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pharmacology and therapeutics Flashcards

1
Q

opium

A

an extract of the juice of the oriental poppy

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2
Q

opiate

A

derived from the opium poppy

morphine like structure

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3
Q

opioid

A

a drug with a morphine like action

act on opioid receptors

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4
Q

what do all opioids act on

A

opioid receptors

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5
Q

examoles of morphine analogues

A

codeine

diamorphine

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6
Q

synthetic opiods that are not derived from morphine structure examples

A

fentanyl

methadone

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7
Q

three types of opioid receptors

A

mu
kappa
delta

all three are GPCR

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8
Q

what is the g protein that all opioid receptors (GPCR) all couoled to. and what mechanisms does this bring

A

Gi proteins
open K+ channels\clode ca2+ channels
cause hyperpolarization of neurones and reduce neurotransmitter release\

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9
Q

analesic effect of mu receptors. where it acts

A

periphery
spinal cord
brain

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10
Q

analgesic effects if delta receptors. where it actsq

A

mainly peripheral

increased expressions in inflammation

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11
Q

analgesic effects of kappa receptors. where it acts

A

spinal

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12
Q

opioid and analgesia

A

effective in most acute and chronic pain

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13
Q

opioid and euphoria

A

feeling of well bring and reduced anxiety

mainly mu mediated

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14
Q

opioid and respiratory depression

A

decreased sensitivity of respeiratory centre (medulla) to pCO2

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15
Q

opioid and cough suppression

A

poor correlation with respiratory depressive actions

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16
Q

opioid peripheral pharmacodynamics

A

inhibition of GI tone and motility

histamine release from mast cells

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17
Q

opioids and inhibition of Gi tone and motility

A

cause constipation

slow drug absorption

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18
Q

opioids and histmaine relase from mast cells

A

opioid receptor independent

therefore cause itching, urticarial
possibly hypotension

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19
Q

endogenous opioid peptides

A

endorphins

enkephalins

dynorphins

endomorphins

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20
Q

endorphins

A

widely distributed in brain

mu receptor

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21
Q

enkephalins

A

widely distributed in the cns and immune cells

mu and delta receotor agonists

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22
Q

dynorphins

A

kappa recetors

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23
Q

three major effects of nsaids

A

anti inflammatory
analgesic
antipyretic

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24
Q

moa of nsaids

A

inhibit cox

prevent the formation of prostagladins and thromboxane from arachinodic acidq

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25
Q

PGH2

A

postagkadin h2

precursor for all prostanoids

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26
Q

prostanoid action. PGE2

A

PGE2 produced in abundance in inflammation.
EP receptors cause sensitisation of 1ary afferents.

PGs enhance the function of :
Bradykinin receptors
TRPV1 channels
P2X receptors

PGE2 produced in abundance in inflammation.
EP receptors cause sensitisation of 1ary afferents.

PGs enhance the function of :
Bradykinin receptors
TRPV1 channels
P2X receptors

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27
Q

issues of nsaids

A 
gastric ulceration
aspirin induced asthma
kidney impairment
IHD
cardiac failure
Peripheral arterial disease
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28
Q

trpv1

A

transceint receptor potential channels type vanilloid 1

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29
Q

what is trpv1 receptors activated by

A

inflammatory conditioins such as temperature, low pH

gste cations leading to depolarixation of sensory nerves and excitatory mediator release

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30
Q

trvp1 and burning sensation

A

agonsits rapidly desentistize the channel leading ti burning sensation

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31
Q

capsaicin

A

vannilloid stimulate the trpv1

agonist rapidly desensitize the channel leading to bunng sensation follwoed by analgesia

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32
Q

capsaicin

A

vannilloid stimulate the trpv1

agonist rapidly desensitize the channel leading to bunng sensation follwoed by analgesia

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33
Q

tramadol moa

A

Weak opioid agonist

metabolized to O desmethyltramdaol a much more potent mu opioid agonist

potentiation of descending monoamine control of pain transmission adds to opioid effect

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34
Q

how does tramadol have a multiple actions

A

weak mu opioid receptor agonist
5-ht releaser
noradernaline reuptake inhibitor

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35
Q

how does tapentadol have multiples actions

A

mu opiod receptor agonist

noradrenaline reuptake inhibitor

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36
Q

tapentadol compared with other drugs

A

provides analgesia comparable to other opiod analgesics such as oxycodone

more tolerable side effect profile

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37
Q

what is tapentadol a caution for

A

seizure prone patients

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38
Q

a2 adrenorece[ptor agonists

A

act on pre synaptic receptors to reduce neurotransmitter release

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39
Q

how adrenoreceptor agonists have analgesic effects

A

reduced excitatory transmitter release in the brain and spinal cord pain pathways but lack selectivity

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40
Q

neuropathic pain caused by

A

Damage to neural tissue

  • trauma, herpes infection, diabetes, chemotherapy,
  • Caused by peripheral and central sensitisation of pain pathways.
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41
Q

neuropathic pain accompanied by

A

Might be accompanied by allodynia (pain due to normally innocuous stimulus)

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42
Q

neuropathic pain treatment

A

difficult to treat

tricylic antidepressants and some antiepileptic drugs

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43
Q

tricyclic antidepressants

A

enhance monoaminergic pain control

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44
Q

antiepileptic drugs

A

pregabalin and gabapentin
1. Interact with VGCC, pre-synaptic NMDA receptors and enhance descending noradrenergic pain control.

  1. Anticonvulsant carbamazepine:
    Treats trigeminal neuralgia effectively
    Acts on VGSC
  2. Lamotrigine:
    Treats post stroke pain, HIV/AIDS-related neuropathy in patients with anti-retroviral therapy
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45
Q

Biological pathway mediating the conversion of phospholipid into prostanoids

A
  1. Prostaglandin synthesis pathway
    - Phospholipid cleaved to release arachidonic acid.
    - Catalysed by phospholipase A2 (PLA2)
    - Important enzyme for AA release= cPLA2
  2. PGH2 synthase converts AA into PGH2 via PGG2.
    COX generates PGG2 & peroxidase generates PGH2.
    -Bound to ER and nuclear envelope membrane.
  3. prostanoid synthesis by synthases
  4. transport
    - PGs synthesised inside the cell
    - PGs transported via ABC transporters
  5. prostanoids bind to prostanoid receptors
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46
Q

cPLA2 structual features. c2 domain

A

c2 domain-binds ca2+ (bridges to membranes)

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47
Q

cPLA2 structural features. catalytic domain

A

hydrolyses the phospholipid

ser228 asp 549

48
Q

CPla2 regulation acute regulation

A

ca2+ binds to the c2 doamin

facilitates binding and juxtaposes to phospholipid

49
Q

cPLA2 regulation. regulation of mrna expression

A

inflammatory mediators can upregulate cpla2 expressionn

glucocorticoid can down regulate cpla2 expression
-induce a repressor protein (s100 protein)

50
Q

cox structural features

A

haem group
-ring structure with central iron atom

exists as homodimers (two identical proteins)
dimerisation facilitated by EGF (Epidermal growth factor)

AA channel where AA enters

51
Q

cox isoforms

A

cox 1 and cox 2

52
Q

cox catalytic reaction

A
  1. Haem is needed to create initial Tyr 385 radical.
  2. AA binds so that the 13-pro(S) hydrogen sits just below Tyr-385.
  3. A tyrosyl radical derivative of Tyr-385 abstracts this hydrogen generating a pentadienyl radical that is trapped by oxygen at carbon-11.
  4. Production of the bicyclic peroxide.
  5. Abstraction of hydrogen to regenerate tyrosyl radical.

Similarities between COX-1

53
Q

wherre are cox 1 ad 2 localised in

A

nuclear envelopes and ER

54
Q

regulation of cox expressions

A

cox 1 expressed constitutuvely (all the time) in most tissues

cox 2 regulated at mRNA level

55
Q

regulation of cox 2 at mRNA level

A

expression induced by growth factrs and inflammatry mediators

antiinflammatory glucocorticoid suppress cox 2 expressions

56
Q

inflammatory mediators that influence the up expression of cox 2

A

IL-1
TNF-a
LPS

57
Q

specific prostanoid synthesis

A

tissue specifityu pf these synthases leads to different mix of prostanoids in different tissues

58
Q

cox 1 housekeeping role

A

gastric cytoprotection

  • PGs stimulate mucus and bicarbopnate secretion, decrease acid secretion
  • renal blood flow autoregulation
59
Q

cox 1 and platelet aggregations

A

enhanced by txa2-platelets

inhibitied by PGI2 (prostacyclin)-endothelail cells

60
Q

cox 1 and cox 2 in terms of size

A

cox 2 larger and more flexible substrate access channel

25% bigger binding site

61
Q

coxibs

A

tricyclic class of cox 2 inhibitors

62
Q

Voltage-gated sodium channels

A

Generate action potential.

e.g Nav 1.7, 1.8, 1.9
Nav 1.6, 1.7, 1.8

63
Q

VGSC:

Tetrodotoxin sensitive

A

Nav 1.1, 1.6, 1.7

Key role= Acute noxious mechanical senstion

Very important in clinical pain.

64
Q

VGSC:

Tetrodotoxin insensitive

A

Nav 1.8, 1.9

Nav 1.8= highly expressed in nociceptors (nociceptor specific)

Role in acute noxious mechanical sensation

Important in acute cold sensation.
Does not inactivate at low temp whereas all other Navs do.

Nav 1.5= expressed in heart

65
Q

Nav 1.7

A

Expressed in DRG, sympathetic ganglion neurons.

Amplifies the generator potentials in neurons expressing it, including nociceptors.

Threshold channels for firing action potentials.

Upregulated after inflammation.

-Remove Nav 1.7= nerves reduces inflammatory pain
=can still fell neuropathic pain (nerve injury)

66
Q

Nav 1.8

A

A sensory neuron-specific channel that is preferentially expressed in DGR, trigeminal ganglia.

Contributes most of the sodium current underlying the action potential upstroke in neurons that expresses it.

Role of Nav 1.8 gene=
Inflammatory and cold pain transmission.
Not in neuropathic pain.

Selective

67
Q

nav 1.9

A

sensory neuron-specific channel that is expressed in DRG sensory neurons and triminal ganglia

doesnt contribute tio uptstroke AP

help control the resting memrbane potential thereby regulate neuronal excitability

68
Q

Selective Nav1.8 blocker

A

Attenuates inflammatory and neuropathic pain

69
Q

VGSC domain structure

A

helix 1-4 voltage sensing domain
loop between D3 and D4- inactivation loop

helix 5-6-
-pore forming domain
(loop between these domains are the selectivity filter
)

70
Q

VG Sodium channel blocker

A

Sodium channels= exist in different activation and inactivation states.

Inhibitors
-Will target specific states= modulated receptor hypothesis

  • Block the closed state
  • Open state/inactivated state
  • Complex state have also been identified= can be selectively inhibited.
  • Subtle block of one of the ion channel states yields safe to use drugs
71
Q

Classification on the types of sodium channel blockers

A
  1. The selectivity for individual sodium channel isotypes or lack of selectivity
  2. The state of the channel they target
  3. A combination of the above two
72
Q

Non-specific sodium channel blockers used as analgesic

A
  1. Carbamazapine
    -anti convulsant
    -stabilises inactivation state of the channel
    -used in trigeminal neuralgia (neuropathic pain)
    Alleviate familial rectal pain syndrome in children.
  2. Phenytoin
    - anti convulsant
    - stabilises inactivated state
    - second choice drug for trigeminal neuralgia
  3. Lidocaine
    - local anaesthetic
    - inhibits open/inactivated channel
    - lidocaine patches/ plasters can be used for local pain.

Specific Nav 1.7

73
Q

chemical aspects of local anaesthetics

A

consists of hydrophobic part
aster or amide linker
basic amine side chain

most are tertiary amine

74
Q

what does the defree of ionisation of local anaesthetics depends on

A

a of the compound and pH fo the environment following HH equation

75
Q

local anaesthetic binding to Navs

A

act in their ionuic form however at first need to be unionised in order to penetrate through the membrane

binding siite at the inner side of the channel towards the cytoplasm

LA inhibit the closed channel via the hydrophobic way

76
Q

N type calcium channels

cav2.2

A

regulate transmitter release at nociceptor terminal

cav2.2 (pore forming subunit)

77
Q

N type calcium channels and neuropathic pain

A

removing cav2.2 is associated with analgesia

78
Q

calcium channel blockers

prialt

A

mviiA toxin inhibits neuropathic pain in animal models via intratheccal route

inhibits cabv2.2

79
Q

calcium channels. gabapentin and pregapentin

A

anti consulvants

dont block the channel pore itself but bind to alpha 2 delta subunit

affects the trafficking and recycling of calcium channel proteins
treat neuropathic pain

80
Q

if gabapentin and pregapentin dont block the channel pore itself how does it provide neuropathic pain relief

A

affect trafficking and memebrane recycling of calcium channel proteins

81
Q

TROX-1

A

small Cav2.2 blocker

binds better to the active and inactive form of the channel

82
Q

Capsaicin target

A

-Activates TRPV1 receptor on the nociceptor neuron.

83
Q

Capsaicin as an analgesic cream

A

-Continuous stimulus has a persistent effect.
-TRPV1 opening.
Significant amounts of calcium flow down its steep electrochemical gradient into nerve fibres.

-TRPV1 also expressed on intracellular organelles.
External capsaicin application can release calcium from the endoplasmic reticulum.

-At conc much higher than required to activate TRPV1, capsaicin can compete with ubiquinone to inhibit directly the electron chain transport.Capsaicin can dissipate mitochondrial transmembrane potential.

If TRPV1 expressing sensory nerve fibres exposed to high conc of capsaicin/ to lower conc in a continuous fashion, high levels of intracellular calcium and the associated enzymatic, cytoskeletal changes and the disruption of mitochondrial respiration lead to impaired local nociceptor function for extended periods.

84
Q

topical capsin and reversible loss of epidermal nerve fibres

A

-Loss of mitochondrial function due to calcium overload.

collapse of nerve endings to the depth where the capsaicin exposure was insufficient to irreversibly overwhelm mitochondrial function.
(leads to a reversible loss of epidermal nerve fibres)

85
Q

tolerance

A

The need to increase the dose to maintain a given effect.

Develops rapidly and compromises therapy with increasing risks of side effects.

86
Q

analgesic tolerancce of morphine

A

-Analgesic tolerance can be detected within 12-24 hrs of morphine administration.

87
Q

dependence

A

Consists of :

  • physical dependence.
  • flu like symptoms
  • strong psychological dependence (craving irrespective of adverse consequence)
  • makes it hard to withdraw opioid therapy even when faced with waning analgesia
88
Q

Cross-tolerance

A

One drug causes tolerance to a different drug.

  • Usually of the same pharmacological class.
  • Frequently exhibited by opioids but rarely complete.
  • Opioid rotation (useful, esp in cancer patients)
  • Bioequivalence tables and convertors are available.
89
Q

Mechanisms of opioid tolerance

A
  1. Pharmacokinetic= opioids undergo biotransformation

2. Pharmacodynamics= change in the way the drug acts

90
Q

Pharmacokinetic Mechanisms of opioid tolerance

A
  • reduction in amount of available drug at the receptor due to increased metabolism or increased efflux
  • opioids undergo significant biotransformation (phase 1= CYP P450, phase 2=UGTs)
  • Opioids are substrates of the efflux transporter P-glycoprotein
91
Q

Pharmacodynamic Mechanisms of opioid tolerance

A

-at the level of receptor signalling, repeated agonist stimulation could cause desensitization (loss of opioid receptor function) by:

  1. reduction in agonist affinity
  2. uncoupling from Gi/o proteins, reduced downstream signaling
  3. receptor internalisation and downregulation
92
Q

Mechanisms for opioid desensitization

A
  1. No evidence for changes in agonist affinity
  2. Inverse relationship between opioid agonist efficacy and tolerance
  3. Uncoupling from downstream signalling
  4. mu-opioid receptor internalization
  5. mu-opioid receptor downregulation
  6. Alterations in signalling mechanisms
  7. Upregulation of the expression of adenylyl cyclase in many areas of the CNS
  8. Opioid receptors can couple to both Gi and Gs proteins
93
Q

Mechanisms of opioid desensitization:

No evidence for changes in agonist affinity

A

Long term exposure to some agonists can desensitize opioid receptors with regard to post-receptor signalling (inhibition of adenylyl cyclase and coupling to potassium and calcium ion channels.)

94
Q

Mechanisms of opioid tolerance:

Inverse relationship between opioid agonist efficacy and tolerance

A
  • Lower efficacy agonists (e.g morphine)= cause more tolerance than higher efficacy agents (fentanyl)
  • High efficacy agonists have more receptor reserve. Don’t have to occupy all of the available receptors to produce a full response.
95
Q

Mechanisms of opioid desensitization:

Uncoupling from downstream signalling

A

Phosphorylation by several different protein kinases (e.g cAMP-dependent PKA, CaMKII, PKC, GPCR, MAPK)

96
Q

Mechanisms of opioid desensitization:

mu-opioid receptor internalization

A

Rapidly follows agonist activation, receptor phosphorylation and recruitment of Beta-arrestin protein.

Agonist dependent:

  • Higher with endogenous peptide ligands, etorphine and dihydroetorphine.
  • Morphine fails to cause much internalisation.
97
Q

Mechanisms of opioid desensitization:

mu-opioid receptor downregulation

A

Disappearance from all cell locations.
Proteolysis in lysosomes/proteasomes.

Agonist selective:

  • Marked reduction in receptor density with the high efficacy agonist etorphine.
  • Limited effect of morphine on receptor numbers.
98
Q

Mechanisms of opioid desensitization:

Alterations in signalling mechanisms

A

Best supported theory

99
Q

Mechanisms of opioid desensitization:

Upregulation of the expression of adenylyl cyclase in many areas of the CNS

A
  • Increased capacity for cAMP generation
  • Reduced sensitivity to inhibition via Galphai
  • Chronic morphine leads to increased expression of specific isoforms of AC that are stimulated by GBgamma subunits
100
Q

Mechanisms of opioid desensitization:

Opioid receptors can couple to both Gi and Gs proteins

A
  • Inhibitory and stimulatory effects mediated by Gi and Gs proteins have been demonstrated by most opioids.
  • A switch in signalling.
101
Q

Combating opioid tolerance

A
  1. Tapentadol (opioid agonist + noradrenaline uptake inhibitor) extends period of analgesia
  2. Evidence= glutamate receptor (NMDA) involvement in opioid tolerance
  3. NMDA receptor antagonists (MK801/ketamine) reduce opioid tolerance and dependence in animals
102
Q

Opioid dependence and withdrawal

A

-Withdrawal after chronic administration leads to severe influenza-like symptoms
(restlessness, yawning, pupillary dilatation, fever, sweating, piloerection, nausea, diarrhoea, insomnia)
(involuntary leg movement, goose pimples= cold turkey)

-Symptoms are maximal around 2 days.
Disappear in about 10 days.
Reversed by re-administration of opioid agonist.
Can be precipitated in tolerant patients by administration of opioid receptor antagonist (e.g naloxone), potentially fatal.

103
Q

Treating opioid overdose, dependence and withdrawal

A
  1. Acute opioid toxicity
    - Naloxone IV= danger of precipitating withdrawal in chronic user
  2. Withdrawal symptoms treated with multiple drugs
104
Q

Substitution therapy

A

-Substitution therapy reduces craving for heroin and other opioids.

105
Q

drugs used in subsitution therapy for opioids

A

=Methadone: MUR full agonist, longer half life than heroin
Taken by mouth under supervision
Does not produce IV heroin-like high
Danger of respiratory depression in overdose.

=Buprenorphine: MUR partial agonist
Ceiling effect reduces overdose danger.
Can precipitate withdrawal symptoms if other opioids (e.g heroin) in system, lofexidine then useful.

106
Q

3 stratedgies in drug discovery

A

phenotypic drug discovery

target based drug discovery

107
Q

[henotypic drug discovery

A

drug discovered on modulation of a cellular phenotype

108
Q

target based drug discovery is split into which 2 designs

A

ligand based drug design

strucrture based drug design

109
Q

target based drug discovery

A

drug debveloped ont the baseis of inhibiting a known target

110
Q

ligand absed drug design

A

prior knowledge of drug leads

generate a pharmacophore model

111
Q

strcture based drug design

A

indepth knowledge of the target from biophysical methods

112
Q

pros of target based approach

A

easierlead optimisaiton

speciifity

knwon mechanism

113
Q

cons of target based approach

A

difficult to define a good target

more difficult to find leads

114
Q

pros of phenotypic approach

A

gives molecules that work

multiple targets

115
Q

cons of phenotypic approach

A

unknown mechanism

activity depends on validity of biological assay

116
Q

choice of drug target

A

correct choice is vital for the success of a drug discovery project

117
Q

stratedgies to identify potential drug targets

A

target identification

drug discovery

pain (6 decks)

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