Y05b. Pharmacopeia: Pain Neuropharmacology

PAST QUESTIONS – K04. Pain Pharmacology (Click to Open)

SYLLABUS (Fourth Edition, 2023)

LEVEL 1	LEVEL 2	LEVEL 3
Analgesics
Opioids
Oxycodone	Buprenorphine
Fentanyl	Remifentanil	Alfentanil
Morphine	Hydromorphone
	Methadone
	Tapentadol
	Tramadol
Non-Opioids
Ketamine	Gabapentin / Pregabalin	Non-steroidal anti-inflammatory drugs
Paracetamol

N.B. The Syllabus tables used in out Pharmacopeia seem incomplete, but that is intentional because we have only included groups/classes/drugs which are mentioned directly in the syllabus or have been asked before in the exams.

TRAINEE EXPECTATIONS

Trainees are expected to understand a drug’s pharmacology in the context of normal physiology, extremes of age (i.e., neonates, paediatrics, and the elderly), obesity, pregnancy (including foetal implications) and critical illness. An understanding of potential toxicity and relevant antidotes is also expected. Agents may be listed in more than one section when they are used for different indications.
This is not an exhaustive list of all drugs relevant to or important in ICU practice. Each drug or classes of drugs have been assigned a details of understanding level outlined below. This is a guide to the minimum level of knowledge expected for that drug.
For classes of drugs where examples are not specified, it is suggested a prototypical drug from the class be studied, as well as the relevant variations within the class exploring the major differences that exist between the agents in that class.

LEVELS OF UNDERSTANDING

Level 1	Level 2	Level 3
For these drugs, a detailed knowledge and comprehension of:	For these drugs a detailed knowledge of:	For these drugs a detailed knowledge of:
Class, Indications, and dose
Mechanism of Action
Pharmacodynamics and Adverse effects
Pharmacokinetics	Important pharmacokinetic differences or considerations when using in ICU
Pharmaceutics

CICMWrecks Tables (Click to Open)

MASTER TABLES	Opiates
	Non-Opiates
	Antidotes
INDIVIDUAL TABLES	Ketamine
	Fentanyl \| Remifentanil (PK and PD)
	Fentanyl \| Morphine
	Morphine \| Fentanyl (PK and AE)
	Morphine \| Fentanyl \| Remifentanil
	Morphine \| Tramadol (MoA, PK, CNS)
	Oxycodone
	Naloxone
	Ibuprofen \| Paracetamol
	Ibuprofen \| Tramadol

MASTER TABLES

OPIATE ANALGESICS

Pharmacopeia - Opiate Analgesics

	MORPHINE	FENTANYL	OXYCODONE	ALFENTANIL	REMIFENTANIL	METHADONE	PETHIDINE	BUPRENORPHINE	HYDROMORPHONE	CODEINE	TRAMADOL
GROUP	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 1	Level 1	Level 1	Level 3	Level 2	Level 2	-	Level 2	Level 2	-	Level 2

INTRODUCTION	naturally occuring phenanthrene derivative from papaver somniferum plant	Tertiary amine which is a synthetic phenylpiperidine derivative	semi-synthetic thebaine (opium alkaloid) derivative	synthetic phenylpiperidine. μ receptor agonist	synthetic phenylpiperdine derivative of fentanyl with a unique metabolism	Potent synthetic analgesic	synthetic phenylpiperidine derivative.	synthetic derivative of the opioid alkaloid thebaine	Pure opioid Semi-synthetic hydrogenated ketone derivative of morphine	Pure opioid Semi-synthetic hydrogenated ketone derivative of morphine naturally occurring phenanthrene alkaloid which is a methylated morphine derivative	Is a synthetic opioid – cyclohexanol derivative Racemic mix.
USES	1. for premedication 2. as an analgesic in the management of moderate to severe pain 3. in the treatment of left ventricular failure 4. to provide analgesia during terminal care, and 5. in combination with kaolin in the symptomatic treatment of diarrhoea	1. to provide the analgesic component in general anaesthesia 2. in combination with a major tranquillizer to produce neuroleptanalgesia 3. to provide analgesia during labour when regional anaesthesia is not in use 4. as an agent used for patient-controlled analgesia 5. in premedication and 6. for palliative care	1. the treatment of moderate to severe pain in patients with cancer and post-operative pain and 2. in the treatment of severe pain requiring a strong opioid.	1. to provide the analgesic component in general anaesthesia 2. in sedation regimens for intensive care, and 3. to obtund the cardiovascular responses to laryngoscopy.	1. to provide the analgesic component in general anaesthesia 2. to provide analgesia/sedation in intensive care 3. to provide analgesia during labour when regional anaesthesia is not in use 4. to provide analgesia/sedation during ‘awake’ fibreoptic intubation.	- Management of severe pain not responsive to alternative treatments - Pain syndromes: neuropathic, cancer pain - Detoxification and maintenance treatment of opioid addiction	1. for premedication 2. as an analgesic in the management of moderate to severe pain and 3. as an antispasmodic agent in the treatment of renal and biliary colic.	1. in the treatment of moderate to severe pain and has been used 2. in sequential analgesia.	1. as an analgesic in the management of moderate to severe pain – acute and chronic	1. pain of mild to moderate severity 2. diarrhoea and excessive ileostomy output and 3. as an antitussive agent and 4. traditionally to provide analgesia for head-injured patients	Analgesia


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	either as a clear liquid for injection, orally in immediate (liquid or tablet) and sustained release (MS Contin)	colourless solution 50mcg/ml, TDpatch (25mcg-100mcg/hr) and as lozenges	white tablets – immediate/sustained release. Paracet Combo in US	colourless solution containing 500mcg/ml in 2 of 5ml vials	white crystalline powder for reconstitution	Tablet, PO solution, Inj	Tab: 50mg Inj: Colourless solution 10/50 mg/l Pethidine HCl	Inj: 300mcg/ml clear, colourless solution PO: 200/400mcg tablets TD patches	Inj: Clear solution with slightly different refractive index from water. May acquire amber discoloration if exposed to light (with no effect on potency) Tablets, liquid, suppositories	Codeine phosphate Tab: 15/30/60mg Syrup: 5mg/ml Inj: Clear colorless solution 60mg/ml Often in fixed dose preparations with paracetamol, ibuprofen or aspirin	immediate release, 12 hour release and 24 hour release tablets, IV


PHARMACODYNAMICS (PD)
PD: Main Action	primarily CNS μ receptor activity, also κ and δ.	μ receptor agonist	primarily μ receptor activity but also has some weak κ and δ receptor activity	Same as Morphine PK features, esp pKa ensure however significant differences to the related opioids such as fentanyl.	Pure mu receptor agonist	Full µ agonist & NMDA antagonist	µ & κ agonist	partial agonist at MoP receptors but dissociates slowly from the latter, leading to prolonged analgesia and low dependence Κ: high affinity, low activity	Same as morphine primarily CNS μ receptor activity, also κ and δ.	very low affinity for opioid receptors. 10% metabolized to morphine - analgesic and constipating effects. antitussive effects of codeine mediated by specific high-affinity codeine receptors
PD: Mode of Action	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	µ: Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release - agonist of κ- and σ-opioid receptors - antagonist of NMDA receptor (hence improved analgesic efficacy and reduced opioid tolerance) - inhibitor of serotonin and norepinephrine uptake.	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	mod affinity for μ receptors, weak κ, δ -in spinal desc inh pathways by inh of neuronal reuptake of norad&serotonin -presynaptic stim of seritonin release
PD: Route & Doses	Dose 5-10mg titrate eff¬ect, may increase x100 with tolerance (relative potency 1)	Bolus: 1-2 mcg/kg inf: 1-2 mcg/kg/hr (relative potency 50-100)	20mg Oxy PO = 10mg Morphine IV (Relative potency 0.5)	7mcg/kg-50 mcg/kg ventilatd (relative potency 10-20)	Dose 1mcg/kg bolus, titrate eff¬ect (relative potency 50-100)	PO dose range 10-225mg (relative potency 1)	PO: 50-150mg Q4hrly IM: 25-150mg IV: 25-100mg Epidural: 25mg (relative potency 0.1)	IM/IV: 0.3-0.6mg Q6hrly SL: 0.2-0.4mg Q6 to Q8hrly Epidural: 0.3mg (relative potency 25)	(relative potency 5-7)	PO/IM: 30-60mg Q6-Q6hrly Rectal: 1mg/kg Not given IV due to hypotension sec histamine release (relative potency 0.1)	Route- PO/IV Dose- 50-100mg QID for all routes (Relative pot 0.2)
PD: Metrics (Onset/ Peak/ Duration)						Peak 1-7.5hrs	Onset PO 15min IM 10min Dur 2-3hrs		IR: Onset 15-20min, Peak 30-60min, Dur 3-4hrs XR: Onset 6hrs, Peak 9hrs, Dur 13hrs	IM absorption ~0.5hrs peak 1hr	onset / duration ~1 hour / 9 hours (immediate release)
PD: Effects	CNS: Opioid receptors present in cerebral cortex, periaqueductal grey, nucleus accumbens, area postrema, thalamus and NTS - Analgesia - Sedation - Respiratory depression - Nausea - Euphoria - Psychotomimetics Seizures (due to M6G metabolite) PNS Excitatory action Histamine release	inhibitory action, modulating the pain response to produce analgesia. less likely to ppt histamine release norad& serotonin axn, excitatory centrally	inhibitory action, modulating the pain response to produce analgesia. Mainly mu receptor actions	inhibitory action, modulating the pain response to produce analgesia.	inhibitory action, modulating the pain response to produce analgesia. shares many of its actions with morphine and related compounds	analgesia, suppression of opioid withdrawal symptoms,	inhibitory action, modulating the pain response to produce analgesia. Antitussive Less histamine release than morphine	inhibitory action, modulating the pain response to produce analgesia. (25x potent)	inhibitory action, modulating the pain response to produce analgesia.	inhibitory action, modulating the pain response to produce analgesia. Opioid Effects from Morphine metabolite. Antitussive effects	CNS: - Analgesia - Hallucinations - Confusion - Delirium - Agitation - Seizures - Coma (Serotonin syndrome) Respiratory depression and constipation
PD: Side Effects / Toxicity	CNS: dysphoria, confusion, ↓LoC, ↓cough reflex, miosis(PNS) CVS: hypotension (↓TPR, blunt baroreceptor reflexes) Resp: dir ↓resp drive indir via obtundation GI: ↓gut motility, ↓SB secretions, CTZ→N+V, constipn, CBD spasm. GU: Urinary retention skin flushing, pruritis(histamine) Dependence, addiction,Tolernce. IT – resp dep (rostral migration)	Similar to other opioids. Differences due to lipid sol. Does not cause delayed respiratory depression because it rapidly diffuses into and out of the CSF. Raised CSHT prolonged infusion may lead to increased duration of action and SE	weak K action may cause some of the negative effects (dysphoria, psychomimetic) Interindividual variability in metabolism. Other standard opioid side effects.	Same as other opioids 10x variability in clearance due to interpersonal variability of CYP3A4	Bradycardia, hypotension, muscle rigidity, May contribute to hyperalgesia following prolonged infusion	sedation, miosis, sweating, hypotension, bradycardia, nausea and vomiting (via binding within the CTZ), and constipation. Arrhythmias, QT prolongation Dependence, tolerance At higher doses, methadone use can result in respiratory depression, overdose, and death	CVS Orthostatic hypotension (histamine release + α blockade). Tachycardia (mild quinidine-like effect & anticholinergic properties) RS Potent resp depressant (TV > RR) Obtunds response to hypoxia and hypercapnia Chest wall rigidity, CNS More euphoria, less N/V GIT dec gastric emptying GU dec uterine tone, inc uterine contractions Inc ADH secretion, Dec adrenal steroid secretion Hallucinations Dependence	Similar to morphine CVS Minimal (dec HR and SBP) RS resp depression, antitussive. Histamine and tryptase release – inc PVR Other: Dec LH inc prolactin Drowsiness, dizziness, headache, confusion, dysphoria, nausea vomiding Less liable to produce dependence	Similar to morphine reduced incidence of pruritus and nausea (which indicates a lower release of histamine)	Markedly inhibits GIT motility – constipation Nausea, vomiting Dizziness Excitatory phenomena Cardiovascular collapse in overdose or IV administration Reports of Bowel perforation sec to dec GIT transit Low propensity for dependence	Dysphoria,Euphoria. Miosis (excitation of Edinger-Westphal nucleus) N/V -CTZ stim. Serotonin syndrome with SSRI /SNRI/MAO/TCA Less resp dep than morphine analgesic effect in CYP2D6 deficiency


PHARMACOKINETICS (PK)						Extensive interindividual differences
PK: Absorption	PO/IV/IM/SC/SL/IT Poor bioavailability 30% (good abs but high 1st pass metab) onset / duration Oral ~30 minutes; I.V.: 5-10 minutes	IV/IM/TD. BA PO 30%SL50%skin>90% onset IM.: 7-8 mins; IV imm; TD 6 hrs duration IM:1-2 hrs; IV:0.5-1hr; TD 12hrs	PO. BA 60-87% onset / duration 10-15 minutes / 3-6 hours	IV onset / duration rapid / 30-60 minutes	IV only onset / duration 1-3 minutes	PO BA 36-100%	PO 45-75% (significant first pass) IM: 100%	Significant firstpass orally SL 44-94% IM 40-90%	Significant first pass metabolism PO BA 60%	PO BA 60-70% Little first pass metabolism	Bioavailability- 75% PO

PK: Distribution	relative lipid sol 1 but crosses BBB pKa 8.0 (25% unionised) slow redistribution	relative lipid sol 500 Rapid redistribution pKa 8.4(10% union)	LipId sol high- crosses BBB	relative lipid sol 90 rapid redistribution pKa 6.5 (95% union) BBB more rapidly	relative lipid sol 50 rapid redistribution pKa 7.1 (70% union)	Highly lipid soluble (less than fentanyl)		Only unchanged buprenorphine reaches CNS	Parenteral: Rapid redistribution to liver, spleen, kidney, skeletal muscle		Crosses placenta Lipid soluble-crosses BBB
Protein binding (PK: Distribution)	prot bind 20-40% (Alb)	prot bind 80-85%	Prot bind ~45%	prot bind 85-90%	Prot bind ~70% (1 acid glycoprotein)	85-90% (α1-acid glycoprotein)	49-67%	96%	8-19%	7%	Prot bind-20%
Volume of distribution (PK: Distribution)	mod Vd 3-4L/kg	Mod Vd 4-6L/kg	Vd 2.6L/kg	Vd 0.5L/kg	Vd 0.3L/kg kids	1-8 L/kg (variation with gender and weight)	3.5 – 5.3 L/kg	3.2L/kg	4 L/kg	5.4 L/kg	Vd- 2.5-3L/kg

PK: Metabolism	Metabolised to morphine-3-glucuronide (70%) and morphine-6-glucuronide (10%) by gut wall and liver. M6G is 10-20 times potent, may accumulate in renal failure	Slow Hepatic, primarily via CYP3A4clearance	CYP3A family metabolism to noroxycodone and via CYP2D6 to oxymorphone (active), both subsequently conjugated	Liver by N – demethylation. Compared to Fent: only 10% pulm uptake , lower clearance rate but shorter t1/2.	Rapid metabolism via blood and Plasma esterase - used in liver/ renal disease, different age, sex, body habitus without sign dose modificn	Extensive first pass by CYP450	Liver N-demethylation to norpethidine and hydrolysis to pethidinic acid	Liver Dralkylation and conjugation to glucuronide - Polar conjugates excreted in bile and hydrolysed by bacteria in GIT	Liver Mainly to hydromorphone-3-glucuronide	Liver – extensive. Major Metabolites: Morphine (O-demethylation), codeine-6-glucuronide (glucuronidation), Norcodeine (N-demethylation) CYP2D6 genetic variability: ‘Fast’ metabolizers produce more morphine	Extensively hepatic via demethylation , glucuronidation, and sulfation; active metabolite by CYP2D6 (M1; O-desmethyl tramadol)

PK: Excretion	Excreted mainly in urine as conjugates with 10% in faeces	excretion Urine 75%	excretion urine	excretion urine	excretion urine	Renal and Faecal after extensive biotransformation	Renal (1-25% unchanged, rest metabolites) Norpethidine accumulates in renal and liver failure, 50% potency of pethidine	Faeces – unchanged Urine – conjugated and deaklylated derivates	Urine – main metabolite (7% unchanged) Faeces	Urine – 17% unchanged Rest metab	Urine 90% (30% unchanged), 10% faeces.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Half time 2-4hrs (large interpatient Variability)	half life I.V.: 2-4 hours, prolonged context sensitive half time	half life 2-4 hrs	half life 1.5 hours (shorter context sensitive compared to fentanyl)	half life Terminal: 10-20 minutes; effective: 3-10 minutes No CSHT	7-59hrs	2.4-7 hrs	5 hrs	IR: 2-3hrs XR: 8-15hrs	2.8hrs	T1/2: ~6-8 hrs; Act metab:7-9hrs; old, hepatic/renal imp.


SPECIAL POINTS	May precipitate encephalopathy in hepatic failure May precipitate coma in hypopituitarism Good reversal with naloxone (does not affect epidural analgesia) Not removed by haemo/peritoneal dialysis	- Incompatible with thiopental - Dialysis - unknown	May precipitate encephalopathy in hepatic failure Good reversal with naloxone	Half life prolonged in elderly, debilitated, hepatic and renal impairment Dialysis - Unknown	Clearance of metabolite remifentanil acid - prolonged in renal impairment (up to 268 hrs) Metabolite concentration significantly increased in ICU patients with mod-severe renal impairment – but no evidence of clinically significant mu-opioid effects Remifentanil not extracted during RRT. Metabolite extracted 25-35% during hemodialysis.	- Lower neuropsychiatric toxicity due to lack of active metabolites - minimal accumulation in renal failure - good BA - low cost - longer duration of action	Severe hypertensive episode with MAOIs Inhibits post-anaesthetic shivering	Partial agonists – antagonizes opioid agents and may precipitate abstinence syndromes in dependent subjects Resp depression not completely reversed by naloxone Not removed by haemodialysis	Reversed by naloxone	Dose to be reduced in renal failure

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NON-OPIATE ANALGESICS

Pharmacopeia - Non-Opiate Analgesics

	PARACETAMOL	KETAMINE	NSAIDS - IBUPROFEN	TRAMADOL	GABAPENTIN	PREGABALIN	?COX Inhibtor
GROUP	Non-Opiate Analgesic	Non-Opiate Analgesic	Non-Opiate Analgesic	Opiate Analgesic	Non-Opiate Analgesic	Non-Opiate Analgesic	Non-Opiate Analgesic
CICM Level of Understanding	Level 1	Level 1	Level 3	Level 2	Level 2	Level 2	Level 3

INTRODUCTION	Acetanalide derivative	Phencyclidine (remember the street drug name PCP) derivative that produces dissociative anesthesia	non selective cycloxygenase inhibitor	Is a synthetic opioid – cyclohexanol derivative Racemic mix.	acetic acid derivative which is a structural analogue of GABA.	GABA analogue ((s)-3-(aminomethyl)- 5-methylhexanoic acid).
USES	Analgesia Anitpyretic	Induction of anaesthesia - Procedural sedation - Analgesia - ?Role in management of depression. - Recreational	Analgesia Antipyretic Antiinflammatory	Analgesia	1. post-herpetic neuralgia 2. painful diabetic neuropathy 3. partial seizures with or without secondary generalization, and 4. neuropathic pain	1. peripheral and central neuropathic pain 2. partial seizures with or without secondary generalization and 3. generalized anxiety disorder


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	Tablets, IV formulation with 10mg/mL containing mannitol, Combination formulations with codeine and non-steroidals	10, 50 or 100mg/ml	200mg tablets, some formulations in combination with codiene	immediate release, 12 hour release and 24 hour release tablets, IV	600/800 mg tablets and 100/300/400 mg capsules	Capsules (containing lactose monohydrate) of varying strengths from 25-300mg.


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Not entirely elucidated 1. Reduced prostaglandin synthesis in areas of inflammation ? COX 3 inhibition a) ↓ PGE2 in Hypothalamus → Anti-pyretic effect 2. Analgesic Effect a) ↓’d central serotonergic reuptake → ↑ descending b) 5HT agonist → enhanced descending inhibitory pain pathways. c) Central inhibition of endocannabinoid uptake d) Peripheral afferent nociceptive chemoreceptor impulse blockade via bradykinin inhibition synergistic with opioid medications, reducing the overall opioid requirement by 20-30%	NMDA receptor antagonism - Inhibits excitatory signaling within CNS - Also inhibits noradrenaline reuptake in sympathetic nerve terminals	Reversibly inhibits COX 1 and 2 enzymes causing decreased production of prostaglandin precursors	mod affinity for μ receptors, weak κ, δ -in spinal desc inh pathways by inh of neuronal reuptake of norad&serotonin -presynaptic stim of seritonin release	structurally related to GABA but does not interact with GABA receptors. The binding site for the drug is the alpha-2-delta subunit of voltage-gated calcium channels. Gabapentin does not interact with sodium channels in vitro (cf. phenytoin, carbamazepine). It may also: 1. partially reduce the response to the glutamate agonist NMDA 2. reduce the release of monoamine neurotransmitters in vitro 3. stimulate glutamate decarboxylase (the enzyme which converts glutamate to GABA), and 4. increase the synaptic release of GABA	Pregabalin is structurally related to GABA but does not interact with GABA receptors. The binding site for the drug is the alpha-2 delta subunit of voltage-gated calcium channels.
PD: Route & Doses	Route: Tablets, IV Dose: 15mg/kg to 1g QID	- 1mg/kg induction dose - 10~20mg analgesia	Tablets for PO/PR	Route- PO/IV Dose- 50-100mg QID for all routes (Relative pot 0.2)	PO only 900-3600mg/day in 3 divided doses Dose reduced in renal failure Discontinuation at least over a week	PO only 150-600mg/day in 2-3 divided doses Dose reduced in renal failure Discontinuation at least over a week
PD: Metrics (Onset/ Peak/ Duration)	onset / duration PO <1 hr / 4-6 hrs, IV 10-15mins / 4-6 hrs		onset 30 mins, duration 6 hours	onset / duration ~1 hour / 9 hours (immediate release)	Peak plasma levels within 2-3hrs
PD: Effects	Functional class: Antipyretic, Analgesic Indications: Mild-moderate pain, Opioid sparing, Antipyretic	CNS: Causes dissociative anaesthesia - Hallucinations - Emergence delirium CVS: Indirect sympathomimetic chronotropy, inotrophy and Hypertension Direct cardiodepressant  if depletion of NA  hypotension Resp - Bronchodilation	As an anti-inflammatory, anti-pyretic and mild analgesic	CNS: - Analgesia - Hallucinations - Confusion - Delirium - Agitation - Seizures - Coma (Serotonin syndrome) Respiratory depression and constipation	CNS Gabapentin has analgesic and anticonvulsant properties and improves sleep in patients with neuropathic pain.	CNS Pregabalin has analgesic, anticonvulsant, and anxiolytic properties
PD: Side Effects / Toxicity	Very safe SE profile. Safe in ped,preg. Toxicity – hepatic and renal toxicity. plasma levels should be plotted on a nomogram and consideration of NAC infusion commenced as appropriate. ALT is a marker of damage.	Increased salivation - Upper airway reflexes intact  laryngospasm - Hypotension if given in shock states - Emergence delirium	Worsen renal function by inhibiting PGE2 and causing vasoconstriction.  risk of thromboembolic events. Increased risk of GI bleeding and ulceration, GORD. Impair platelet function May reduce the beneficial eff¬ects of aspirin	Dysphoria,Euphoria. Miosis (excitation of Edinger-Westphal nucleus) N/V -CTZ stim. Serotonin syndrome with SSRI /SNRI/MAO/TCA Less resp dep than morphine analgesic effect in CYP2D6 deficiency	Dizziness, ataxia, nystagmus, somnolence, tremor, diplopia, nausea, and vomiting occur with a frequency >5%. Leucopenia, erectile dysfunction, and weight gain	PD: Side Effects / Toxicity Very safe SE profile. Safe in ped,preg. Toxicity – hepatic and renal toxicity. plasma levels should be plotted on a nomogram and consideration of NAC infusion commenced as appropriate. ALT is a marker of damage. Increased salivation - Upper airway reflexes intact  laryngospasm - Hypotension if given in shock states - Emergence delirium Worsen renal function by inhibiting PGE2 and causing vasoconstriction.  risk of thromboembolic events. Increased risk of GI bleeding and ulceration, GORD. Impair platelet function May reduce the beneficial eff¬ects of aspirin Dysphoria,Euphoria. Miosis (excitation of Edinger-Westphal nucleus) N/V -CTZ stim. Serotonin syndrome with SSRI /SNRI/MAO/TCA Less resp dep than morphine analgesic effect in CYP2D6 deficiency Dizziness, ataxia, nystagmus, somnolence, tremor, diplopia, nausea, and vomiting occur with a frequency >5%. Leucopenia, erectile dysfunction, and weight gain Weight gain in diabetic patients Dizziness, somnolence Blurry vision, reduced visual acuity, diplopia


PHARMACOKINETICS (PK)
PK: Absorption	PO bioavailability 60-90% (Small intest)	A: 20% oral bioavailability	Rapidly absorbed 85% bioavailability	Bioavailability- 75% PO	PO BA 60%	PO BA >90% Rapidly absorbed in fasted state

PK: Distribution	Lipid solubility intermediate pKa 9.5		pKa 4.5, weak acid therefore mostly unionised, abs via gut and SB	Crosses placenta Lipid soluble-crosses BBB	CSF concentration ~20% of plasma Present in breastmilk	Crosses placenta and seen in breastmilk
Protein binding (PK: Distribution)	Low protein binding (5%)	25%	99% protein bound (may displace highly protein bound drugs such as warfarin altering PD properties)	Prot bind-20%	Not protein bound	Not protein bound
Volume of distribution (PK: Distribution)	Vd = 1L/kg	3l/kg	Very small Vd 0.1L/kg	Vd- 2.5-3L/kg	0.85 L/kg	0.56 L/kg

PK: Metabolism	Metabolised by the liver to glucuronide, sulphate and cysteine conjugates.	Hepatic metabolism with active norketamine metabolite	hepatic via oxidation	Extensively hepatic via demethylation , glucuronidation, and sulfation; active metabolite by CYP2D6 (M1; O-desmethyl tramadol)	Not metabolized	Minimal 0.9% N-methylated pregabalin

PK: Excretion	Renal excretion of glucuronide, sulphide metabolites. Inactive, build up in renal failure.	Renal elimination	excreted as metabolites in urine 1% unchanged	Urine 90% (30% unchanged), 10% faeces.	Renal – unchanged	Renal – 98% unchanged
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	half life ~2 hours - prolonged in overdosage and renal dx.	T1/2a 15 mins, T1/2b 2~3 hours, CSHT 40mins at 5 hours	half life 2-3 hours	T1/2: ~6-8 hrs; Act metab:7-9hrs; old, hepatic/renal imp.	T1/2: 5-7 hrs Clearance proportional to creatinine clearance	T1/2: 6.3hrs


SPECIAL POINTS					- enhances analgesic effect of morphine - removed by haemodialysis	Avoid in galactose intolerance, lactase deficiency or glucose-galactose malabsorption - Removed by haemodialysis (conc reduced by 50% after 4hrs)

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ANTIDOTES

Pharmacopeia - Neuro Antidotes

	NALOXONE	N-ACETYL CYSTEINE (NAC)	PRALIDOXIME
GROUP	Antidote	Antidote	Antidote
CICM Level of Understanding	Level 3	Level 3	Level 3

INTRODUCTION
USES	- the reversal of respiratory depression due to opioids - the diagnosis of suspected opioid overdose and has been used in the treatment of. - clonidine overdose	- paracetamol overdose - non-paracetamol induced fulminant hepatic failure - prevention of contrast nephropathy - mucolytic therapy	- Organophosphate poisoning - Acetylcholinesterase Inhibitor toxicity (Neostigmine, Pyridostigmine)


PHARMACEUTICS (PC)
PC: Chemical	substituted oxymorphone derivative. pKa = 8.0	Synthetic derivative of cysteine	Synthetic oxime of Pyridine-2-carboxaldehyde
PC: Presentation	clear solution for injection containing 0.02/0.4 mg/ml of naloxone hydrochloride	IV or oral formulation 200mg/mL compatible with 5% dextrose	IV: Reconstituted 1gm solution IM: auto-injector 600mg/2ml


PHARMACODYNAMICS (PD)
PD: Main Action	competitive antagonist at mu-, delta-, kappa-, and sigma-opioid receptors	antioxidant and glutathione inducer	antidote to organophosphate
PD: Mode of Action	Reversal of MoP receptor effects such as sedation, hypotension, respiratory depression, and the dysphoric effects of partial agonists Will precipitate acute withdrawal symptoms in opiate addicts	- Metabolized to cysteine → Regeneration of sulphydril groups and glutathione - acting as an alternate substrate for conjugation - reduces disulfide bonds in mucoproteins	reactivator of phosphorylated Acetylcholinesterase by promoting hydrolysis
PD: Route & Doses	IV/IM - Reversal of post-operative respiratory depression and coma: 20-40mcg IV PRN - For opioid overdose reversal 0.4-2 mg IM/IV → Via infusion a 5mcg/kg/hr - Reversal of S/Es of opioids: 1-4 mcg/kg - Increased cardiac contractility in septic shock at doses 1mg/kg IV	IV, PO, Neb (inhaled) IV: 1st : 150mg/kg in 200ml dextrose over 15mins 2nd : 50mg/kg in 500ml over 4hrs 3rd : 100mg/kg in 1l over 16hrs	IV/IM/SC OP poisoning: 30 mg/kg IV (max 2gm) (600mg IM every 15min upto 1.8gm, SC if no IV access) over 20 min; follow by 8-10 mg/kg/hr (max 650mg) maintenance IV infusion Acetylcholinesterase Inhibitor Toxicity: (Neostigmine, Pyridostigmine) 1-2 g IV followed by 250 mg increments q5min PRN
PD: Metrics (Onset/ Peak/ Duration)	Onset: 1-3 mins Peak effect: 15 mins Duration: 30 mins > Less than the effect site time of most opioids → requirement for repeat dosing or infusion.	Duration: short	Onset: 5-15 min
PD: Effects	- CVS: > 0.3 mg/kg → ↑MAP - RESP: nil - CNS: Drowsiness at high dose, Decreased pain tolerance - OTHER: Sphincter of oddi spasm	- Reduces hepatotoxicity - mucolytic
PD: Side Effects / Toxicity	Rapid onset of withdrawal symptoms in opioid drug addiction At High Doses: - Hypertension - Tachycardia - Arrhythmias	usually in 1st hr: - rash around infusion site - angiooedema - bronchospasm - hypo/hyper tension Mx: stop, give antihistamine, then restart at slowest infusion rate	Cardiac arrest, hypertension, tachycardia muscle rigidity, weakness Transient transaminitis


PHARMACOKINETICS (PK)
PK: Absorption	91% absorption but Oral BA 2% due to extensive first-pass metabolism	PO: BA low	-

PK: Distribution
Protein binding (PK: Distribution)	46%	66-97% Albumin	None
Volume of distribution (PK: Distribution)	2 L/kg Highly lipid soluble	0.5 L/kg	0.6-2.7 L/kg may increase in severe organophosphate intoxication

PK: Metabolism	Liver via glucuronidation to naloxone-3-glucouronide	Liver Deacetylated to cysteine -> normal metabolism (Rapid)	Liver

PK: Excretion		Unchanged: 40% urine, 3% feces	Urine: 80% metabolites + unchanged
- Clearance (PK: Excretion)	25 ml/min/kg
- Half Life (PK: Excretion)	0.5-1.5 hrs	5.5 hrs	3-4 hr (IM, IV)


SPECIAL POINTS	effective in alleviating the pruritus, nausea, and respiratory depression associated with the epidural or spinal administration of opioids.

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INDIVIDUAL TABLES

KETAMINE

Pharmacopeia - Non-Opiate Analgesics

	KETAMINE
GROUP	Non-Opiate Analgesic
CICM Level of Understanding	Level 1

INTRODUCTION	Phencyclidine (remember the street drug name PCP) derivative that produces dissociative anesthesia
USES	Induction of anaesthesia - Procedural sedation - Analgesia - ?Role in management of depression. - Recreational


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	10, 50 or 100mg/ml


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	NMDA receptor antagonism - Inhibits excitatory signaling within CNS - Also inhibits noradrenaline reuptake in sympathetic nerve terminals
PD: Route & Doses	- 1mg/kg induction dose - 10~20mg analgesia
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CNS: Causes dissociative anaesthesia - Hallucinations - Emergence delirium CVS: Indirect sympathomimetic chronotropy, inotrophy and Hypertension Direct cardiodepressant  if depletion of NA  hypotension Resp - Bronchodilation
PD: Side Effects / Toxicity	Increased salivation - Upper airway reflexes intact  laryngospasm - Hypotension if given in shock states - Emergence delirium


PHARMACOKINETICS (PK)
PK: Absorption	A: 20% oral bioavailability

PK: Distribution
Protein binding (PK: Distribution)	25%
Volume of distribution (PK: Distribution)	3l/kg

PK: Metabolism	Hepatic metabolism with active norketamine metabolite

PK: Excretion	Renal elimination
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2a 15 mins, T1/2b 2~3 hours, CSHT 40mins at 5 hours


SPECIAL POINTS

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FENTANYL | REMIFENTANIL
Pharmacokinetics and Pharmacodynamics

Pharmacopeia - Opiate Analgesics

	FENTANYL	REMIFENTANIL
GROUP	Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 1	Level 2

PHARMACOKINETICS (PK)
PK: Absorption	IV/IM/TD. BA PO 30%SL50%skin>90% onset IM.: 7-8 mins; IV imm; TD 6 hrs duration IM:1-2 hrs; IV:0.5-1hr; TD 12hrs	IV only onset / duration 1-3 minutes

PK: Distribution	relative lipid sol 500 Rapid redistribution pKa 8.4(10% union)	relative lipid sol 50 rapid redistribution pKa 7.1 (70% union)
Protein binding (PK: Distribution)	prot bind 80-85%	Prot bind ~70% (1 acid glycoprotein)
Volume of distribution (PK: Distribution)	Mod Vd 4-6L/kg	Vd 0.3L/kg kids

PK: Metabolism	Slow Hepatic, primarily via CYP3A4clearance	Rapid metabolism via blood and Plasma esterase - used in liver/ renal disease, different age, sex, body habitus without sign dose modificn

PK: Excretion	excretion Urine 75%	excretion urine
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	half life I.V.: 2-4 hours, prolonged context sensitive half time	half life Terminal: 10-20 minutes; effective: 3-10 minutes No CSHT

PHARMACODYNAMICS (PD)
PD: Main Action	μ receptor agonist	Pure mu receptor agonist
PD: Mode of Action	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release
PD: Route & Doses	Bolus: 1-2 mcg/kg inf: 1-2 mcg/kg/hr (relative potency 50-100)	Dose 1mcg/kg bolus, titrate eff¬ect (relative potency 50-100)
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	inhibitory action, modulating the pain response to produce analgesia. less likely to ppt histamine release norad& serotonin axn, excitatory centrally	inhibitory action, modulating the pain response to produce analgesia. shares many of its actions with morphine and related compounds
PD: Side Effects / Toxicity	Similar to other opioids. Differences due to lipid sol. Does not cause delayed respiratory depression because it rapidly diffuses into and out of the CSF. Raised CSHT prolonged infusion may lead to increased duration of action and SE	Bradycardia, hypotension, muscle rigidity, May contribute to hyperalgesia following prolonged infusion

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FENTANYL | MORPHINE

Pharmacopeia - Opiate Analgesics

	FENTANYL	MORPHINE
GROUP	Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 1	Level 1

INTRODUCTION	Tertiary amine which is a synthetic phenylpiperidine derivative	naturally occuring phenanthrene derivative from papaver somniferum plant
USES	1. to provide the analgesic component in general anaesthesia 2. in combination with a major tranquillizer to produce neuroleptanalgesia 3. to provide analgesia during labour when regional anaesthesia is not in use 4. as an agent used for patient-controlled analgesia 5. in premedication and 6. for palliative care	1. for premedication 2. as an analgesic in the management of moderate to severe pain 3. in the treatment of left ventricular failure 4. to provide analgesia during terminal care, and 5. in combination with kaolin in the symptomatic treatment of diarrhoea


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	colourless solution 50mcg/ml, TDpatch (25mcg-100mcg/hr) and as lozenges	either as a clear liquid for injection, orally in immediate (liquid or tablet) and sustained release (MS Contin)


PHARMACODYNAMICS (PD)
PD: Main Action	μ receptor agonist	primarily CNS μ receptor activity, also κ and δ.
PD: Mode of Action	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release
PD: Route & Doses	Bolus: 1-2 mcg/kg inf: 1-2 mcg/kg/hr (relative potency 50-100)	Dose 5-10mg titrate eff¬ect, may increase x100 with tolerance (relative potency 1)
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	inhibitory action, modulating the pain response to produce analgesia. less likely to ppt histamine release norad& serotonin axn, excitatory centrally	CNS: Opioid receptors present in cerebral cortex, periaqueductal grey, nucleus accumbens, area postrema, thalamus and NTS - Analgesia - Sedation - Respiratory depression - Nausea - Euphoria - Psychotomimetics Seizures (due to M6G metabolite) PNS Excitatory action Histamine release
PD: Side Effects / Toxicity	Similar to other opioids. Differences due to lipid sol. Does not cause delayed respiratory depression because it rapidly diffuses into and out of the CSF. Raised CSHT prolonged infusion may lead to increased duration of action and SE	CNS: dysphoria, confusion, ↓LoC, ↓cough reflex, miosis(PNS) CVS: hypotension (↓TPR, blunt baroreceptor reflexes) Resp: dir ↓resp drive indir via obtundation GI: ↓gut motility, ↓SB secretions, CTZ→N+V, constipn, CBD spasm. GU: Urinary retention skin flushing, pruritis(histamine) Dependence, addiction,Tolernce. IT – resp dep (rostral migration)


PHARMACOKINETICS (PK)
PK: Absorption	IV/IM/TD. BA PO 30%SL50%skin>90% onset IM.: 7-8 mins; IV imm; TD 6 hrs duration IM:1-2 hrs; IV:0.5-1hr; TD 12hrs	PO/IV/IM/SC/SL/IT Poor bioavailability 30% (good abs but high 1st pass metab) onset / duration Oral ~30 minutes; I.V.: 5-10 minutes

PK: Distribution	relative lipid sol 500 Rapid redistribution pKa 8.4(10% union)	relative lipid sol 1 but crosses BBB pKa 8.0 (25% unionised) slow redistribution
Protein binding (PK: Distribution)	prot bind 80-85%	prot bind 20-40% (Alb)
Volume of distribution (PK: Distribution)	Mod Vd 4-6L/kg	mod Vd 3-4L/kg

PK: Metabolism	Slow Hepatic, primarily via CYP3A4clearance	Metabolised to morphine-3-glucuronide (70%) and morphine-6-glucuronide (10%) by gut wall and liver. M6G is 10-20 times potent, may accumulate in renal failure

PK: Excretion	excretion Urine 75%	Excreted mainly in urine as conjugates with 10% in faeces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	half life I.V.: 2-4 hours, prolonged context sensitive half time	Half time 2-4hrs (large interpatient Variability)


SPECIAL POINTS	- Incompatible with thiopental - Dialysis - unknown	May precipitate encephalopathy in hepatic failure May precipitate coma in hypopituitarism Good reversal with naloxone (does not affect epidural analgesia) Not removed by haemo/peritoneal dialysis

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MORPHINE | FENTANYL
Pharmacokinetics and Adverse Effects

Pharmacopeia - Opiate Analgesics

	MORPHINE	FENTANYL
GROUP	Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 1	Level 1


PHARMACOKINETICS (PK)
PK: Absorption	PO/IV/IM/SC/SL/IT Poor bioavailability 30% (good abs but high 1st pass metab) onset / duration Oral ~30 minutes; I.V.: 5-10 minutes	IV/IM/TD. BA PO 30%SL50%skin>90% onset IM.: 7-8 mins; IV imm; TD 6 hrs duration IM:1-2 hrs; IV:0.5-1hr; TD 12hrs

PK: Distribution	relative lipid sol 1 but crosses BBB pKa 8.0 (25% unionised) slow redistribution	relative lipid sol 500 Rapid redistribution pKa 8.4(10% union)
Protein binding (PK: Distribution)	prot bind 20-40% (Alb)	prot bind 80-85%
Volume of distribution (PK: Distribution)	mod Vd 3-4L/kg	Mod Vd 4-6L/kg

PK: Metabolism	Metabolised to morphine-3-glucuronide (70%) and morphine-6-glucuronide (10%) by gut wall and liver. M6G is 10-20 times potent, may accumulate in renal failure	Slow Hepatic, primarily via CYP3A4clearance

PK: Excretion	Excreted mainly in urine as conjugates with 10% in faeces	excretion Urine 75%
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Half time 2-4hrs (large interpatient Variability)	half life I.V.: 2-4 hours, prolonged context sensitive half time

PD: Side Effects / Toxicity	CNS: dysphoria, confusion, ↓LoC, ↓cough reflex, miosis(PNS) CVS: hypotension (↓TPR, blunt baroreceptor reflexes) Resp: dir ↓resp drive indir via obtundation GI: ↓gut motility, ↓SB secretions, CTZ→N+V, constipn, CBD spasm. GU: Urinary retention skin flushing, pruritis(histamine) Dependence, addiction,Tolernce. IT – resp dep (rostral migration)	Similar to other opioids. Differences due to lipid sol. Does not cause delayed respiratory depression because it rapidly diffuses into and out of the CSF. Raised CSHT prolonged infusion may lead to increased duration of action and SE

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MORPHINE | FENTANYL | REMIFENTANIL

Pharmacopeia - Opiate Analgesics

	MORPHINE	FENTANYL	REMIFENTANIL
GROUP	Opiate Analgesic	Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 1	Level 1	Level 2

INTRODUCTION	naturally occuring phenanthrene derivative from papaver somniferum plant	Tertiary amine which is a synthetic phenylpiperidine derivative	synthetic phenylpiperdine derivative of fentanyl with a unique metabolism
USES	1. for premedication 2. as an analgesic in the management of moderate to severe pain 3. in the treatment of left ventricular failure 4. to provide analgesia during terminal care, and 5. in combination with kaolin in the symptomatic treatment of diarrhoea	1. to provide the analgesic component in general anaesthesia 2. in combination with a major tranquillizer to produce neuroleptanalgesia 3. to provide analgesia during labour when regional anaesthesia is not in use 4. as an agent used for patient-controlled analgesia 5. in premedication and 6. for palliative care	1. to provide the analgesic component in general anaesthesia 2. to provide analgesia/sedation in intensive care 3. to provide analgesia during labour when regional anaesthesia is not in use 4. to provide analgesia/sedation during ‘awake’ fibreoptic intubation.


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	either as a clear liquid for injection, orally in immediate (liquid or tablet) and sustained release (MS Contin)	colourless solution 50mcg/ml, TDpatch (25mcg-100mcg/hr) and as lozenges	white crystalline powder for reconstitution


PHARMACODYNAMICS (PD)
PD: Main Action	primarily CNS μ receptor activity, also κ and δ.	μ receptor agonist	Pure mu receptor agonist
PD: Mode of Action	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release
PD: Route & Doses	Dose 5-10mg titrate eff¬ect, may increase x100 with tolerance (relative potency 1)	Bolus: 1-2 mcg/kg inf: 1-2 mcg/kg/hr (relative potency 50-100)	Dose 1mcg/kg bolus, titrate eff¬ect (relative potency 50-100)
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CNS: Opioid receptors present in cerebral cortex, periaqueductal grey, nucleus accumbens, area postrema, thalamus and NTS - Analgesia - Sedation - Respiratory depression - Nausea - Euphoria - Psychotomimetics Seizures (due to M6G metabolite) PNS Excitatory action Histamine release	inhibitory action, modulating the pain response to produce analgesia. less likely to ppt histamine release norad& serotonin axn, excitatory centrally	inhibitory action, modulating the pain response to produce analgesia. shares many of its actions with morphine and related compounds
PD: Side Effects / Toxicity	CNS: dysphoria, confusion, ↓LoC, ↓cough reflex, miosis(PNS) CVS: hypotension (↓TPR, blunt baroreceptor reflexes) Resp: dir ↓resp drive indir via obtundation GI: ↓gut motility, ↓SB secretions, CTZ→N+V, constipn, CBD spasm. GU: Urinary retention skin flushing, pruritis(histamine) Dependence, addiction,Tolernce. IT – resp dep (rostral migration)	Similar to other opioids. Differences due to lipid sol. Does not cause delayed respiratory depression because it rapidly diffuses into and out of the CSF. Raised CSHT prolonged infusion may lead to increased duration of action and SE	Bradycardia, hypotension, muscle rigidity, May contribute to hyperalgesia following prolonged infusion


PHARMACOKINETICS (PK)
PK: Absorption	PO/IV/IM/SC/SL/IT Poor bioavailability 30% (good abs but high 1st pass metab) onset / duration Oral ~30 minutes; I.V.: 5-10 minutes	IV/IM/TD. BA PO 30%SL50%skin>90% onset IM.: 7-8 mins; IV imm; TD 6 hrs duration IM:1-2 hrs; IV:0.5-1hr; TD 12hrs	IV only onset / duration 1-3 minutes

PK: Distribution	relative lipid sol 1 but crosses BBB pKa 8.0 (25% unionised) slow redistribution	relative lipid sol 500 Rapid redistribution pKa 8.4(10% union)	relative lipid sol 50 rapid redistribution pKa 7.1 (70% union)
Protein binding (PK: Distribution)	prot bind 20-40% (Alb)	prot bind 80-85%	Prot bind ~70% (1 acid glycoprotein)
Volume of distribution (PK: Distribution)	mod Vd 3-4L/kg	Mod Vd 4-6L/kg	Vd 0.3L/kg kids

PK: Metabolism	Metabolised to morphine-3-glucuronide (70%) and morphine-6-glucuronide (10%) by gut wall and liver. M6G is 10-20 times potent, may accumulate in renal failure	Slow Hepatic, primarily via CYP3A4clearance	Rapid metabolism via blood and Plasma esterase - used in liver/ renal disease, different age, sex, body habitus without sign dose modificn

PK: Excretion	Excreted mainly in urine as conjugates with 10% in faeces	excretion Urine 75%	excretion urine
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Half time 2-4hrs (large interpatient Variability)	half life I.V.: 2-4 hours, prolonged context sensitive half time	half life Terminal: 10-20 minutes; effective: 3-10 minutes No CSHT


SPECIAL POINTS	May precipitate encephalopathy in hepatic failure May precipitate coma in hypopituitarism Good reversal with naloxone (does not affect epidural analgesia) Not removed by haemo/peritoneal dialysis	- Incompatible with thiopental - Dialysis - unknown	Clearance of metabolite remifentanil acid - prolonged in renal impairment (up to 268 hrs) Metabolite concentration significantly increased in ICU patients with mod-severe renal impairment – but no evidence of clinically significant mu-opioid effects Remifentanil not extracted during RRT. Metabolite extracted 25-35% during hemodialysis.

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MORPHINE | TRAMADOL
Mechanism of Action, Pharmacokinetics, CNS Effects

Pharmacopeia - Analgesics

	MORPHINE	TRAMADOL
GROUP	Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 1	Level 2

PHARMACODYNAMICS (PD)
PD: Main Action	primarily CNS μ receptor activity, also κ and δ.	mod affinity for μ receptors, weak κ, δ
PD: Mode of Action	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release	mod affinity for μ receptors, weak κ, δ -in spinal desc inh pathways by inh of neuronal reuptake of norad&serotonin -presynaptic stim of seritonin release
PD: Effects	CNS: Opioid receptors present in cerebral cortex, periaqueductal grey, nucleus accumbens, area postrema, thalamus and NTS - Analgesia - Sedation - Respiratory depression - Nausea - Euphoria - Psychotomimetics Seizures (due to M6G metabolite) PNS Excitatory action Histamine release	CNS: - Analgesia - Hallucinations - Confusion - Delirium - Agitation - Seizures - Coma (Serotonin syndrome) Respiratory depression and constipation

PHARMACOKINETICS (PK)
PK: Absorption	PO/IV/IM/SC/SL/IT Poor bioavailability 30% (good abs but high 1st pass metab) onset / duration Oral ~30 minutes; I.V.: 5-10 minutes	Bioavailability- 75% PO

PK: Distribution	relative lipid sol 1 but crosses BBB pKa 8.0 (25% unionised) slow redistribution	Crosses placenta Lipid soluble-crosses BBB
Protein binding (PK: Distribution)	prot bind 20-40% (Alb)	20%
Volume of distribution (PK: Distribution)	mod Vd 3-4L/kg	2.5-3L/kg

PK: Metabolism	Metabolised to morphine-3-glucuronide (70%) and morphine-6-glucuronide (10%) by gut wall and liver. M6G is 10-20 times potent, may accumulate in renal failure	Extensively hepatic via demethylation , glucuronidation, and sulfation; active metabolite by CYP2D6 (M1; O-desmethyl tramadol)

PK: Excretion	Excreted mainly in urine as conjugates with 10% in faeces	Urine 90% (30% unchanged), 10% faeces.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Half time 2-4hrs (large interpatient Variability)	T1/2: ~6-8 hrs; Act metab:7-9hrs; old, hepatic/renal imp.


SPECIAL POINTS	May precipitate encephalopathy in hepatic failure May precipitate coma in hypopituitarism Good reversal with naloxone (does not affect epidural analgesia) Not removed by haemo/peritoneal dialysis

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OXYCODONE

Pharmacopeia - Opiate Analgesics

	OXYCODONE
GROUP	Opiate Analgesic
CICM Level of Understanding	Level 1

INTRODUCTION	semi-synthetic thebaine (opium alkaloid) derivative
USES	1. the treatment of moderate to severe pain in patients with cancer and post-operative pain and 2. in the treatment of severe pain requiring a strong opioid.


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	white tablets – immediate/sustained release. Paracet Combo in US


PHARMACODYNAMICS (PD)
PD: Main Action	primarily μ receptor activity but also has some weak κ and δ receptor activity
PD: Mode of Action	Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release
PD: Route & Doses	20mg Oxy PO = 10mg Morphine IV (Relative potency 0.5)
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	inhibitory action, modulating the pain response to produce analgesia. Mainly mu receptor actions
PD: Side Effects / Toxicity	weak K action may cause some of the negative effects (dysphoria, psychomimetic) Interindividual variability in metabolism. Other standard opioid side effects.


PHARMACOKINETICS (PK)
PK: Absorption	PO. BA 60-87% onset / duration 10-15 minutes / 3-6 hours

PK: Distribution	LipId sol high- crosses BBB
Protein binding (PK: Distribution)	Prot bind ~45%
Volume of distribution (PK: Distribution)	Vd 2.6L/kg

PK: Metabolism	CYP3A family metabolism to noroxycodone and via CYP2D6 to oxymorphone (active), both subsequently conjugated

PK: Excretion	excretion urine
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	half life 2-4 hrs


SPECIAL POINTS	May precipitate encephalopathy in hepatic failure Good reversal with naloxone

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NALOXONE

Pharmacopeia - Neuro Antidotes

	NALOXONE
GROUP	Antidote
CICM Level of Understanding	Level 3

INTRODUCTION
USES	- the reversal of respiratory depression due to opioids - the diagnosis of suspected opioid overdose and has been used in the treatment of. - clonidine overdose


PHARMACEUTICS (PC)
PC: Chemical	substituted oxymorphone derivative. pKa = 8.0
PC: Presentation	clear solution for injection containing 0.02/0.4 mg/ml of naloxone hydrochloride


PHARMACODYNAMICS (PD)
PD: Main Action	competitive antagonist at mu-, delta-, kappa-, and sigma-opioid receptors
PD: Mode of Action	Reversal of MoP receptor effects such as sedation, hypotension, respiratory depression, and the dysphoric effects of partial agonists Will precipitate acute withdrawal symptoms in opiate addicts
PD: Route & Doses	IV/IM - Reversal of post-operative respiratory depression and coma: 20-40mcg IV PRN - For opioid overdose reversal 0.4-2 mg IM/IV → Via infusion a 5mcg/kg/hr - Reversal of S/Es of opioids: 1-4 mcg/kg - Increased cardiac contractility in septic shock at doses 1mg/kg IV
PD: Metrics (Onset/ Peak/ Duration)	Onset: 1-3 mins Peak effect: 15 mins Duration: 30 mins > Less than the effect site time of most opioids → requirement for repeat dosing or infusion.
PD: Effects	- CVS: > 0.3 mg/kg → ↑MAP - RESP: nil - CNS: Drowsiness at high dose, Decreased pain tolerance - OTHER: Sphincter of oddi spasm
PD: Side Effects / Toxicity	Rapid onset of withdrawal symptoms in opioid drug addiction At High Doses: - Hypertension - Tachycardia - Arrhythmias


PHARMACOKINETICS (PK)
PK: Absorption	91% absorption but Oral BA 2% due to extensive first-pass metabolism

PK: Distribution
Protein binding (PK: Distribution)	46%
Volume of distribution (PK: Distribution)	2 L/kg Highly lipid soluble

PK: Metabolism	Liver via glucuronidation to naloxone-3-glucouronide

PK: Excretion
- Clearance (PK: Excretion)	25 ml/min/kg
- Half Life (PK: Excretion)	0.5-1.5 hrs


SPECIAL POINTS	effective in alleviating the pruritus, nausea, and respiratory depression associated with the epidural or spinal administration of opioids.

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IBUPROFEN | PARACETAMOL

Pharmacopeia - Non-Opiate Analgesics

	NSAIDS - IBUPROFEN	PARACETAMOL
GROUP	Non-Opiate Analgesic	Non-Opiate Analgesic
CICM Level of Understanding	Level 3	Level 1

INTRODUCTION	non selective cycloxygenase inhibitor	Acetanalide derivative
USES	Analgesia Antipyretic Antiinflammatory	Analgesia Anitpyretic


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	200mg tablets, some formulations in combination with codiene	Tablets, IV formulation with 10mg/mL containing mannitol, Combination formulations with codeine and non-steroidals


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Reversibly inhibits COX 1 and 2 enzymes causing decreased production of prostaglandin precursors	Not entirely elucidated 1. Reduced prostaglandin synthesis in areas of inflammation ? COX 3 inhibition a) ↓ PGE2 in Hypothalamus → Anti-pyretic effect 2. Analgesic Effect a) ↓’d central serotonergic reuptake → ↑ descending b) 5HT agonist → enhanced descending inhibitory pain pathways. c) Central inhibition of endocannabinoid uptake d) Peripheral afferent nociceptive chemoreceptor impulse blockade via bradykinin inhibition synergistic with opioid medications, reducing the overall opioid requirement by 20-30%
PD: Route & Doses	Tablets for PO/PR	Route: Tablets, IV Dose: 15mg/kg to 1g QID
PD: Metrics (Onset/ Peak/ Duration)	onset 30 mins, duration 6 hours	onset / duration PO <1 hr / 4-6 hrs, IV 10-15mins / 4-6 hrs
PD: Effects	As an anti-inflammatory, anti-pyretic and mild analgesic	Functional class: Antipyretic, Analgesic Indications: Mild-moderate pain, Opioid sparing, Antipyretic
PD: Side Effects / Toxicity	Worsen renal function by inhibiting PGE2 and causing vasoconstriction.  risk of thromboembolic events. Increased risk of GI bleeding and ulceration, GORD. Impair platelet function May reduce the beneficial eff¬ects of aspirin	Very safe SE profile. Safe in ped,preg. Toxicity – hepatic and renal toxicity. plasma levels should be plotted on a nomogram and consideration of NAC infusion commenced as appropriate. ALT is a marker of damage.


PHARMACOKINETICS (PK)
PK: Absorption	Rapidly absorbed 85% bioavailability	PO bioavailability 60-90% (Small intest)

PK: Distribution	pKa 4.5, weak acid therefore mostly unionised, abs via gut and SB	Lipid solubility intermediate pKa 9.5
Protein binding (PK: Distribution)	99% protein bound (may displace highly protein bound drugs such as warfarin altering PD properties)	Low protein binding (5%)
Volume of distribution (PK: Distribution)	Very small Vd 0.1L/kg	Vd = 1L/kg

PK: Metabolism	hepatic via oxidation	Metabolised by the liver to glucuronide, sulphate and cysteine conjugates.

PK: Excretion	excreted as metabolites in urine 1% unchanged	Renal excretion of glucuronide, sulphide metabolites. Inactive, build up in renal failure.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	half life 2-3 hours	half life ~2 hours - prolonged in overdosage and renal dx.


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IBUPROFEN | TRAMADOL

Pharmacopeia - Non-Opiate Analgesics

	NSAIDS - IBUPROFEN	TRAMADOL
GROUP	Non-Opiate Analgesic	Opiate Analgesic
CICM Level of Understanding	Level 3	Level 2

INTRODUCTION	non selective cycloxygenase inhibitor	Is a synthetic opioid – cyclohexanol derivative Racemic mix.
USES	Analgesia Antipyretic Antiinflammatory	Analgesia


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	200mg tablets, some formulations in combination with codiene	immediate release, 12 hour release and 24 hour release tablets, IV


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Reversibly inhibits COX 1 and 2 enzymes causing decreased production of prostaglandin precursors	mod affinity for μ receptors, weak κ, δ -in spinal desc inh pathways by inh of neuronal reuptake of norad&serotonin -presynaptic stim of seritonin release
PD: Route & Doses	Tablets for PO/PR	Route- PO/IV Dose- 50-100mg QID for all routes (Relative pot 0.2)
PD: Metrics (Onset/ Peak/ Duration)	onset 30 mins, duration 6 hours	onset / duration ~1 hour / 9 hours (immediate release)
PD: Effects	As an anti-inflammatory, anti-pyretic and mild analgesic	CNS: - Analgesia - Hallucinations - Confusion - Delirium - Agitation - Seizures - Coma (Serotonin syndrome) Respiratory depression and constipation
PD: Side Effects / Toxicity	Worsen renal function by inhibiting PGE2 and causing vasoconstriction.  risk of thromboembolic events. Increased risk of GI bleeding and ulceration, GORD. Impair platelet function May reduce the beneficial eff¬ects of aspirin	Dysphoria,Euphoria. Miosis (excitation of Edinger-Westphal nucleus) N/V -CTZ stim. Serotonin syndrome with SSRI /SNRI/MAO/TCA Less resp dep than morphine analgesic effect in CYP2D6 deficiency


PHARMACOKINETICS (PK)
PK: Absorption	Rapidly absorbed 85% bioavailability	Bioavailability- 75% PO

PK: Distribution	pKa 4.5, weak acid therefore mostly unionised, abs via gut and SB	Crosses placenta Lipid soluble-crosses BBB
Protein binding (PK: Distribution)	99% protein bound (may displace highly protein bound drugs such as warfarin altering PD properties)	Prot bind-20%
Volume of distribution (PK: Distribution)	Very small Vd 0.1L/kg	Vd- 2.5-3L/kg

PK: Metabolism	hepatic via oxidation	Extensively hepatic via demethylation , glucuronidation, and sulfation; active metabolite by CYP2D6 (M1; O-desmethyl tramadol)

PK: Excretion	excreted as metabolites in urine 1% unchanged	Urine 90% (30% unchanged), 10% faeces.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	half life 2-3 hours	T1/2: ~6-8 hrs; Act metab:7-9hrs; old, hepatic/renal imp.


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Y05b. Pharmacopeia: Pain Neuropharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLES

OPIATE ANALGESICS

Pharmacopeia - Opiate Analgesics

NON-OPIATE ANALGESICS

Pharmacopeia - Non-Opiate Analgesics

ANTIDOTES

Pharmacopeia - Neuro Antidotes

INDIVIDUAL TABLES

KETAMINE

Pharmacopeia - Non-Opiate Analgesics

FENTANYL | REMIFENTANIL
Pharmacokinetics and Pharmacodynamics

Pharmacopeia - Opiate Analgesics

FENTANYL | MORPHINE

Pharmacopeia - Opiate Analgesics

MORPHINE | FENTANYL
Pharmacokinetics and Adverse Effects

Pharmacopeia - Opiate Analgesics

MORPHINE | FENTANYL | REMIFENTANIL

Pharmacopeia - Opiate Analgesics

MORPHINE | TRAMADOL
Mechanism of Action, Pharmacokinetics, CNS Effects

Pharmacopeia - Analgesics

OXYCODONE

Pharmacopeia - Opiate Analgesics

NALOXONE

Pharmacopeia - Neuro Antidotes

IBUPROFEN | PARACETAMOL

Pharmacopeia - Non-Opiate Analgesics

IBUPROFEN | TRAMADOL

Pharmacopeia - Non-Opiate Analgesics

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Y05b. Pharmacopeia: Pain Neuropharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLES

OPIATE ANALGESICS

Pharmacopeia - Opiate Analgesics

NON-OPIATE ANALGESICS

Pharmacopeia - Non-Opiate Analgesics

ANTIDOTES

Pharmacopeia - Neuro Antidotes

INDIVIDUAL TABLES

KETAMINE

Pharmacopeia - Non-Opiate Analgesics

FENTANYL | REMIFENTANILPharmacokinetics and Pharmacodynamics

Pharmacopeia - Opiate Analgesics

FENTANYL | MORPHINE

Pharmacopeia - Opiate Analgesics

MORPHINE | FENTANYLPharmacokinetics and Adverse Effects

Pharmacopeia - Opiate Analgesics

MORPHINE | FENTANYL | REMIFENTANIL

Pharmacopeia - Opiate Analgesics

MORPHINE | TRAMADOLMechanism of Action, Pharmacokinetics, CNS Effects

Pharmacopeia - Analgesics

OXYCODONE

Pharmacopeia - Opiate Analgesics

NALOXONE

Pharmacopeia - Neuro Antidotes

IBUPROFEN | PARACETAMOL

Pharmacopeia - Non-Opiate Analgesics

IBUPROFEN | TRAMADOL

Pharmacopeia - Non-Opiate Analgesics

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FENTANYL | REMIFENTANIL
Pharmacokinetics and Pharmacodynamics

MORPHINE | FENTANYL
Pharmacokinetics and Adverse Effects

MORPHINE | TRAMADOL
Mechanism of Action, Pharmacokinetics, CNS Effects