pharmacology and therapeutics Flashcards
opium
an extract of the juice of the oriental poppy
opiate
derived from the opium poppy
morphine like structure
opioid
a drug with a morphine like action
act on opioid receptors
what do all opioids act on
opioid receptors
examoles of morphine analogues
codeine
diamorphine
synthetic opiods that are not derived from morphine structure examples
fentanyl
methadone
three types of opioid receptors
mu
kappa
delta
all three are GPCR
what is the g protein that all opioid receptors (GPCR) all couoled to. and what mechanisms does this bring
Gi proteins
open K+ channels\clode ca2+ channels
cause hyperpolarization of neurones and reduce neurotransmitter release\
analesic effect of mu receptors. where it acts
periphery
spinal cord
brain
analgesic effects if delta receptors. where it actsq
mainly peripheral
increased expressions in inflammation
analgesic effects of kappa receptors. where it acts
spinal
opioid and analgesia
effective in most acute and chronic pain
opioid and euphoria
feeling of well bring and reduced anxiety
mainly mu mediated
opioid and respiratory depression
decreased sensitivity of respeiratory centre (medulla) to pCO2
opioid and cough suppression
poor correlation with respiratory depressive actions
opioid peripheral pharmacodynamics
inhibition of GI tone and motility
histamine release from mast cells
opioids and inhibition of Gi tone and motility
cause constipation
slow drug absorption
opioids and histmaine relase from mast cells
opioid receptor independent
therefore cause itching, urticarial
possibly hypotension
endogenous opioid peptides
endorphins
enkephalins
dynorphins
endomorphins
endorphins
widely distributed in brain
mu receptor
enkephalins
widely distributed in the cns and immune cells
mu and delta receotor agonists
dynorphins
kappa recetors
three major effects of nsaids
anti inflammatory
analgesic
antipyretic
moa of nsaids
inhibit cox
prevent the formation of prostagladins and thromboxane from arachinodic acidq
PGH2
postagkadin h2
precursor for all prostanoids
prostanoid action. PGE2
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
issues of nsaids
gastric ulceration aspirin induced asthma kidney impairment IHD cardiac failure Peripheral arterial disease
trpv1
transceint receptor potential channels type vanilloid 1
what is trpv1 receptors activated by
inflammatory conditioins such as temperature, low pH
gste cations leading to depolarixation of sensory nerves and excitatory mediator release
trvp1 and burning sensation
agonsits rapidly desentistize the channel leading ti burning sensation
capsaicin
vannilloid stimulate the trpv1
agonist rapidly desensitize the channel leading to bunng sensation follwoed by analgesia
capsaicin
vannilloid stimulate the trpv1
agonist rapidly desensitize the channel leading to bunng sensation follwoed by analgesia
tramadol moa
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
how does tramadol have a multiple actions
weak mu opioid receptor agonist
5-ht releaser
noradernaline reuptake inhibitor
how does tapentadol have multiples actions
mu opiod receptor agonist
noradrenaline reuptake inhibitor
tapentadol compared with other drugs
provides analgesia comparable to other opiod analgesics such as oxycodone
more tolerable side effect profile
what is tapentadol a caution for
seizure prone patients
a2 adrenorece[ptor agonists
act on pre synaptic receptors to reduce neurotransmitter release
how adrenoreceptor agonists have analgesic effects
reduced excitatory transmitter release in the brain and spinal cord pain pathways but lack selectivity
neuropathic pain caused by
Damage to neural tissue
- trauma, herpes infection, diabetes, chemotherapy,
- Caused by peripheral and central sensitisation of pain pathways.
neuropathic pain accompanied by
Might be accompanied by allodynia (pain due to normally innocuous stimulus)
neuropathic pain treatment
difficult to treat
tricylic antidepressants and some antiepileptic drugs
tricyclic antidepressants
enhance monoaminergic pain control
antiepileptic drugs
pregabalin and gabapentin
1. Interact with VGCC, pre-synaptic NMDA receptors and enhance descending noradrenergic pain control.
- Anticonvulsant carbamazepine:
Treats trigeminal neuralgia effectively
Acts on VGSC - Lamotrigine:
Treats post stroke pain, HIV/AIDS-related neuropathy in patients with anti-retroviral therapy
Biological pathway mediating the conversion of phospholipid into prostanoids
- Prostaglandin synthesis pathway
- Phospholipid cleaved to release arachidonic acid.
- Catalysed by phospholipase A2 (PLA2)
- Important enzyme for AA release= cPLA2 - PGH2 synthase converts AA into PGH2 via PGG2.
COX generates PGG2 & peroxidase generates PGH2.
-Bound to ER and nuclear envelope membrane. - prostanoid synthesis by synthases
- transport
- PGs synthesised inside the cell
- PGs transported via ABC transporters - prostanoids bind to prostanoid receptors
cPLA2 structual features. c2 domain
c2 domain-binds ca2+ (bridges to membranes)
cPLA2 structural features. catalytic domain
hydrolyses the phospholipid
ser228 asp 549
CPla2 regulation acute regulation
ca2+ binds to the c2 doamin
facilitates binding and juxtaposes to phospholipid
cPLA2 regulation. regulation of mrna expression
inflammatory mediators can upregulate cpla2 expressionn
glucocorticoid can down regulate cpla2 expression
-induce a repressor protein (s100 protein)
cox structural features
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
cox isoforms
cox 1 and cox 2
cox catalytic reaction
- Haem is needed to create initial Tyr 385 radical.
- AA binds so that the 13-pro(S) hydrogen sits just below Tyr-385.
- A tyrosyl radical derivative of Tyr-385 abstracts this hydrogen generating a pentadienyl radical that is trapped by oxygen at carbon-11.
- Production of the bicyclic peroxide.
- Abstraction of hydrogen to regenerate tyrosyl radical.
Similarities between COX-1
wherre are cox 1 ad 2 localised in
nuclear envelopes and ER
regulation of cox expressions
cox 1 expressed constitutuvely (all the time) in most tissues
cox 2 regulated at mRNA level
regulation of cox 2 at mRNA level
expression induced by growth factrs and inflammatry mediators
antiinflammatory glucocorticoid suppress cox 2 expressions
inflammatory mediators that influence the up expression of cox 2
IL-1
TNF-a
LPS
specific prostanoid synthesis
tissue specifityu pf these synthases leads to different mix of prostanoids in different tissues
cox 1 housekeeping role
gastric cytoprotection
- PGs stimulate mucus and bicarbopnate secretion, decrease acid secretion
- renal blood flow autoregulation
cox 1 and platelet aggregations
enhanced by txa2-platelets
inhibitied by PGI2 (prostacyclin)-endothelail cells
cox 1 and cox 2 in terms of size
cox 2 larger and more flexible substrate access channel
25% bigger binding site
coxibs
tricyclic class of cox 2 inhibitors
Voltage-gated sodium channels
Generate action potential.
e.g Nav 1.7, 1.8, 1.9
Nav 1.6, 1.7, 1.8
VGSC:
Tetrodotoxin sensitive
Nav 1.1, 1.6, 1.7
Key role= Acute noxious mechanical senstion
Very important in clinical pain.
VGSC:
Tetrodotoxin insensitive
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
Nav 1.7
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)
Nav 1.8
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
nav 1.9
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
Selective Nav1.8 blocker
Attenuates inflammatory and neuropathic pain
VGSC domain structure
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
)
VG Sodium channel blocker
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
Classification on the types of sodium channel blockers
- The selectivity for individual sodium channel isotypes or lack of selectivity
- The state of the channel they target
- A combination of the above two
Non-specific sodium channel blockers used as analgesic
- Carbamazapine
-anti convulsant
-stabilises inactivation state of the channel
-used in trigeminal neuralgia (neuropathic pain)
Alleviate familial rectal pain syndrome in children. - Phenytoin
- anti convulsant
- stabilises inactivated state
- second choice drug for trigeminal neuralgia - Lidocaine
- local anaesthetic
- inhibits open/inactivated channel
- lidocaine patches/ plasters can be used for local pain.
Specific Nav 1.7
chemical aspects of local anaesthetics
consists of hydrophobic part
aster or amide linker
basic amine side chain
most are tertiary amine
what does the defree of ionisation of local anaesthetics depends on
a of the compound and pH fo the environment following HH equation
local anaesthetic binding to Navs
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
N type calcium channels
cav2.2
regulate transmitter release at nociceptor terminal
cav2.2 (pore forming subunit)
N type calcium channels and neuropathic pain
removing cav2.2 is associated with analgesia
calcium channel blockers
prialt
mviiA toxin inhibits neuropathic pain in animal models via intratheccal route
inhibits cabv2.2
calcium channels. gabapentin and pregapentin
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
if gabapentin and pregapentin dont block the channel pore itself how does it provide neuropathic pain relief
affect trafficking and memebrane recycling of calcium channel proteins
TROX-1
small Cav2.2 blocker
binds better to the active and inactive form of the channel
Capsaicin target
-Activates TRPV1 receptor on the nociceptor neuron.
Capsaicin as an analgesic cream
-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.
topical capsin and reversible loss of epidermal nerve fibres
-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)
tolerance
The need to increase the dose to maintain a given effect.
Develops rapidly and compromises therapy with increasing risks of side effects.
analgesic tolerancce of morphine
-Analgesic tolerance can be detected within 12-24 hrs of morphine administration.
dependence
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
Cross-tolerance
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.
Mechanisms of opioid tolerance
- Pharmacokinetic= opioids undergo biotransformation
2. Pharmacodynamics= change in the way the drug acts
Pharmacokinetic Mechanisms of opioid tolerance
- 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
Pharmacodynamic Mechanisms of opioid tolerance
-at the level of receptor signalling, repeated agonist stimulation could cause desensitization (loss of opioid receptor function) by:
- reduction in agonist affinity
- uncoupling from Gi/o proteins, reduced downstream signaling
- receptor internalisation and downregulation
Mechanisms for opioid desensitization
- No evidence for changes in agonist affinity
- Inverse relationship between opioid agonist efficacy and tolerance
- Uncoupling from downstream signalling
- mu-opioid receptor internalization
- mu-opioid receptor downregulation
- Alterations in signalling mechanisms
- Upregulation of the expression of adenylyl cyclase in many areas of the CNS
- Opioid receptors can couple to both Gi and Gs proteins
Mechanisms of opioid desensitization:
No evidence for changes in agonist affinity
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.)
Mechanisms of opioid tolerance:
Inverse relationship between opioid agonist efficacy and tolerance
- 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.
Mechanisms of opioid desensitization:
Uncoupling from downstream signalling
Phosphorylation by several different protein kinases (e.g cAMP-dependent PKA, CaMKII, PKC, GPCR, MAPK)
Mechanisms of opioid desensitization:
mu-opioid receptor internalization
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.
Mechanisms of opioid desensitization:
mu-opioid receptor downregulation
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.
Mechanisms of opioid desensitization:
Alterations in signalling mechanisms
Best supported theory
Mechanisms of opioid desensitization:
Upregulation of the expression of adenylyl cyclase in many areas of the CNS
- 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
Mechanisms of opioid desensitization:
Opioid receptors can couple to both Gi and Gs proteins
- Inhibitory and stimulatory effects mediated by Gi and Gs proteins have been demonstrated by most opioids.
- A switch in signalling.
Combating opioid tolerance
- Tapentadol (opioid agonist + noradrenaline uptake inhibitor) extends period of analgesia
- Evidence= glutamate receptor (NMDA) involvement in opioid tolerance
- NMDA receptor antagonists (MK801/ketamine) reduce opioid tolerance and dependence in animals
Opioid dependence and withdrawal
-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.
Treating opioid overdose, dependence and withdrawal
- Acute opioid toxicity
- Naloxone IV= danger of precipitating withdrawal in chronic user - Withdrawal symptoms treated with multiple drugs
Substitution therapy
-Substitution therapy reduces craving for heroin and other opioids.
drugs used in subsitution therapy for opioids
=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.
3 stratedgies in drug discovery
phenotypic drug discovery
target based drug discovery
[henotypic drug discovery
drug discovered on modulation of a cellular phenotype
target based drug discovery is split into which 2 designs
ligand based drug design
strucrture based drug design
target based drug discovery
drug debveloped ont the baseis of inhibiting a known target
ligand absed drug design
prior knowledge of drug leads
generate a pharmacophore model
strcture based drug design
indepth knowledge of the target from biophysical methods
pros of target based approach
easierlead optimisaiton
speciifity
knwon mechanism
cons of target based approach
difficult to define a good target
more difficult to find leads
pros of phenotypic approach
gives molecules that work
multiple targets
cons of phenotypic approach
unknown mechanism
activity depends on validity of biological assay
choice of drug target
correct choice is vital for the success of a drug discovery project
stratedgies to identify potential drug targets
target identification
drug discovery
