though R present in different in tissues, effects diverse

Ex: inhalants - interact with multiple R to produce effects

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15
Q

Limitations to Law of Mass Action

A
  1. All L, R equally available to each other
  2. Binding of drug + R does not alter either drug or R –> not case when drug substrate for R is metabolic enzyme
  3. Binding of drug to R is reversible…frequently not
  4. R+drug either bound to each other or not bound ie no ambiguous, partial states
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16
Q

Effect of drug

A

proportional to concentration of ligand molecules available to bind
 Function of dose, method of administration

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17
Q

Lag Time

A

delay from dosing to onset of pharmacological effects
 Can be DT relative difficulty of ligand reaching R (pharmacokinetics) or from post-transduction delay (pharmacodynamics)

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18
Q

Example of a R with lag time

A

glucocorticoid R = nuclear: when not bound to ligand such as (cortisol, another GC) receptors are located in cytosol

Once activated: complex brought to nucleus –> induces transcription of genes coding from anti-inflammatory proteins, inhibits transcription of genes usually upregulated by inflammatory mediators

Onset of activity = post-transduction (long lag time)

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19
Q

Agonist

A

ligand that binds to R, usually activates it same way that endogenous molecules would

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20
Q

Full Agonist

A

Fully activates receptor

Eg morphine

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21
Q

Partial agonist

A

does not fully activate –> produces less intense maximum effect

ex: buprenorphine

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22
Q

Neutral Antagonist

A

ligand will bind to receptor, but unable to activate

Assoc usually competitive –> Can be overcome by administrating large enough amount of agonist

Can also be non-competitive

Ex: flumazenil: competitive neutral antagonist at benzo site on GABAA R

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23
Q

Reverse Agonist

A

ligands activate R but will induce opposite effects to agonist ligands

If R has baseline effect that is not nil, admin of reverse agonist will decrease baseline effect –> ex if agonist effect provides analgesia, then reverse agonist will increase pain sensation

Ex: Ro 19-4603 at benzo binding site on GABAA R

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24
Q

Naloxone

A

Opioid antagonist but at low doses, enhances analgesia effects

Proposed MOA: increasing effect of endogenous ligands, up regulation of postsynaptic R, inhibiting of counteraction by Gs proteins, uncoupling of filament A, attenuating increase in expression of GFAP

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25
Q

Receptor State Theory

A
  • R by default in non-activated form, needs agonist ligand to be activated
  • Non-activated form represents most of R – without presence of agonist ligand, some R can exits in their activated form
  • Role of ligand not to activate R but stabilize activated form

Major implications:
o Existence of a baseline agonist effect for R
o Differentiated btw antagonist drugs, inverse agonist drugs

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26
Q

Primary Structure of a R

A

Linear sequence of amino acids

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27
Q

Secondly Structure

A

Regular local sub-structure (α-helix or ß-sheets)

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28
Q

Tertiary Structure

A

Three-dimensional structure of a single peptide molecule

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29
Q

Quaternary Structure

A

combination of multiple tertiary structure of different proteins linked together

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30
Q

Function of VG Na ion channels

A

o Conduct sodium cation into cell  action potential generated
o As membrane potential increases conformational central pore changes –> increased sodium permeability, influx of sodium ions
 Conformation change made possible by presence of particular transmembrane-spanning segments (α-helices) called voltage sensors

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31
Q

Ternary Complex Model

A
  • Relevant for GPCRs
  • Sensitivity for [LR] system and pot of agonists = subject to availability of external agonists
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32
Q

Competitive antagonists

A
  • Will shift dose response curve R: will need more agonist to have same maximal effect
  • Can be overcome by administrating large enough amount of agonist
  • Ex: flumazenil, butorphanol at MOR, naltrexone/naloxone under basal conditions
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33
Q

Reverse Agonists - examples

A

ligands activate R but will induce opposite effects to agonist ligands
 AKA inverse agonist
 Ex: Ro 19-463, diphenhydramine at H1R, all H2R, naloxone/naltrexone when MOR bound to GPCR

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34
Q

Ionotropic R

A

 “Fast response”
 L, VG
 Activation causes flow of ions across plasma membrane
 Ion channels = Na, Ca, K, GABAA, nicotinic, NMDA

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35
Q

Metabotropic R

A

 “Slow response”
 Activated via ligand
 Activation –> series of intracellular events via second messenger cascade
 GPCR: adrenergic R, opioid, GABAB, mAChR, dopaminergic, histaminergic

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36
Q

Na Ion Channel Structure

A

1 large alpha subunit with 4 homologous domains (DI, DII, DIII, DIV)
-Each domain: 6 helical segments
-S4 segment = voltage-sensing segment

When membrane potential increases, these S4 (positively charged) segments move toward extracellular side of membrane –> change conformation of channel

Two accessory beta subunits

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37
Q

What are two other important features of the Na R structure?

A

o DIII, S6 = inactivation particle of H gate
o DIII, S5-S6 and DIV, S5-S6: segments implicated in H gate

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38
Q

Where do LA bind?

A

o DIV, S6: binding site of LA

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39
Q

Three States of the Na R

A
  1. Resting
  2. Open
  3. Closed/Inactive
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40
Q

MOA NaV

A

At rest, RMP -70mV – m gate closed, voltage sensor S4 in each domain

S4 senses when MP increases to -55mV – rapid opening of activation (m) gate

Opening of activation (m) gate allows Na ions to flood into cell, raises MP to +30mV

At -55mV, inactivation gate (H gate) starts to close but closes MUCH more slowly (0.5-2msec)

Once H gate closed, not capable of reopening for 2-5msec – allows membrane to repolarize, return to resting state

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41
Q

Modulated R Hypothesis

A

 Preferential binding to inactivated, activated states – low affinity for resting state
 Can only access DIV, S6 from intracellular side
 Lipid soluble LA gains intracellular access via crossing lipid bilayer
* More lipid soluble, faster onset
 Poorly lipid soluble LA must enter channel when open during activated state

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42
Q

Guarded R Hypothesis

A

 R for LA inside channel, channel must be open for R binding site to be accessible
 LA binds to R with constant affinity

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43
Q

Use-dependent (phasic) block

A

frequency-dependent blockade, repeated depolarization
* More binding sites made available, increased binding of LA, increased depth of blockade

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44
Q

Tonic Block

A

Blockade constant

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45
Q

NaV 1.1

A

peripheral neurons, CNS, cardiomyocytes

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46
Q

NaV 1.2

A

CNS, embryonic PNS

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47
Q

NaV 1.3

A

peripheral neurons, CNS, cardiomyocytes

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48
Q

NaV 1.4

A

skeletal m

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49
Q

NaV 1.5

A

cardiomyocytes***, CNS, GI

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50
Q

NaV 1.6

A

CNS, DRG, peripheral neurons, cardiomyocytes

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51
Q

NaV 1.7

A

CNS, DRG, peripheral neurons, cardiomyocytes, Schwann cells, neuroendocrine

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52
Q

NaV 1.8

A

DRG

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53
Q

NaV 1.9

A

DRG

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54
Q

GABA A R

A
  • Fast response anion channels – allow passage of chloride anions into cell, CNS in mammals
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55
Q

Activation of GABA A R?

A
  • Activation: hyperpolarization of neuron  inhibits subsequent depolarization of neuron –> reducing CNS activity
  • γ-Aminobutyric acid = main agonist
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56
Q

Anesthetic Drugs that work at GABA A

A

o Most anesthetic drugs that work on GABAA do not directly activate R
o Induce allosteric change ie change conformation/quaternary structure of R = allosteric modulation

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57
Q

Positive Allosteric Modulators at GABA A

A

barbiturates, benzos, propofol, etomidate, alfaxalone, inhalants, ethanol – allow greater hyperpolarization

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58
Q

Negative Allosteric Modulators at GABA A

A

flumazenil, decreases efficiency of R

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59
Q

What is true about most anesthetics at the GABA A R?

A

o Most anesthetic drugs that work on GABAA do not directly activate R at clinically useful doses –> allosteric modulators

 Most able to directly activate R if used at doses much greater than what used clinically EXCEPT benzos – BENZOS CAN NEVER DIRECTLY ACTIVATE GABAA

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60
Q

GABA Binding Site

A

EC R at a/b subunit interface

Increases IC Cl –> hyperpolarization

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61
Q

Benzos

A

alpha subunit interface with gamma subunit
Decrease rate of dissociation of GABA, increases duration of channel opening

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62
Q

Barbiturates

A

Beta subunit interface with alpha or gamma subunit

Decrease rate of dissociation of GABA, increases duration of channel opening

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63
Q

Neurosteroids

A

beta subunit interface

Facilitates movement of Cl into pore

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64
Q

Etomidate

A

alpha/beta subunit interface

Increased frequency of channel opening, increased affinity for GABA
Also enhances effect of other drugs

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65
Q

Propofol

A

beta subunit interface

Decreases rate of dissociation of GABA, increases duration of channel opening

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66
Q

Inhalants

A

alpha/beta subunit interface

Decreases rate of dissociation of GABA, increases duration of channel opening

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67
Q

Picrotoxin

A

2nd TM helix of ion channel

Non-competitive antagonist, blocks Cl conduction

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68
Q

Structure of GABA A R

A

 α , ß , γ subunits (2a, 2b, γ)
 Each subunit: four TM-spanning (α-helix) segments, create chloride channel
 TM2 lines ion channel

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69
Q

AMPA R?

A
  • α-aminohydroxymethylisoxazolepropionic acid

Amino
Hydroxy
Methyl
Iso
Xazole
Proprionic acid

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70
Q

AMPA R Structure

A

4 subunits

Each subunit having four TM segments, creates cation channel

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71
Q

AMPA R Function

A

–LG ionotropic R: allows Na in, K out

–Assoc with agonist ligand, conformation changes, channel options - amt of glutamine released in synapse dictates amt of cation transfer

–Degree of depolar of postsynaptic neuron induced by AMPA-R action

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72
Q

AMPA Activation and Assoc with NMDA

A

Activation of AMPA R normally STIMULATORY, upregulated in chronic pain states – why NMDA antagonists beneficial for windup/chronic pain

Multiple or stronger depolarization of postsynaptic membrane also release Mg plug from NMDA so that channel opens  further depolarization
* Weak AMPA R activation will not activate NMDA
* Strong AMPA R activation will activate NMDA

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73
Q

NMDA R

A

o LG, VG ionotropic R: cation channel allows Na+ < Ca2+ into cell, K+ exits cell
 Mostly influx of Ca that allows cell to become more positive
o Mg2+ keeps channel closed until strong enough depolarization of postsynaptic membrane occurs

Tetramere structure with 2 homologous subunits

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74
Q

NMDA R agonists

A

o Glutamate, aspartate= main endogenous agonist
 Glycine = co-agonist

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75
Q

NR1 Subunit

A
  • Required for R function
  • Increased activity with tissue injury, hyperalgesia
  • Co-localized with a2 centrally, peripherally
  • Increases COX-1 activity
  • Glycine, D-serine can bind
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76
Q

NR2 Subunit

A
  • 4 variants/subtypes
  • Determines sensitivity of R, required for R function
  • Increased activity with tissue injury
  • Glutamate, aspartate binding site
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77
Q

Modulators of NMDA

A

Mg, Na, Ca, Cu, Zn, K – “My Nana Can Coach Zebra Karate”

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78
Q

MOA NMDA R

A

 Pre-synaptic neuron releases glutamate or aspartate (excitatory amino acids) – binds to NMDA, AMPA at NR2 subunit
 Partial postsynaptic depolarization from AMPA R, expulsion of Mg from NMDA once stimulus from AMPA sufficient – allows full channel to be opened
 Once open, Ca/Na flow in, K flows out of NMDA (Na, K for AMPA)
* Increases intracellular Ca – acts as second messenger
* Activation of Ca-dependent kinase, calcium/calmodulin-dependent protein kinase II (CaMkII)
* Increase in Na conductance
* Activates formation of NO –> increases positive retrograde signal, releases glutamate from presynaptic neuron
* Hyperalgesia, central sensitization, chronic pain, long-term potentiation

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79
Q

NMDA R Antagonists

A

amantadine, gabapentin, ketamine/phencyclidine derivatives, ethanol, xenon, N2O, some opioids (methadone, tramadol)

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80
Q

Ketamine, Tiletamine

A

non-competitive antagonists
 Binds to phencyclidine site inside ion channel –> must be open for binding
 MOA: decreases frequency, opening time of Ca channel – prevents Ca, Na influx; prevents firing of second order (afferent) neuron
* Also depresses activity of thalamacocortical activity, limbic system, nuclei in RAAS

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81
Q

GPCR

A
  • To transduce extracellular signals, some TM receptors use intermediaries
    o Intermediaries= Guanine nucleotide-binding proteins (G-proteins)
  • Second messengers = series of intracellular biochemical events
    o Initiated by receptor-ligand interaction  clinical effect
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82
Q

Structure of GPCR

A
  • GTP (guanosine triphosphate) : supplies energy for G-protein receptors
  • Structure
    o 7 TM spanning proteins with N and C terminal
    o Coupled to heterodimeric proteins: alpha, beta, gamma
     On alpha subunit, coupling domain btw 5-6
    o Binding of ligand causes hydrolysis of GTP to GDP, provides energy for something to happen inside cell
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83
Q

Gs

A

Increase in adenylyl cyclase
Increased cAMP production
Activation of phosphokinase A

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84
Q

Gq

A

Phospholipase C activated –> IP3, DAG
Activation of PKC
Increased in Ca in cytoplasm

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85
Q

Gi

A

Blocks adenylyl cyclase activity

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86
Q

Pharmacodynamics

A

effects of drug on whole body

Evaluation of potency, efficacy, concentration-response relationships, effective dose, lethal dose, therapeutic index

General principal: more drug = more effects
o Occurrences of U shaped, inverted U shaped dose response curves

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87
Q

Hormesis

A

dose-response relationships characterized by stimulatory effects at low dose and inhibitory effects at higher dose
o Inverted U-shaped dose-response curve
o Ex: Naloxone

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88
Q

Emax

A

Maximum efficacy, maximal pharmacological effect of drug or ligand pharmacological effect (E) of drug directly proportional to percentage of activated R

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89
Q

Receptor State Theory

A

existence of a baseline agonist effect (E0)

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90
Q

Hill’s Equation

A

Hill’s Equation: E= (Emax -E0)[L] / (Kd + [L])

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91
Q

Potency

A

concentration of drug needed to obtain a pharmacological effect equal to 50% of Emax , ie EC50
o Lower EC50 less drug needed to achieve required effect, higher potency of drug
o Ex: buprenorphine more potent than morphine

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92
Q

ED50

A

dose of drug necessary to induce desired effect in 50% of animals

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93
Q

LD50

A

dose of drug necessary to induce death in 50%

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94
Q

TD50

A

toxic dose; dose of drug necessary to induce toxic effects in 50% of patients
 Replaces lethal dose in human trials

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95
Q

ED90, ED95

A

ED90 = effective dose in 90% of population
ED95 = effective dose in 95% of population

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96
Q

Therapeutic Index

A

= ratio LD50 :ED50 or TD50 :ED50
 Higher therapeutic index, safer drug considered
 Doesn’t take slope of concentration-response curve into effect
* Ex: two drugs A, B with same TD and given at ED90¬ – induce significantly different prevalence of SE
* TD not a useful measure of drug’s clinical safety

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97
Q

Application of Therapeutic Index

A

A: ED90 significantly different than TD90 – most of population will benefit from A without experiencing significant SE.

B: ED90 not very different than TD90 – large part of population encounter toxic SEs

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98
Q

Pharmacokinetcs

A

body initiates its actions on drug (absorption, distribution, metabolism, and elimination (ADME)

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99
Q

Zero Order PK

A

process occurs at constant rate

Change of drug concentration in body fluid (plasma, urine) occurs at constant rate irrespective of concentration of drug present in body fluid

STRAIGHT LINE: y=mx+b

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100
Q

What is true about the general metabolism of drugs and rate at which reactions can occur?

A

o Most occur as saturable processes (Michaelis-Menten kinetics): speed at which process occurs has upper limit that can be reached

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101
Q

Pharmacodynamics

A

Drug initiates its action on body (D is for drug)
o Interaction of free drug with receptor –> effect response
 Effect response = directly proportional to ratio of R drug concentration to total R concentration

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102
Q

Single Response Systems

A

Where maximal response is measured, effect response measured approaches an asymptote
 Effect response = Max achievable response*concentration/(EC50 + [drug])

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103
Q

Tachyphylaxis

A

o Sometimes relationship btw [drug], effect response reflects changes in sensitivity of signaling pathway to presence of drug
 Ex: R tachyphylaxis, other unknown processes
 Better representation by equation using hill coefficient, modifies steepness of effect response curve

104
Q

Free Hormone Hypothesis

A

hormone (or drug) present in protein-bound, unbound (or free) forms in equilibrium

Activity of drug or hormone at its site of action proportional to concentration of free drug or free hormone in plasma
* Irrespective of total drug or hormone concentration
* Free drugs can diffuse readily to sites of action
 Allows linkage of plasma concentration to drug’s effect response
 Plasma PK: degree, extent, duration of drug effect

105
Q

Half-Life Elimination

A
  • Time interval needed for plasma concentration to be reduced by 50%
106
Q

Half Life Elimination with Zero Order Kinetics

A

half-life= function of plasma [ ] of drug at beginning of time interval
–Parameter not constant

107
Q

Half Life Elimination with First Order Kinetics

A

elimination half-lives fixed at constant rate per unit time

108
Q

Rate of Metabolism Affected by:

A

species, age, gender, BW, dz states (esp renal, hepatic dz), drug interactions

109
Q

Drug Elimination and Steady State

A

~4-5 half-lives must pass before change in dose achieves new steady state plasma concentration (at about 97% of total)

Therefore, 4-5 half-lives must pass after cessation of administration before effectively all of drug is eliminated

110
Q

Loading dose

A
  • Loading dose= C(desired)Vc
    o Apparent volume of central compartment (Vc) usually used for calculating loading doses for rapidly acting or toxic drugs, ex: induction agents
     Vdss is used for CRI
111
Q

Mass of Drug in Body

A

Mass of drug in body proportional to concentration measured in sample space (often plasma) at any time.

Expressed as: XB=C*Vd
–XB= mass of drug in body
–C=concentration
–Vd= Proportionally constant, apparent volume of distribution
* Apparent bc does not represent any particular physiologic or anatomic space

112
Q

Vc

A

Volume of circulation, aka volume of central compartment

113
Q

Vdss

A

vol of distribution at steady state, sum of all volumes (central and peripheral)

114
Q

Factors that Affect volume of distribution

A

o State of hydration
o Age and gender
o Body weight
o Body composition
 Fat, muscle, water ratios
o Protein content of serum especially for protein bound drugs
o Plasma expanders such as lipids after meal
o Drug interactions

115
Q

Total Body Clearance

A

o Volume of blood from which drug completely removed per unit of time
 Volume per unit time, often normalized by body weight (ex: mL/min/kg)
o Measure of efficiency of drug elimination, often directly compared or contrasted with CO in species under examination

Sum of clearance achieved by all mechanisms:
hepatic+renal+other = total

116
Q

Extraction Ratio

A

fraction of drug removed from blood on each pass of blood through liver

ER = (Ca-Cv)/Ca where Hepatic clearance is then equal to flow through the liver (Q)*ER

117
Q

Hepatic Clearance

A

Rate of blood flow through liver * (drug concentration in arterial blood – drug concentration in venous blood)/drug concentration in artieral blood

Cl(H) = [Q(Ca-Cv)]/Ca

118
Q

Liver and Clearance

A

Most body systems, processes = saturable: liver in each individual has maximum capacity for removing drug from blood when no blood flow constrictions

Capacity for drug elimination by combination of biotransformation, excretion by bile = function of liver mass, amount/activity of enzymes of drug metabolism that present in individuals hepatocytes

119
Q

Intrinsic Clearance

A

Maximum capacity for drug removal from blood = intrinsic ability of liver to remove drug, innate capacity of liver to clear drug

120
Q

When Intrinsic Clearance «< HBF…

A

hepatic clearance = intrinsic clearance (ClH = ClI)

Limiting factor (rate limiting step) of clearance NOT BF dependent, dependent on intrinsic clearance

Ex:
*Variations in plasma protein binding of drug can significantly alter rate of excretion
*Induction of hepatic enzymes: large effect on elimination rate

121
Q

When Intrinsic Clearance&raquo_space;> HBF…

A

hepatic clearance = rate of HBF (ClH¬ = QH)

In this case, alterations in HBF profoundly influence rate of hepatic clearance

Dependent on: CO, normal structure/function of hepatic BV

122
Q

Renal Clearance

A

Relationship between rate of change of amount of drug in urine, plasma [drug]

123
Q

Clearance of drug from plasma by kidneys

A

achieved by summation of renal filtration, active renal tubular secretion of drug into the urinary ultrafiltrate, diminished by any tubular resorption of drug

ClR= (RF/C) + (RS/C) + (RR/C)
* RF= rate of renal filtration
* RS= rate of renal secretion
* RR= rate of renal resorption
C = concentration

124
Q

What is renal filtration a function of?

A

function of GFR, plasma concentration of unbound drug

125
Q

If fraction of unbound drug is one…

A

renal clearance = GFR

126
Q

If renal clearance > GFR*unbound fraction…

A

Renal Secretion must be occurring

127
Q

If renal clearance < GFR*unbound fraction…

A

Renal Resorption must be occurring

128
Q

Absorption

A

Drugs formulated for standard delivery methods absorbed by concentration-dependent processes that are linear (first-order processes)

129
Q

When drugs administered by routes other than IV

A

rate of absorption across membranes (barriers to entry) proportional to difference in concentration across membrane, area of membrane, permeability of membrane to drug
o Manipulate surface area: admin in aliquots at multiple sites

130
Q

Are CRIs and transdermal patches zero or first order kinetics?

A

administration of drug constant per unit time (zero order)

131
Q

Other Challenges with Drug Absorption

A

Concentration of drug in formulation determines steepness of diffusion gradient for drug absorption

Concentration of drug diluted prior to injection or post injection DT H2O movement (osmotic gradient)
o Lymph/blood flow, CO, factors controlling local BF alter concentration gradient
o Proximity of administration to impermeable boundaries (fascial planes, fat) alter rate of drug absorption
 Controllable by appropriate injection site choice
o Unexpected inefficiency, toxicity with high-potency drugs bc of changes in rate, extent of drug absorption

132
Q

Bioavailability

A

–Fraction of drug that finds way into systemic circulation
–NOT equal to fraction of dose absorbed as some is removed via metabolism
–Also affected by biotransformation

133
Q

Three components that make up bioavailability?

A
  1. Peak plasma concentration
  2. Time to reach plasma concentration
  3. Area under the curve
134
Q

Bioavailability of given route…

A

calculated by comparing the total drug exposure of the dose with that achieved when the same dose is given IV

135
Q

Principle of Superimposition

A

response to any combination of inputs must equal sum of responses when input separately

If it obeys this, considered linear pharmacokinetic model
 Input = dose, output = sample’s drug concentration
 Drugs that display first order kinetics

Predictable plasma concentrations after changes in drug where 2x dose = 2x plasma concentration

136
Q

Stochastic System

A

each molecule of drug introduced to body, moves through system independently of all molecules of same drug introduced to system

Example: in horses, primary metabolite of cute (oxyphenobutazone) interferes with parent moiety’s metabolism - non-stochastic system

137
Q

Importance about Drug Assays

A

Capable of accurately measuring concentrations at least 10x lower than minimum effective concentrations

138
Q

Experiments in PK

A

Design determined by elimination rate constant/elimination HL

Not possible to predict HL of drug accurately unless several samples collected over 2-3 HL
o If pilot data on species unavailable, allometric scaling from other species

139
Q

Common Ax drugs and PKs

A

Anesthetic drugs = lipophilic, increases need for biotransformation (saturable process)
 Also affect CO, regional tissue blood flow

Common that ax drugs have non-linear PK
* Ability to extrapolate results to novel clinical situations requires demonstration whether drug behaves with linear PK
* Eg perform experiment with multiple doses

Formulation admin by route other than IV: attention to effect of formula needed  access to PK of active moiety after IV inj

140
Q

Naive Data Pooled Set

A

Least desirable

All data from all animals pulled together for data analysis

Approach loses opportunity to develop understanding of differences btw animals within population or variance within populations

141
Q

When use naive pooled data set?

A

necessary when each individual only able to be sampled 1-2x
* Sample vol large vs circulating blood vol
* Act of sampling likely to alter PK at subsequent time points
* Species difficult to evaluate, capture, restrain

142
Q

Standard Two Stage Approach

A

Most common, similar individuals from target population with each individual sampled at same time points, on multiple occasions after dosing

Following washout period (>5 half lives): dosed again, sampled to evaluate either dose proportionality or effect of chosen manipulation on drug’s PK

Linear mixed models, factors for dose, sequence, animal, sequence + animal interactions, etc

143
Q

PK-PD Study

A

Embellishment of two stage approach where data collected to measure drug concentration +/- drug effects

OBJECTIVE MEASURE

Surrogate: biological markers (intermediate enzyme activities) or second messenger concentration

144
Q

MOA PK-PD Studies

A

Data from each animal analyzed independently, combined to generate estimates for population variables

evaluate correlation between dose and effect, predict ideal doses better, to gain better understanding of drug’s effect on pathophysiological processes

145
Q

Disadvantage of PK-PD Studies

A

Need large number of sample time points per animal to estimate larger number of variables accurately

146
Q

POP PK Studies

A

Evaluate PK of drug in clinical cases
 Small # samples (usually 2-5) taken from each case at times convenient for case
 Alternatively small # cases sampled frequently to describe PK adequately

147
Q

Goal of POP PK Studies

A

 Need suitable structural model for PK of drug (previous study)

 Allows identification of factors within clinical population that might markedly alter PK, alter efficacy/toxicity of drug

148
Q

Single Compartment Model

A

After IV bolus, rapid distribution to one compartment

149
Q

Two Compartment Model

A

IV bolus: rapid distribution then drug moves out of central compartment, into other compartment (body compartment)

150
Q

Three Compartment Model

A

After IV bolus, plasma concentration peaks –> exponential decline, 3 distinct phases
* Initial rapid drop
* Rate of decrease then slows
* Steady, predictable decrease

Explained by movement of drug between a central (V1), 2 peripheral compartments (V2 & V3)

151
Q

V1

A

central compartment, equilibrates with effect site (brain), from which drug removed from body (e.g. liver metabolism, renal excretion)

152
Q

V2, V3

A

V2, V3:“reservoirs” where drug moves from V1, no connection with effect site
* V2 (mostly muscle) better perfused than V3 (fat, bone), smaller capacity to absorb drugs vs V3

153
Q

Why Use Compartment Models

A

Purpose: evaluate data so as to derive estimates of PK variables, estimates may then be used to make predictions of outcome

Plot time and concentration on semi logarithmic axes, check whether data can be described by a single straight line
 if so, one compartment model
 If not, check has a two compartment model

154
Q

Mathematical Models for PK Model Fitting

A
  1. Monte Carlo
  2. Simplex
  3. Gauss-Newton, Marquadt
155
Q

Monte Carlo

A

Directly compare minimizing criterion using random iterations to vary parameter estimates
* Robust to poor initial parameter estimates
* Slow, computer intensive
* Care should be taken not to restrict number of iterations greatly

156
Q

Simplex

A

Directly compare minimizing criterion using simple stepwise approach
* Robust to poor initial parameter estimates
* Slow, computer intensive
* Start with large step sizes, gradually reduce step size through several runs of minimization process to avoid finding false solutions
* Usually starting point

157
Q

Gauss-Newton and Marquardt

A

Gradient methods, use either first or second order derivatives of minimizing criterions
* Require good initial estimates in order to proceed
* High reliability of finding best solution

158
Q

Non-Compartment Models

A

o Applicable to both stochastic, non stochastic PK – allows calculation of volumes of distributions, clearance, mean time parameters
o Mean time parameters: average total time spent by molecules in kinetic space after introduction to that space

159
Q

Homogenous Kinetic Space

A

analogous to single compartment

160
Q

Heterogenous Kinetic Space

A

grouping of multiple independent compartments of complex compartment model

161
Q

Mathematics for Non-Compartmental Modeling

A

–Simpler
–Area under concentration vs time curve from time of introduction of dose (t=0) to infinity (AUC)
–Area under first moment of concentration vs time curve from time of dosing until infinity (AUMC)
–Linear or log linear trapezoid models

162
Q

What is the most common error assoc with non compartmental models?

A

failing to define PK curve for adequate time period

Large portion of total area under portion of curve that after last quantified time point ie portion of curve that is extrapolated

If proportion of total area that was extrapolated is greater than 20%, that experimental design was inadequate for approach to data analysis

163
Q

Physiologically based PK models (PBPK):

A

allow for individual organ, tissue blood flow as proportion of cardiac output
 Allow determination of extraction ratio for each organ of interest, drug clearance achieved by that organ, estimation of organ/tissue drug concentration
 Allow understanding of effect of drug recirculation on arterial, venous drug concentrations

164
Q

Delayed Absorption or Distribution

A

lag btw dosing and changes in concentrations or between appearance of drug in sample space and distribution to site of action
 NSAIDS

165
Q

Constant Rate Therapy

A

maintenance of specific plasma concentration, consequent effect desired
–Usually IV, also patches, slow release injectable agents

Requires constant rate of absorption

166
Q

Intermittent Bolus Injection

A

plasma drug concentration reaches a peak, decreases as re-distribution, clearance occurs
o Loading dose, effect maintained by repeat injections
o Oscillations: inconsistent levels in targeted effect
o Result in administration of large total drug dose, slower/longer recovery from effect

167
Q

CRI

A

Eliminates peaks, troughs
o Better quality of effect, decrease in total drug dose delivered

168
Q

CRI - Bags

A

Gravity Dependent

Speed of infusion depends on:
–Diameter/length of connecting tube
–size of drops
–size of cannula
–viscosity of agent
–height of fluid
–venous pressure of patient
–As bag empties, infusion rate decreases - needs readjusting

169
Q

Syringe Drivers for CRIs

A

If higher than heart: siphoning may occur DT weight of liquid –> larger drug volume administered than programmed
o Resolved by protection against syringe plunger moving faster than motor drive

If lower than vascular port: less agent infused than programmed DT back pressure from venous bed, weight of liquid

170
Q

Other Risks with Syringe Drivers

A
  • Infusion sets should incorporate one way valve system
  • If syringe driver positioned vertically, outlet placed downwards - avoid infusing bubbles formed by gas coming out of solution
171
Q

Rate Controlled Infusions (Non-PK-Dependent CRIs)

A

Use of loading dose then adjustment of infusion rate based on patient needs

Smoother ax, less drug used overall, requires frequent fine tuning adjustments

172
Q

Problem with Standard CRIs

A

 Beginning = too low of a plasma concentration
 Over time mass accumulates; prolonged –> undesired effects

173
Q

Pharmacokinetic-dependent infusion systems

A

manually controlled using RCI or stepped infusion, or electronically controlled with computer adjusting speed of infusion: Target Controlled Infusion (TCI)

174
Q

Limitations with TCI

A

 More reliant technique on preexisting PK data, more achieved plasma drug concentration depends on quality, relevance of PK model used/similarities of patient and experimental subjects

 Deviations from conditions under which PK data obtained may result in unexpected plasma concentrations

175
Q

Zero Order Kinetics

A

Elimination rate INDEPENDENT of drug concentration

Observed when elimination mechanisms saturated ex elimination by particular enzyme of which there are only small quantities

Linear on linear scale, curved outward on log scale

176
Q

TCI MOA

A

Drug infused must equal amount of drug eliminated = steady-state plasma drug concentration (CSS)

 First order elimination: mass of drug eliminated per unit time depends on plasma drug concentration at steady state of agent (Css), clearance (Cl)

177
Q

What does a maintenance infusion rate for TCI depend on?

A
  1. Target plasma concentration at steady state
  2. Drug’s total body clearance
178
Q

Elimination HL Parameters

A

~4-5 times elimination half-life for plasma drug concentration to approach its accumulation plateau (same as non-PK dependent CRI)

–Loading Dose

179
Q

Loading Dose

A

cause plateau to be reached sooner
 Calculating LD: dose required to fill central compartment (VC) or calculating dose to fill total distribution volume at steady state (VSS)
 VC: plasma concentration will be low, VSS: Overshoot

180
Q

Stepped Infusions

A

Series of CRIs aimed at reaching targeted plasma drug concentrations as rapidly as possible while neither over or undershooting

Fast initial infusion to fill central compartment, followed by maintenance infusion determined by desired target or central compartment drug concentrations, drug’s rate of clearance

Very rigid, difficult to adapt to clinical situations

181
Q

BET

A

Bolus - Elimination - Transfer
Precursor to TCI system

182
Q

B of BET

A

Bolus
Loading Dose

183
Q

E of BET

A

Elimination
Steady state rate of infusion according to drug’s elimination

184
Q

T of BET

A

Transfer
Exponentially decreasing rate to match redistribution of drug from central compartment to peripheral sites

185
Q

How BET Precursor to TCI

A

computer programed with set of PK parameters for species/drug, algorithm calculates infusion rate necessary to achieve target concentrations

Accuracy dependent on PK variables used to program device
* Calculated of percentage prediction error (PE%) as difference btw measured, predicted values

186
Q

Percentage Prediction Error (%)

A

= (measured concentration – predicted concentration)/predicted concentration x 100%

187
Q

MDPE%

A

mean prediction error (MDPE%)

Using values of PE% derived at each measurement point, number of induces of performance in individual subject calculated

Measure of bias to indicate whether measured concentrations systemically above or below targeted values

Measures inaccuracy, typical size of difference btw measured and targeted concentrations

188
Q

Wobble

A

measures total intra individual variability in performance error

189
Q

Divergence

A

systematic time-related changes in measured concentrations away from or towards the targeted concentration

190
Q

Positive Value

A

widening of gap between predicted, measured value

191
Q

Negative Value

A

Measured and predicted values converging over time

192
Q

Context Sensitive Half Time

A

time from end of infusion necessary for patients plasma’s drug concentration to decrease by 50%

193
Q

CSHL and Short Term Infusions

A

CSHL depends on redistribution

194
Q

Clinical Efficacy of Bolus Dose

A

clinical effect mostly dependent on redistribution of drug from brain to other tissues

195
Q

CSHL with Long Term Infusions

A

peripheral compartments saturated, CSHL approaches true elimination half-life of drug

196
Q

CSHL with Modern Length Infusions

A

CSHL will depend on drug’s distribution, elimination

197
Q

Decrement Time

A

time in which decrease in concentration modeled specifically for compartment of effect site

Allows for clinician to better predict a stop infusion time for end of surgery (percentage), duration of infusion (context), context-sensitive effect site decrement time requires for necessary decrease

198
Q

Drug Interactions - three types

A
  1. Physiochemical
  2. PK
  3. PD
199
Q

Physiochemical

A

o Two incompatible drugs mixed together in vitro

o Interactions: changes in physical stability of complex formulations, changes in solubility with precipitation, changes in chemical stability of active or excipient ingredients, absorption onto delivery device surfaces, chelation or chemical reactions (reduction or oxidation)

200
Q

PK Interactions

A

Interactions during different PK phases of A, D, E or biotransformation

201
Q

Example of a Beneficial PK Interaction

A

epinephrine + Lidocaine to prolong its effect / absorption locally)

202
Q

PK Interactions: Distribution

A

Drug interactions can change distribution (but not clinically relevant in anesthesia)

203
Q

PK Interactions: Alterations in Plasma Binding

A

competition btw drugs for same binding site thought to be important

Displacement of drug from protein binding does not markedly alter unbound fraction in circulation, affects elimination rate more than efficacy

204
Q

Drug-drug interactions during biotransformation

A

more frequent

Clinical significant: depends on hepatic intrinsic clearance for each drug

Extent of genetic polymorphism among breeds, individuals of same species
* Ex: MDR1 frame shift mutation

205
Q

Elimination and PK Drug Interactions

A

Inhibition of clearance: results in increase in drug concentration

Increased clearance: decreased in drug blood concentration, lack of efficacy +/- therapeutic failure

Inhibition, induction of drug clearance can affect CYPs (phase I metabolism) or transporters (Phase III metabolism)

206
Q

Effect of Increased CO during TCI/CRI with drugs with high intrinsic hepatic clearance

A

decreases in plasma drug concentration, consequent changes to efficacy
 Vice versa
 Alteration in hepatic clearance related to change in CO described with propofol in humans, sheep, pigs

207
Q

PD Drug Interactions

A

Result in modification of response of body to one or more concomitantly administered drugs
 DT alterations of R sensitivity or affinity to one agent by other

Example: MAC sparing drug

208
Q

How Assess PD Interactions

A
  1. Isobolographic Analysis
  2. Response Surface Modeling Techniques
209
Q

Isobolographic Analysis

A

Evaluate effects of different [ ] of two agents on specific effect (ex loss of consciousness)

Different dosing pair combinations resulting in same effects evaluated

Isobole constructed by drawing line through “iso-effective” combinations

210
Q

Isobolographic Analysis: line of additivity or additive interactions

A

straight line through btw two [ ]s for each single agent associated with same effect

–Synergism: concave, up shaped isotope
–Infra-additivity: concave-down isotope

211
Q

Downside of Isobolographic Analysis

A

Only 2 dimensional, information only on specific level eg EC50

212
Q

Response Surface Analysis

A

More complete set of effect levels (EC01-EC99)

3D graphs, incorporates all available isoboles for different levels of effect

Each single combination of two drugs: point on surface, height = drug effect of interest

213
Q

ADR/ADEs

A

ADR (adverse drug reactions), adverse drug events (ADE): describe events that include undesired effects and inefficacy, relative to expected effects after drug administration

214
Q

Examples of ADR Categories

A

dose-related, non-dose related, dose- and time-related, time-related, withdrawal, unexpected inefficacy

215
Q

Tachyphylaxis of Tolerance

A
  • Drugs that induce physiological adaptation, R downregulation/tachyphylaxis, enzyme induction or inhibition can result in time-related undesired effects
    o Direct effects or be caused by drug interactions
    o Developing tolerance: onset of inefficacy – clenbuterol, opiate analgesics
216
Q

In what group of drug are ADEs most commonly reported?

A

NSAIDS

217
Q

Drug Metabolism

A

Two phases: phase I, II

218
Q

Xenobiotic Drug Metabolism

A

metabolized by either or both phases depending on physiochemical properties of drug, species of animal

219
Q

Phase I Biotransformation

A

Goal: convert fat-soluble (lipophilic) compounds into:
o Water-soluble (hydrophilic) compounds ready for immediate renal clearance
o Add chemically reactive sites to relatively chemically inert molecule for further biotransformation

220
Q

Secondary Biotransformation

A

further Phase I interactions or conjugation reactions

221
Q

Examples of Phase I Reaction

A

Oxidation - CYP, others
Reduction
Hydrolysis
Hydration
Isomerization
Ring-Crystalization

222
Q

Phase II

A

Conjugation reactions attach exogenous compound covalently to substrate which increases molecular weight, water solubility

223
Q

Phase III

A

needs further transport across biological membranes, recently labeled as Phase III

224
Q

Phase I Biotransformation

A

Majority performed by cytochrome p450 isoenzymes (CYPs), localized in liver

on endoplasmic reticulum of metabolically active cells
o Responsible for oxidation, reduction, hydrolysis, hydration reactions
 Prepare xenobiotics for Phase II conjugation)
o CYPs: hemoproteins (spectral absorbance 450 nm when reduced, complexed with CO)

225
Q

Naming of CYP Proteins

A

 Families represented by Arabic number
 Subfamilies: capital letter
 Final Arabic number= individual enzymes

226
Q

CYP2B11

A

: propofol hydroxylation, breed differences in propofol metabolism

Also contributes to alfax, barbiturate metabolism

227
Q

CYP3A

A

main contributor to medetomidine metabolism

228
Q

Other Important CYP in Dogs

A
  • Phenobarbital increases activity of CYP2B11, 2C21, 3A26
  • Rifampin induces CYP 3A26
  • Omeprazole induces CYP 1A2
229
Q

Enzyme Induction

A

–Slow process: days to weeks
– Effect on drug concentration can alter treatment outcomes
–Clinical relevance mostly confined to drugs with low intrinsic hepatic clearance
–Process usually reversible

230
Q

CYP Inhibition

A
  1. Competitive
  2. Non-competitive
  3. Uncompetitive
  4. Mechanism-Based
231
Q

Examples of Drugs with Inhibitory CYP Activity

A

Propofol - rats, hamsters
Medetomidine - dogs, rats, fish
Dexmed - dogs, rats
Atipamezole - dogs

232
Q

CYP Inhibition - Important Considerations

A

 Inhibition of biotransformation usually reversible
 Occasionally irreversible, permanent enzyme activity loss until new enzymes synthesized
 CYP inhibition usually immediate response (unlike induction)

233
Q

Clinical Consequences of Inhibited CYP

A

higher plasma drug concentrations +/- prolonged elimination HL
 Increased risk of accumulation, toxic effects

234
Q

Phase II MOA

A

Mechanisms: glucuronidation, sulfation, methylation, acetylation, amino acid conjugation, glutathione conjugation, fatty acid conjugation
 Glucuronidation: most important form
* Occurs with alcohols, phenols, hydroxylamines, carboxylic acids, etc

235
Q

Which is the most important form of Phase II reactions

A

Glucuronidation

236
Q

Glutathione

A

protective compound
 Removal of potentially toxic electrophilic compounds
 Epoxides, haloalkanes, nitroalkanes, alkenes, aromatic halo/nitro compounds

237
Q

Sulfation

A

major metabolic pathway for phenols

238
Q

Enzymes that Facilitate Conjugation Reactions

A

sulfotransferases (SULT), UDP-glucuronosyltransferases (UGT), glutathione S transferase (GST)

239
Q

Phase III Biotransformation

A

–Transport of metabolites via transporters in intestine, liver, kidney, brain
–Transmembrane Transporters

240
Q

Examples of Transmembrane Transporters

A

P-glycoprotein (P-gp)
organic anion-transporting polypeptide 2(OATP2)
multidrug resistance-associated protein (MRP)

241
Q

ABC Transporters

A

ATP-binding casette transporters

Multidrug resistance Assoc protein, P-glycoprotein

242
Q

ABC Transports

A
  • Utilize energy from ATP to transport substrate across the cell membrane
243
Q

ABC transporters Locations - liver

A

canicular membrane –> biliary excretion of both parent drugs, metabolites; transporters involved in said excretion
* Also sinusoidal membrane, drug uptake from blood to hepatocytes

244
Q

ABC transporters Locations - kidney

A

organic anion, cation transport systems found on brush border, basolateral membranes of tubular epithelial cells = responsible excretion of drugs into urine

245
Q

Isomers

A

Drugs often carbon based entities, multiples structural molecular forms:

246
Q

Constitutional Isomers

A

= same number, type of atoms, connectivity btw atoms differs (ex: propane vs cyclopropane)
 Pose little practical clinical problem

247
Q

Stereoisomers

A

occur DT inflexibility of carbon-carbon double bonds (cis-trans isomers) or carbon molecule may have four different covalently bonded moieties, creates one or more chirally active centers (enantiomers, diastereomers)

248
Q

R-S Naming System

A

Orientation of molecule in space, reading direction of descending atomic mass
o Clockwise R: R for rectus, straight
o Anticlockwise S, ex S-ketamine = active isomer: S for sinister, left

249
Q

D-L Naming System

A

polarized light rotates to right when passed through solution of an enantiomer  dextrorotatory (+) isomer, image = levorotatory (-) isomer

250
Q

Cis-Trans Isomers

A

differences in affinity for drug R or metabolizing enzymes
 Products rarely have more than minor contamination of less active isomer

251
Q

Chirally Active Stereoisomers

A

pose a major consideration for clinical pharmacology
o Two types of chiral stereoisomers: enantiomers and diastereomers

252
Q

What are the two types of chiral stereoisomers?

A
  1. Enantiomers
  2. Diastereomers
253
Q

Racemic Mixtures

A

Products with both enantiomers, diastereomers

254
Q

Diastereomers

A

No planar symmetry

255
Q

Enantiomers

A

chirally active stereoisomers with planar symmetry, one form = mirror image of other
* Molecule with two active chiral centers = possibility of four isomers
o Two of possible pairings = symmetry, are stereoisomers but the other four pairings do not have planar symmetry

Boards: Pharmacology (9 decks)

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