Pharmacology 6 Flashcards
Briefly, what are local anaesthetic agents, and what are they used for?
LAs are membrane stabilisers that block the propagation of action potentials along neuronal axons. They are used extensively throughout anaesthesia for analgesia, regional anaesthesia and as adjuncts to general anaesthesia. They may also be used for their antiarrhythmic properties.
What are the components of an neuronal axon?
- Phospholipid bilayer
- Membrane receptor proteins
- Transmembrane proteins forming pores, channels or transport mechanisms.
Describe the phases of transmission of a neuronal action potential
Phase 1: Resting transmembrane potential (TMP) of -80mV is maintained by Na/K/ATPase. 3xNa out, 2xK in for 1xATP.
Phase 2: An AP is initiated at the synapse, causing a stimulus which opens voltage-gated Na channels, allowing influx and increasing TMP to +30mV. (Depolarisation)
Phase 3: Voltage-gated K channels open allowing efflux of K+ ions. Na/K/ATPase continues its activity, restoring resting TMP. (Repolarisation)
Describe the mechanism of action of local anaesthetic agents
- Block axonal voltage-gated Na channels.
- Prevent depolarisation + propagation of AP.
- Exert effects INTRACELLULARLY, thus must cross membrane.
- Crossing membrane depends on amount of UNCHARGED drug.
- Intracellular effect exerted by IONISED drug.
- Degree of action possibly related to number of ‘open’ Na channels, thus LAs have less affinity for resting-state neurones.
- Clinical effects mediated through increase in threshold for depolarisation, slowing of conduction and decrease in slope and amplitude of AP
How do the physical properties of a nerve affect speed of onset of LA action?
- Small-diameter neurones affected prior to large
- Myelinated fibres are blocked prior to unmyelinated
How are LAs categorised?
Structurally - Esters and Amides
Esters: Ring-COOR1-N-R2/R3
Amides: Ring-NHCOR1-N-R2/R3
Why is pKa relevant to local anaesthetic agents?
- Determines relative ionisation state of LA molecule in a given solution
- LAs are weak bases, thus will be ionised more below pKa
- Crossing membrane to exert LA effect requires UNIONISED drug
- At physiological pH, a lower pKa will result in more unionised drug to cross membranes.
- Thus pKa determines speed of onset. (Lower pKa = faster onset)
Outline the physical properties of local anaesthetic agents
- Produced as hydrochloric salts as need to be water-soluble
- Single-use ampoules are preservative-free, though ‘heavy’ preparations contain glucose
- Multi-use ampoules may contain preservatives eg. Na metabisulphite or methyl parahydroxybenzoate and fungicide
- Many concentrations are available for different applications eg. topical vs IV vs subarachnoid
Outline the pharmacokinetics of local anaesthetic agents
A:
- Dependent on route/site of administration (vascularity)
- Affected by vasoactive properties of particular LA. eg. Cocaine vasoconstriction / amethocaine (tetracaine) vasodilatation + erythema
- Affected by co-administration of adrenaline
D:
- Dependent upon plasma protein binding
- More highly-bound = longer duration of effect
M:
- Dependent upon type of LA
- Esters are hydrolysed by plasma esterases (mainly pseudocholinesterase) -> short half-life
- Ester hydrolysis produces para-aminobenzoic acid (PABA) -> potential for anaphylaxis
- Amides are metabolised in the liver and may have active metabolites.
E:
-Amides are excreted renally, mainly following metabolism. 5% unchanged.
List the commonly used local anaesthetic agents
- Lidocaine
- Bupivacaine
- Ropivacaine
- Prilocaine
- Cocaine
- Topical agents (EMLA, Ametop)
What are the preparations and uses of lidocaine?
1% + 2% for surgical anaesthesia
5% for topical patches (use limited)
10% for topical airway anaesthesia
Uses:
- Local anaesthesia (onset <2mins, duration 20-40mins)
- Adjunctive analgesic for general anaesthesia as IVI
- Class Ib antiarrhythmic for Rx of ventricular tachyarrhythmias
What is levobupivacaine and why is it widely used?
- Pure S-enantiomer of bupivacaine
- Less cardiotoxic
- Higher hepatic metabolism
What are the features of ropivacaine?
-Long-lasting LA (though
What are the features of prilocaine?
- Amide similar to lidocaine, though more intermediate duration of action.
- Less vasodilatation and less protein bound than lidocaine -> increased VD -> less CNS/cardiotoxicity
- Used in Biers block (IVRA) as a 2% hyperbaric solution.
- Causes methaemoglobinaemia due to aromatic ring metabolism to o-toluidine. This oxidises the Ferrous haem ion to its Ferric (Fe3+) form which binds O2 more avidly, causing tissue hypoxia.
What are the features of cocaine?
- Ester of benzoic acid
- Mainly used for nasopharyngeal mucosal anaesthesia for anaesthetic and vasoconstrictor effect (local NA reuptake inhibitor)
- Readily crosses BBB
- Vasoconstrictive properties affect coronary circulation -> may cause dysrhythmias and death
- Hydrolysed in the liver (in contrast to other ester LAs)
What are the types and features of topical local anaesthetics in use?
EMLA:
- Eutectic mixture of local anaesthetic
- 2.5% lidocaine + 2.5% prilocaine = 5%
- Used prior to cannulation esp. in paeds
Ametop(TM):
- 4% tetracaine (amethocaine)
- Avoids prilocaine in kids
- Causes local vasodilatation
State the maximum safe doses of commonly used LAs (+/- adrenaline)
Lidocaine - 3mg/kg (7mg/kg) Bupivacaine - 2mg/kg (2.5mg/kg) Levobupivacaine - 2.5mg/kg Ropivacaine 4mg/kg Prilocaine - 6mg/kg (9mg/kg)
Which drugs may be co-administered with local anaesthetics and why?
Adrenaline:
- Prolongs duration of effect due to slower absorption
- Unsafe for use in blocks involving end-arteries (eg. penile/digital blocks)
Opioids:
- mu receptor activation potentiates block in spinal, epidural and caudal anaesthetics
- Effect not equivalent with peripheral nerve blocks
Clonidine:
- Centrally acting α2 blocker
- Potentiates neuraxial blockade
- Sedative and hypotensive effect must be taken into account
Glucose:
-Increases density of injectate enables manipulation of block height and laterality
List the side effects of LAs
- Antiarrhythmic (Ib)
- Foetal ion trapping, especially during foetal distress (due to acidosis)
- Methaemoglobinaemia (prilocaine, benzocaine, lidocaine[rare])
- Allergy (usually PABA mediated)
- Toxicity
What are the features of LA toxicity?
Neurological:
- Early excitatory - Altered taste, perioral tingling, tinnitus
- Progresses to twitching + seizures
- Finally coma/death
Cardio:
- Dose-dependent cardiac depression
- Arrhythmia
- CV collapse/death
What is the mechanism of action of paracetamol?
- COX-3 inhibition
- Found predominantly in the brain
- Inhibition of prostaglandins produces antipyretic and analgesic effects
- Thought to have relatively weak anti-inflammatory action
What is the mechanism of action of aspirin?
- COX-1/-2 inhibition
- Irreversible
- COX-2 inhibition prevents platelets from producing TXA2 (a promoter of platelet aggregation)
- Vascular endothelium continues to produce PGI2 (prostacyclin), which inhibits aggregation -> antiplatelet effect
Outline the pharmacokinetics of aspirin
A:
- Upper GIT
- 70% bioavailability
M:
- By esterases in gut wall/liver
- First order kinetics
E:
-Renal
Outline the pharmacokinetics of paracetamol
A:
- Upper GIT
- 70-90% bioavailability
M:
-Liver
E:
-Renal
What are the main toxic effects of aspirin?
- GI upset
- Skin reactions
- Bronchospasm (^leukotrienes)
- Hepatic/renal impairment
- Reyes syndrome (in kids)
- Bone marrow suppression (rare)
What are the main toxic effects of paracetamol?
- GI upset
- Skin reactions (rare)
- Thrombocytopaenia
- Liver necrosis
- Renal impairment with prolonged use
What are the features of aspirin overdose?
- N+V
- Tinnitus -> deafness
- Hyperventilation -> resp alkalosis
- Salicylic acid -> metabolic acidosis
Rarely:
- Convulsions
- Pulm oedema
- Hyperthermia
- Renal failure
- Reyes syndrome (hepatic encephalopathy following viral illness. 20-40% mortality)
Describe the mechanism of toxicity in paracetamol overdose
- Excess doses saturate the normal enzyme pathways for hepatic metabolism.
- Paracetamol then gets metabolised by mixed-function oxidases, resulting in a toxic metabolite normally inactivated by glutathione.
- Rapid exhaustion of glutathione stores results in accumulation of toxic metabolite and hepatocyte (and renal tubular cell) necrosis.
List the clinical features of paracetamol overdose
- Usually asymptomatic for up to 24h
- N+V
- Anorexia
- RUQ pain
- Deranged LFTs
- Prolonged PT
- Peak toxicity at 36-48h
- Fulminant liver failure
Discuss the COX pathway
Arachidonic acid is converted into multiple active compounds via cyclo-oxygenase enzymes 1-3
COX-1:
- Constitutive
- Found in most tissues, importantly platelets, stomach and kidneys
- Induces prostaglandin production
- Induced 2-4x by inflammation
COX-2:
- Predominantly inducible, though constitutive in kidneys, brain, testicles and tracheal mucosa
- Induces inflammatory prostaglandins
- Induced 10-20x by inflammation
- Short half-life
- Larger binding site than COX-1 (target for -coxib drugs)
COX-3:
- Predominantly constitutive in the CNS
- Inhibited by paracetamol
What are the classes NSAID drugs?
- Salicylates eg. aspirin
- Propionates eg. Ibuprofen / Naproxen
- Phenylacetates eg. Diclofenac
- Indoles eg. Indometacin
- Coxibs eg. Parecoxib / Celecoxib
- Oxicams eg. Piroxicam / Meloxicam
What are the main therapeutic effects of NSAIDs?
- Anti-inflammatory action
- Reduced inflammatory prostaglandins - Analgesic action
- Reduced sensitisation of nociceptive nerve endings by prostaglandins - Antipyretic action
- Reduced production of CNS prostaglandins which alter hypothalamic ‘thermostatic point’
What are the main side-effects of NSAIDs?
- Gastric irritation (primarily via COX-1 effect)
- Reduced renal perfusion (esp. if volume status/renal perfusion already suboptimal)
- Platelet inhibition (via COX-1 -> TXA2 inhibition)
- Increased thrombosis / cardiovascular risk (not well understood, not specific to COX-2 inhibitors)
- Increased risk of bronchospasm (^leukotrienes via lipoxygenase activity when COX inhibited)
List the NSAID drugs in order of GI risk (low->high)
Coxibs Aspirin (low-dose) Ibuprofen Aspirin (high-dose) Diclofenac Naproxen Indometacin Piroxicam Ketorolac
For how long do NSAIDs affect platelet function?
Aspirin:
- Irreversible
- 7-10 days
Other NSAIDs:
- Reversible
- up to 3 days
How should NSAIDs be managed before surgery/regional anaesthesia?
Low risk surgery:
-Omit morning of surgery
High risk surgery:
-Check individual risk/unit policy
Regional:
-Aspirin/NSAIDs not contraindicated
What are the endogenous opioids?
- Peptides which act as physiological neurotransmitters and neuromodulators
- Include endorphins, enkephalins and dynorphins
- Modulate response to pain stimuli
- Regulate hunger, thirst and temperature
- Influence mood, immunity and the ANS
How are the endogenous opioids produced?
Derived from precursor proteins found in CNS:
- Pro-opiomelanocortin (POMC):
- Cleaved to produce ACTH, 𝛽-lipotropin, 𝛾-lipotropin + 𝛽-endorphin - Proenkephalin (PENK)
- Cleaved to produce Met- and Leu-enkephalin (pentapeptides) - Prodynorphin (PDYN)
- Cleaved to produce Dynorphins A + B
How are opioid drugs classified?
Natural:
- Morphine
- Codeine
- Thebaine
Semi-synthetic:
- Diamorphine
- Oxycodone
- Dihydrocodeine
- Buprenorphine
- Hydromorphone
- Oxymorphone
Synthetic:
- Phenylpiperidines (fentanyl, alfentanil, sufentanil, remifentanil, pethidine)
- Propion anilides (methadone)
- Morphinans (levorphanol)
- Benzomorphans (pentazocine, phenazocine, cyclazocine)
How are opioid receptors classified?
According to structure and function:
- µ -receptor
- κ-receptor
- δ-receptor
All are GPCRs of Gi/o type
- Inhibit Adenylyl Cyclase (𝛼-subunit), increasing K (𝛾-subunit) / reducing Ca influx (𝛽-subunit).
- Hyperpolarises cell and inhibits presynaptic neurotransmitter release
Discuss the µ-opioid receptor
-Coded by OPRM1 on Chr6
Agonists:
- Morphine and analogues
- Buprenorphine (partial)
- 𝛽-endorphin
- Met/Leu-enkephalin
Effects:
- Analgesia
- Sedation
- Resp depression
- Constipation
- Physical dependence
Antagonists:
- Naloxone
- Naltrexone
- Nalbuphine
- Nalorphine
Discuss the κ-opioid receptor
-Coded by OPRK1 on Chr8
Agonists:
- Morphine
- Dynorphin
- Nalorphine
- Nalbuphine
- Pentazocine
Effects:
- Spinal analgesia
- Sedation
- Miosis
- Dysphoria
Antagonists:
- Naloxone
- Naltrexone
Discuss the δ-opioid receptor
-Coded by OPRD1 on Chr1
Agonists:
- Met/Leu-enkephalin
- Etorphine
Effects:
- Analgesia
- Growth hormone release
Antagonist:
-Naloxone
Where are opioid receptors found?
Brain:
- Periaqueductal grey matter (analgesia)
- Nucleus raphe magnus (analgesia)
- Amygdala (behaviour)
- Hippocampus (behaviour)
- Cortex (behaviour)
Spine:
-Laminae I + II of dorsal horn (substantia gelatinosa)
GI tract:
- Myenteric plexus (constipation)
- presynaptic inhibition of ACh release
Discuss the analgesic mechanisms of opioids
Reduction of afferent signalling in dorsal horn of cord
-Through presynapic inhibition (eg. preventing substance P release from afferents)
Enhancement of descending inhibitory pathway in periaqueductal grey matter and nucleus raphe magnus in medulla -> dorsal horn inhibition
-Through disinhibition of descending pathways (inhibition of GABAergic pathways)
Compare the physiochemical properties of some common opioids
Morphine:
- Relative potency (RP) 1
- Lipid solubility (LP) 1
- pKa 7.9
Fentanyl:
- RP 100
- LP 800
- pKa 8.4
Alfentanil:
- RP 5
- LP 125
- pKa 6.4
Remifentanil:
- RP 100
- LP 20
- pKa 7.1
List side effects of opioid use
CNS:
- Resp dep.
- Eu/dysphoria
- Addiction/dependence
Eyes:
-Miosis
Skin:
- Pruritus
- Histamine release
- Anaphylaxis
GIT:
- Constipation
- Spasm
- Sphincter of Oddi spasm
Bladder:
-Urinary retention
How are µ agonists classified?
Structurally:
Morphinans
- Morphine, codeine (natural)
- Diamorphine, oxycodone, dihydrocodeine (semi-synth)
Phenylpiperidines
-Fentanyl, al-/sufentanil, pethidine (synth)
Diphenylpropylamines
-Methadone, dextropropoxyphene (synth)
Esters
-Remifentanil (synth)
What is the oral bioavailability of morphine?
25%
Outline the pharmacokinetics of morphine
- Relatively low lipid solubility, crosses BBB slowly
- Peak effect at 10 mins following IV bolus
- Metabolised in liver and gut, mainly by glucuronidation and partly by demethylation (to normorphine)
- Main metabolite M3G is inactive and excreted in urine/bile
- M6G is more potent than morphine and can accumulate
- T1/2 is ~3h but variable (100-400mins)
How does diamorphine differ from morphine?
- Semi-synthetic morphine derivative
- 3,6-diacetylmorphine
- Pro-drug with no intrinsic activity
- Rapidly metabolised by tissue/plasma esterases to 6-monoacetylmorphine (6-MAM) and then to morphine
- Diamorph / 6-MAM are much more lipid soluble than morphine and thus cross BBB quickly enabling quick onset of effect (once metabolised)
How does papaveretum differ from morphine?
- Semi-synthetic mixture of hydrochlorides of opium alkaloids
- Contains morphine, codeine and papaverine (approx 80% morphine)
How does oxycodone differ from morphine?
- Semi-synthetic thebaine derivative
- Codeine molecule with 6-OH group replaced by ketone group, single bond between C7-C8 and -H in position 14 replaced by -OH
- Full µ agonist
- Similar potency + T1/2 to morphine
- Higher oral bioavailability (60%)
- Undergoes mainly N-demethylation to noroxycodone (weak activity) but also O-demethylation to oxymorphone (significant activity)
How does pethidine differ from morphine?
- Phenylpiperidine
- 1/10 potency of morphine
- Oral bioavailability 50%
- More lipid soluble + crosses BBB faster
- Shorter duration of action
- Metabolised by phase 1 in liver to metabolites including norpethidine (epileptogenic), which can accumulate in renal dysfunction
- Pethidine + MAOIs = CVS instability, convulsions + coma
How does fentanyl differ from morphine?
- Phenylpiperidine
- Most potent opioid available in UK (100x morphine)
- 580x lipid solubility of morphine, readily crosses BBB -> rapid onset
- Context-sensitive T1/2 (dose dependent) due to rapid redistribution but slower (+variable) elimination
- Dealkylated to norfentanyl (inactive). No active metabolites
- Can be given transdermally, but takes ~2 days to reach steady state
How is fentanyl used in anaesthesia?
Small doses (<2mcg/kg) -Short-acting analgesic
Moderate doses (>5mcg/kg) -Obtunds CVS response to laryngoscopy
High doses (>50mcg/kg)
- CVS stability + obtunded adrenal response to surgery
- Can cause bradycardia and chest wall rigidity
Post-op
- FPCA
- IV bolus
How does alfentanil differ from fentanyl?
- Also phenylpiperidine
- 1/5 potency of fentanyl
- More rapid onset due to low pKa -> 90% unionised
- Short action, fast redistribution but lower lipid sol. -> lower Vd.
- Demethylated to inactive metabolites
How does remifentanil differ from fentanyl?
- Ester derivative of fentanyl
- Similar potency
- Similar speed of onset
- Rapid metabolism via ester hydrolysis by non-specific plasma/tissue esterases to clinically insignificant carboxylic acid derivative excreted renally
- T1/2𝛽 10-20mins, independent of renal function
- CSHT 5 mins (independent)
- Tissue esterase activity decreases with age
How does tramadol differ from morphine?
- Phenylpiperidine analogue of codeine
- Racemic mixture of two stereoisomers. One is a weak agonist at all OPRs + inhibits 5-HT reuptake; other inhibits NA reuptake (responsible for part of the analgesic effect non-reversible by naloxone)
- Similar potency to pethidine (1/10 morphine)
- 75% oral bioavailability
- Minimal resp depression / GI effects
- Less physical dependence
- N&V/sedation are main side effects
- O-desmethyl metabolite has increased μ activity and may accumulate in renal impairment
