Pharmacology 7 Flashcards
How are opioids classified according to intrinsic activity?
Strong
-Full, potent agonists eg. morphine
Weak
- ie. codeine - full agonist but significantly lower potency
- Tramadol is similar in terms of potency but due to other extraopioid effects is not adequately classified in this system
Intermediate
- Partial agonists eg. buprenorphine
- Mixed agonist-antagonists eg. nalbuphine
Antagonists
-Occupy receptor but have no intrinsic activity eg. naloxone
Contrast efficacy and potency
Efficacy: Maximal response (ie. intrinsic activity)
Potency: Inverse of the dose required to achieve a response
How does codeine differ from morphine?
- Codeine is the pro-drug 3-methyl morphine
- Metabolised in the liver. Mainly by glucuronidation, also by N-demethylation to norcodeine and 10% by O-demethylation to morphine (providing much of the analgesic effect)
- Demethylation by CYP2D6 - significant variability in expression (absent in 9% Caucasians)
- Bioavailability 50% (higher than morphine) due to lower 1st pass metabolism
- Similar T1/2𝛽 to morphine (3h)
How does dihydrocodeine differ from codeine?
- Semi-synthetic analogue of codeine with similar pharmacokinetics
- Also metabolised by CYP2D6
- Low oral bioavailability (20%)
How does buprenorphine differ from morphine?
- Semi-synthetic thebaine derivative
- Partial agonist
- Agonist at μ receptor
- Antagonist at κ receptor
- Agonist at nociceptin receptor (NOR) -> anti-opioid effect
- Bell-shaped dose/response curve due to increasing effect of action at NOR at high doses
- Produces opioid SEs as per intrinsic activity
- High receptor affinity -> slow dissociation -> long duration (10h) -> difficult to reverse
- Very low bioavailability
- Metabolised by CYP3A4 to norbuprenorphine which is a full δ and NOR agonist and a partial μ and κ agonist
- Excreted in bile
In what situations may buprenorphine use be problematic?
- Will limit response to pure μ agonists up to 24h
- Should be stopped/converted at least 24h prior to surgery
- May precipitate withdrawal if given to opioid-dependent patients
How is nalorphine used?
- Historical opioid antagonist used as a reversal agent
- Partial agonist
- Replaced in practice by naloxone
Discuss nalbuphine
- Morphinan
- Chemically related to naloxone
- Mixed opioid agonist-antagonist
- Agonist at κ receptor
- Antagonist at μ receptor
- Equipotent with morphine
- 3-4h duration of action
- 10% oral bioavailability
- Historically used in prehospital care, but compromised subsequent analgesia
- Withdrawn in 2003
Discuss pentazocine
- Benzomorphan
- Mixed opioid agonist-antagonist
- Agonist at κ receptor
- Antagonist at μ receptor
- Significant hallucinogenic effects
- Causes significant catecholamine release -> ↑HR/BP
Discuss naloxone
- Oxymorphone derivative
- Pure μ antagonist
- Higher affinity for μ but will antagonise at other opioid receptors
- Low oral bioavailability
- T1/2𝛽 2.5h
- Duration 30-45min
- Can be effective in Rx of non-opioid central depressants ?by excitatory mechanism
- May precipitate withdrawal, HTN, arrhythmias and pulmonary oedema
Discuss naltrexone
- Oxymorphone derivative
- -Pure μ antagonist
- Higher affinity for μ but will antagonise at other opioid receptors
- High oral bioavailability
- Long T1/2
- Duration 24h
- Used in maintenance therapy of detoxed opioid users
- Must be discontinued prior to surgery for opioid drugs to have effect
What are the precursors to acetylcholine?
AcetylCoA + choline
What happens in the presynaptic nerve terminal during an action potential?
Opening of N-type (neuronal) Ca channels -> Ca influx -> fusion of ACh vesicles with presynaptic membrane -> exocytosis
Ca binding to synaptotagmin on vesicular membrane encourages association with SNARE complexes joining vesicles to presynaptic membrane
The amount of ACh released is known as a quantum. Quantal size is affected by frequency of stimulation.
How may presynaptic transmission be prevented pathologically?
LEMS -> Abs to N-type Ca channels
Textile cone snail toxin -> block N-type Ca channels
How is the presynaptic release of ACh regulated?
Presynaptic nicotinic AChRs (α3β2)
Structually different from postsynaptic NAChRs (α1β1) and ganglionic NAChRs (α3β4)
Activation increases ACh release, inhibition reduces.
‘fade’ and phase II depolarizing block is thought to be due to blockade of presynaptic NAChRs.
What is the current carried by a single open NAChR?
5pA
3x10^7 ions/s
Discuss ACh binding
NAChRs are pentameric with a 2xα, β, δ, ε structure.
Binding site is at the junction between the α-δ and α-ε subunits.
Occupation of both binding sites induces conformational change in the α subunits, opening the pore and causing Na influx.
Discuss the postsynaptic motor endplate AP
Muscle RMP -85mV
Activation of NAChRs causes Na influx. Each opening <1ms
Only a small proportion of AChRs need to be opened to reach threshold for EPP (-70mV) and opening of voltage-gated Na channels.
This causes membrane depolarisation to +15mV and propagation of AP to T-tubules
How does NAChR density vary?
Why is this important?
May be up- or down-regulated:
Up-regulation:
- Spinal cord transection
- Severe burns
- Prolonged immobility
- Severe sepsis
- Guillain-Barre
Down-regulation:
- Organophosphate poisoning
- Nicotine ingestion (CNS)
- Early Alzheimer’s (CNS)
Up-regulation involves proliferation of extrajunctional fetal-type NAChRs (2xα, β, γ, δ) with longer opening times. Use of sux in up-regulated conditions increases risk of hyperkalaemia and associated arrhythmia. Non-depolarising NMBAs require higher doses due to resistance.
NAChRs may be blocked in MG, increasing sensitivity to non-depolarising agents and decreasing sensitivity to depolarising agents
Discuss AChE
Enzyme
Present in post-synaptic clefts
Commonly forms associations of tetramers loosely anchored to membrane through collagen Q
Cleaves ester link between acetyl and choline groups of ACh
Two binding sites - anionic and esteratic
Discuss excitation-contraction coupling
- AP reaches T-tubule
- VG L-type Ca channels open (α1, α2, β, γ, δ)
- Triggers opening of RyR1 in membrane of SR
- Allows release of Ca (stored bound to calsequestrin in SR) into sarcoplasm
- Ca binds to troponin causinig contraction of muscle fibres
How are NMBAs classified?
Depolarising / Non-depolarising
Non-depolarising:
Aminosteroids (-oniums)
Benzylisoquinoliniums (-curiums)
Discuss AChE inhibitors
Inhibit ester hydrolysis of ACh
Three groups:
Group 1:
- Bind to anionic site only
- eg. Edrophonium
Group 2:
- Bind to both anionic and esteratic sites
- Vary in lipid solubility and duration of action
- eg. neostigmine + pyridostigmine (non-lipid soluble), physostigmine (lipid soluble)
Group 3 :
- Bind to esteratic site only
- Irreversible inhibition of AChE
- eg. Organophosphates
Increase conc. of ACh in synaptic cleft. However, also block plasma cholinesterase and increase {ACh} at muscarinic and nicotinic ganglia.
Thus neostigmine is combined with glycopyrrolate (antimuscarinic)
Discuss the primary targets for neurotoxins
Post-synaptic NAChR
-α-neurotoxins in snake venom
Pre-synaptic neurotransmitter release / SNARE proteins
- β-neurotoxins in snake venom (ACh)
- Tetanus toxin (prevents GABA/glycine release, disinhibiting stretch reflexes -> severe spasm
- Botulinum toxin (Inhibition of ACh release -> flaccid paralysis)
AChE
-eg. organophosphates
Generally α-neurotoxins in snake venom are more readily reversed than β
