PAST QUESTIONS – K02. Pharmacology Related to the Nervous System (Click to Open)
SYLLABUS (Fourth Edition, 2023)
| LEVEL 1 | LEVEL 2 | LEVEL 3 |
|---|---|---|
| Local Anaesthetics | Other | Antidepressants |
| Amides | Nimodipine | Monoamine oxidase inhibitors (MAO-i) |
| Lignocaine | Selective serotonin reuptake inhibitors (SSRIs) | |
| Bupivacaine | Serotonin-Noradrenaline reuptake inhibitors (SNRIs) | |
| Ropivacaine | Tricyclic anti-depressants (TCAs) | |
| Anticonvulsants | ||
| Midazolam | Phenytoin | Lamotrigine |
| Levetiracetam | ||
| Phenobarbitone | ||
| Sodium Valproate | ||
| Sedative / Hypnotic drugs | Antipsychotics | |
| Benzodiazepines | Barbituates | First generation antipsychotics |
| Midazolam | Thiopentone | Haloperidol |
| Diazepam | Second generation antipsychotics | |
| Other | Olanzapine | |
| Dexmedetomidine | Quetiapine | |
| Ketamine | ||
| Propofol | ||
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 | Sedatives |
| Antidepressants | |
| Antipsychotics | |
| Local Anaesthetics | |
| Anticonvulsants | |
| Miscellaneous | |
| INDIVIDUAL TABLES | |
| – Sedatives | Propofol |
| Midazolam | |
| Propofol | Midazolam | |
| Midazolam | Dexmedetomidine | |
| Dexmedetomidine | Ketamine | |
| Dexmedetomidine | Propofol | |
| Ketamine | Midazolam | |
| Lignocaine / Lidocaine | |
| – Anticonvulsants | Phenytoin |
| Phenytoin | Levetiracetam | |
| Valproic Acid | Carbamazepine | |
| Gabapentin | |
| – Antipsychotics | Haloperidol |
| Haloperidol | Diazepam | |
| – Local Anaesthetics | Bupivacaine |
MASTER TABLES
SEDATIVES
Pharmacopeia - Sedatives
| PROPOFOL | MIDAZOLAM (BENZODIAZEPINES) | DIAZEPAM (BENZODIAZEPINES) | KETAMINE | DEXMEDETOMIDINE | THIOPENTONE | PHENOBARBITONE | |
|---|---|---|---|---|---|---|---|
| GROUP | Sedative / Hypnotic | Sedative / Hypnotic | Sedative / Hypnotic | Sedative / Hypnotic | Sedative / Hypnotic | Sedative / Hypnotic | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 | Level 1 | Level 1 | Level 1 | Level 1 | Level 2 | Level 3 |
| INTRODUCTION | 2,6-di-isopropyl phenol Chemically inert phenolic derivative | - Benzodiazepine - Imidazole ring in its structure - Accounts for water solubility And rapid metabolism - 2-3x potent Diazepam | Benzodiazepine | Phencyclidine (remember the street drug name PCP) derivative that produces dissociative anesthesia | Central alpha2 agonist Greater selectivity for A2 than clonidine | 5-ethyl-5`-(1-methylbutyl)-2-thiobarbituric acid and is the sulphur analogue of pentobarbital | barbituric acid derivative |
| USES | Short term sedation Induction and maintenance of anaesthesia Maintenance of sedation | Sedative, amnesic+ anxiolytic, antiepileptic | 1. in the short-term treatment of anxiety 2. in the treatment of status epilepticus 3. for muscle spasm in tetanus and other spastic conditions 4. for alcohol withdrawal, and for 5. premedication and 6. sedation during endoscopy and procedures performed under local anaesthesia. | Induction of anaesthesia - Procedural sedation - Analgesia - ?Role in management of depression. - Recreational | Short term sedation Adjunct sedative when ventilator weaning in delirious and agitated patients | short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties | - long-lasting barbiturate and anticonvulsant used in the treatment of all types of seizures, except for absent seizures - Sedation - sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties |
| PHARMACEUTICS (PC) | |||||||
| PC: Chemical | |||||||
| PC: Presentation | Milky white emulsion 1% Soya bean lipid/Egg phosphatide Sodium hydroxide Weak org acid pKa 11- unionised | Clear solution pH 3.5 (IV/IM), Tablet pKa 6.5 – 89% un-ionized | Solution: Clear, yellow solution and as a white oil-in-water emulsion for injection containing 5 mg/ml. Tab: 2/5/10 mg Syrup: 0.4/1 mg/ml Supp: 10 mg | 10, 50 or 100mg/ml | Clear, colourless solution IV only in Aus (PO overseas) Comparitively expensive, D-stereoisomer | pale yellowish-white powder-bitter taste and garlicy odour. readily dissolves producing alkaline solution due to S−(strongly basic and attracts H+) reconstituted stable for ~ 1 week | Tablets. IV solution either 65mg or 130mg/1ml |
| PHARMACODYNAMICS (PD) | |||||||
| PD: Main Action | |||||||
| PD: Mode of Action | selective modulation of GABA-A receptor (agonism) (distinct from modulatory site for barbiturates and benzos, and GABA itself) - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction Diazepam has kappa-opioid agonist activity in vitro, which may explain the mechanism of benzodiazepine-induced spinal analgesia | NMDA receptor antagonism - Inhibits excitatory signaling within CNS - Also inhibits noradrenaline reuptake in sympathetic nerve terminals | Selective central α2 agonism Inhibition of noradrenaline release in locus ceruleus Peripherally at higher doses | increasing the duration of GABA-dependent chloride channel opening. | acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal. |
| PD: Route & Doses | Induction: 2-2.5mg/kg Maintenance: 1-5mg/kg/hour Both sig. less in critically ill | 2-2.5mg initially then 1mg boluses to eff¬ect | The adult oral dose is 2–60 mg/day in divided doses; the initial intravenous dose is 10–20 mg, increasing according to clinical effect. | - 1mg/kg induction dose - 10~20mg analgesia | 0.3-1mcg/kg/hr | Induction: 3-5mg/kg | Status: Loading 15-20mg/kg Maintenance 2mg/kg/day in divided doses |
| PD: Metrics (Onset/ Peak/ Duration) | |||||||
| PD: Effects | CNS: Sedation and hypnosis (Rapid distribution across BBB) No analgesia Burst suppression Decreases cerebral VO2, blood flow and ICP CVS: signifi¬cant drop in BP due to decreased TPR, but without a reflex tachycardia (infusion rate dependent) Resp: Dose dependent resp depression, apnoea GIT: Anti-emetic | CNS: Sedative, reduces epileptiform activity, increases confusion and disorientation, amnesic properties more prominent than sedative eff¬ects CVS: minor hypotension has been reported Resp: respiratory depression - synergistic with opioids | CVS A transient decrease in the blood pressure and a slight decrease in the cardiac output may occur, following the intravenous administration of diazepam. The coronary blood flow is increased, secondary to coronary arterial vasodilation; a decrease in myocardial oxygen consumption has also been reported. RS Large doses cause respiratory depression; hypoxic drive is depressed to a greater degree than is hypercarbic drive.DIAzEPAM 101 CNS Diazepam is anxiolytic and decreases aggression, although paradoxical excitement may occur. sedation, hypnosis, and anterograde amnesia occur after the administration of diazepam. The drug has anticonvulsant and analgesic properties, and depresses spinal reflexes. | CNS: Causes dissociative anaesthesia - Hallucinations - Emergence delirium CVS: Indirect sympathomimetic chronotropy, inotrophy and Hypertension Direct cardiodepressant if depletion of NA hypotension Resp - Bronchodilation | CNS: sedation: REM sleep-like state,min respiratory depression Analgesia without as much confusion or disorientation as benzos. Pts easily aroused. Spinal cord analgesia Decreases cerebral VO2, blood flow and ICP No antiemesis CVS: Higher doses cause peripheral α2 effects – vasoconstriction, followed by hypotension and bradycardia (Decreased sympathetic output) Resp: Minimal Resp depression | CNS: depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, maximally reduces brain VO2 and anticonvulsant activity Resp: dose-dependent Resp depression | - depresses the sensory cortex, decreases motor activity, and alters cerebellar function. - also capable of producing a dose-dependent respiratory depression |
| PD: Side Effects / Toxicity | Hypotension (baroreceptor sens. blunted, decreased sympathetic tone). Painful on injection. Propofol syndrome: Metabolic acidosis, hyperlipidaemia, myocardial failure, death- common in children | Respiratory depression and excessive sedation with overdosage Same CYP as alfentanil (increases e¬ffect) | Depression of the CNs, including drowsiness, ataxia, and headache, may complicate the use of diazepam. Rashes, gastrointestinal upsets, and urinary retention have also been reported. Tolerance and dependence may occur with prolonged use of benzodiazepines; acute withdrawal of benzodiazepines in these circumstances may produce insomnia, anxiety, confusion, psychosis, and perceptual disturbances. Intravenous diazepam is highly irritant to veins; the oil-in-water preparation is less so. | Increased salivation - Upper airway reflexes intact laryngospasm - Hypotension if given in shock states - Emergence delirium | Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia Later, hypotension and bradycardia. Rebound HTN on ceasing dose Dry mouth, nausea | Reflex tachycardia (Due to dose dep CO, SV and TPR) Dosedep Respiratory depression. CBF, ICP, and brain VO2. Severe anaphylaxis in 1 in 20000. May precipitate acute porphyria | causes few systemic side effects, but its use is limited mainly due to the high rate of sedation and cognitive impairment. Toxicity: - CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation) - oliguria, tachycardia, hypotension, lowered body temperature, and coma. - Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. |
| PHARMACOKINETICS (PK) | |||||||
| PK: Absorption | A: onset / duration 30 seconds / 3-10 minutes | A : IV,PO,In,IM poor oral bioavailability 45% | Diazepam is rapidly absorbed after oral administration; the bioavailability is 86–100%. Absorption after intramuscular administration is slow and erratic. | A: 20% oral bioavailability | A: Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration | A: IV onset / duration I.V.: 30-60 seconds / 5-30 minutes | Variable rates of absorption |
| PK: Distribution | pKa 11 very high lipid sol Crosses placenta | lipid soluble at physiological pH (pKa 6.5). high lipid sol crosses BBB | Lipid soluble (rapid distribution) | High lipid solubility pKa 7.6 | |||
| Protein binding (PK: Distribution) | 97-99% | 95% | 99% | 25% | 95% | 72-86% | 20 to 45% |
| Volume of distribution (PK: Distribution) | 2-10L/kg 60l/kg after 10 day infusion ↓ in elderly | 1-2 L/kg | 0.8–1.4 l/kg | 3l/kg | 2l/kg (steady state) | ~1.6L/kg | not available |
| PK: Metabolism | Hepatic to partially inactive metabolites (water soluble sulfate and glucuronide conjugates(~50%) Clearance > liver blood flow, ∴extrahepatic metabolism | hepatic via CYP3A4, and glucuronidation active metabolite | Hepatic to active metabolites. Major metabolite is desmethyldiazepam (half life 100hrs). other metabolites are oxazepam (which is further metabolized by glucuronidation) and temazepam. | Hepatic metabolism with active norketamine metabolite | Hepatic via CYP and glucuronidation inactive metabolites | Hepatic, primarily to inactive metabolites, when given as an infusion may develop zero order kinetics due to enzyme saturation | Hepatic (mostly via CYP2C19). |
| PK: Excretion | Urine (~88% as metabolites,40% as glucuronide) | excreted in urine (as glucuronide conjugated metabolites) | urine as oxidized and glucuronide derivatives; <1% is excreted unchanged. | Renal elimination | Excreted in urine | renal, reduce dose by one quarter when CrCl <10 | 20-40% unchanged in urine |
| - Clearance (PK: Excretion) | |||||||
| - Half Life (PK: Excretion) | half life Biphasic: Initial 40 min; Terminal 4-7 hrs (up to 60hrs) | half life 1-4 hrs prolonged in cirrhosis, CRF, CCF, obesity, elderly | elimination half-life is 20–40 hours. | T1/2a 15 mins, T1/2b 2~3 hours, CSHT 40mins at 5 hours | Large variation in CSHT with infusion length (T1/2 5 minutes after 10 minutes IV, T1/2 240 minutes after 8 hour IV) | half life 3-11.5hrs | 50-160 hours |
| SPECIAL POINTS | - potentiates non-depolarizing muscle relaxants. - adsorbed onto plastic - not removed by dialysis. |
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ANTIDEPRESSANTS
Pharmacopeia - Antidepressants
| AMITRIPTYLINE TCA | FLUOXETINE SSRI | VENLAFAXINE SNRI | PHENYLZINE MAO-I | |
|---|---|---|---|---|
| GROUP | Antidepressant - Tricyclic anti-depressants | Antidepressant - Selective serotonin reuptake inhibitors | Antidepressant - Serotonin-Noradrenaline reuptake inhibitors | Antidepressant - Monoamine oxidase inhibitors |
| CICM Level of Understanding | Level 3 | Level 3 | Level 3 | Level 3 |
| PHARMACODYNAMICS (PD) | ||||
| PD: Mode of Action | Competitively inhibit neuronal uptake (uptake 1) of noradrenaline and serotonin, thereby increasing their concentrations in the synapse Additional: 1. Antimuscarinic 2. Antihistamine Alpha-adrenoreceptor antagonism | Inhibition of SERT transporter increases synaptic 5-HT. No effect on NET | Inhibition of serotonin re-uptake (SERT) and noradrenaline re-uptake (NET). Low affinity for NET at low doses. Little muscarinic, H1 or alpha1 antagonism effects | Irreversible MAO A and B inhibition leading to accumulation of: 1. Noradrenaline 2. Serotonin Dopamine |
| PD: Side Effects / Toxicity | 1. Initially increase suicidality in youth 2. CNS- sedation (H1), seizures 3. Anti-Ach: dry mouth, constipation, urinary retention, blurred vision CVS- postural hypotension OVERDOSE: 1. CVS - Sinus tachy - QT prolongation - QRS prolongation VT/VF (Sodium channel blockade) - RBBB - Labile BP 2. CNS - Excitation and seizures then depression 3. Mydriasis, hyperthermia Treatment: 1. Benzos for seizures 2. Hyperventilation and sodium bicarbonate if QRS prolonged Avoid inotropes if possible | Serotonin A/E (shared by all AD): - Insomnia/somnolence - N/V/D - Sexual- low libido, impotence Initial suicidality | 1. Serotonin A/E 2. Norad- HTN, tachycardia | 1. Serotonin 2. Histamine 3. Anticholinergic 4. Anti-alpha 5. Adrenergic Interacts with other antidepressants, foods high in tyramine (cheese) and sympathomimetic |
| PHARMACOKINETICS (PK) | ||||
| PK: Absorption | Well-absorbed PO with high first pass. | 50:50 racemic mixture Well absorbed | High first pass- F=45% | Incomplete data available |
| PK: Distribution | Very lipid soluble | Incomplete data available | ||
| Protein binding (PK: Distribution) | Highly protein bound | much lower PB (30%) | ||
| Volume of distribution (PK: Distribution) | Large Vd | |||
| PK: Metabolism | Hepatic phase 1 and 2 metabolism | Hepatic metabolism | Hepatic 2D6 metabolism to desvenlafaxine (active) | Incomplete data available |
| PK: Excretion | Renal excretion | Does require dose adjustment in renal failure for metabolites | Renal elimination. | Renal elimination of metabolites |
| - Clearance (PK: Excretion) | ||||
| - Half Life (PK: Excretion) | T1/2= 30-45 hours | T1/2= 10 hours | Duration depends on time taken for MAO synthesis | |
| SPECIAL POINTS |
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ANTIPSYCHOTICS
Pharmacopeia - Antipsychotics
| HALOPERIDOL | CHLORPROMAZINE | OLANZAPINE | RISPERIDONE | CLOZAPINE | QUETIAPINE | |
|---|---|---|---|---|---|---|
| GROUP | First Generation Antipsychotics (D2-Antagonism) | First Generation Antipsychotics (D2-Antagonism) | Second Generation Antipsychotics/Atypical (D2-Antagonism/5-HT2a) | Second Generation Antipsychotics/Atypical (D2-Antagonism/5-HT2a) | Second Generation Antipsychotics/Atypical (D2-Antagonism/5-HT2a) | Second Generation Antipsychotics/Atypical (D2-Antagonism/5-HT2a) |
| CICM Level of Understanding | Level 3 | - | Level 3 | - | - | Level 3 |
| INTRODUCTION | Risperidone is an atypical antipsychotic with limited antimuscarinic effects | Atypical antipsychotic used in treatment refractory schizophrenia | Atypical antipsychotic | |||
| USES | - Schizophrenia - Nausea and vomiting - Motor tics and hiccupping - Acute confusional states and delirium in intensive care - Premedication - Palliative care | 1. Antipsychotic 2. Nausea and vomiting associated with terminal illness 3. Intractable hiccups | - Psychosis - Bipolar and acute mania | - Psychosis - Delerium - Mania - Agitation - Behavioural disturbances of dementia | Treatment resistant schizophrenia only | 1. Psychosis 2. Bipolar disorder 3. Agitation |
| PHARMACEUTICS (PC) | ||||||
| PC: Chemical | ||||||
| PC: Presentation | Oral tablets, syrup and clear colourless solution for injection | Tablets, syrup, suppositories, straw coloured solution for injection (IM) | Oral wafer, tablet | Tablets, orally dissolving tablets, oral solution, Depot (2 weekly) | - Start 12.5mg BD and uptitrate - Max dose 150mg BD - Comes as tablets or oral suspension | IR and SR tablets Start 50mg nocte and uptitrate to 300mg nocte Dose reduce by 30-50% in elderly |
| PHARMACODYNAMICS (PD) | ||||||
| PD: Main Action | ||||||
| PD: Mode of Action | Centrally acting D2 blockade and post-synaptic GABA antagonism | Central D2 blockade. Antagonism of serotonergic, histaminergic muscarinic and alpha-adrenergic receptors | D2 receptor antagonism, 5HT-R antagonism, H1-R/M-R/alpha1-R antagonism | D2<5-HT2a, no anticholinergic effects | D2<5-HT2a and H1-R antagonism | |
| PD: Route & Doses | ||||||
| PD: Metrics (Onset/ Peak/ Duration) | ||||||
| PD: Effects | CVS: Minimal cardiovascular effects but has antagonistic effects at alpha adrenergic receptors that may cause hypotension in the presence of hypovolaemia CNS: Induces neurolepsis, a state characterized by diminished motor activity, anxiolysis, and indifference to environment. Seizure threshold is raised GIT: Powerful antiemetic Metabolic/Other: Causes hyperprolactinaemia | CVS - - Negatively inotropic and has alpha-adrenergic blockade. This causes postural hypotension and reflex tachycardia - Increased CBF - PR and QTc prolongation CNS - Neurolepsis, sedation and anxiolysis - Lowers seizure threshold - Increases sleep time but majority is REM sleep Resp - Respiratory depressant - Decreased bronchial secretions Renal: Anticholinergic activity may produce urinary retention GIT: Antiemetic. Increased appetite Metabolic/other - Insulin release is impaired - ADH released is impaired - Prolactin release is increased | CVS: Orthostatic hypotension CNS: Somnolence. Lowers seizure threshold GIT: Dysphagia Metabolic/Other: Hyperglycaemia and increased risk of developing diabetes | CVS: Postural hypotension. QTc CNS: Obtundation. Risk in parkinson’s or lewy-body dementia. NMS GIT. Weight gain. Antiemetic Metabolic/Other. Leukopenia, neutropenia and agranulocytosis have been reported | CVS: Myocarditis and cardiomyopathy (monitor ECG, troponin and echo) CNS: Highly sedating Haem: Agranulocytosis in 1-2% and thus need to monitor FBC GIT: Significant Constipation | sedating |
| PD: Side Effects / Toxicity | 1. Extrapyramidal Reactions - Tardive dyskinesia occurs in 20% of patients taking the drug for >1 year. Women and elderly are more susceptible - Acute dystonic reactions occur in 2% of patients in first 72 hour especially in young men. These include torticollis, oculogyric crisis and laryngospasm 2. Neuroleptic malignant syndrome - Typically develops over 24-72 hours ad is characterized by hyperthermia, generalized hypertonicity, autonomic instability and fluctuating LOC - Increased muscle tone may lead to chest wall rigidity and myonecrosis. Treatment includes dantrolene and bromocriptine 3. Cardiovascular - May prolong QTc - Hypotension in context of hypovolaemia but this is less pronounded in oral administration 4. Hyperprolactinaemia - Galactorrhoea and gynaecomastia - Hypothalamic effects may lead to increased weight gain | |||||
| PHARMACOKINETICS (PK) | ||||||
| PK: Absorption | well absorbed orally with bioavailability of 60-80% orally | well absorbed orally but bioavailability of 30% due to first pass metabolism in liver and gut wall | Good oral absorption | 66% oral biovailability | Good oral absorption | Good oral absorption |
| PK: Distribution | ||||||
| Protein binding (PK: Distribution) | 92% | 95% | 98% | Highly protein bound | Highly protein bound | Protein bound |
| Volume of distribution (PK: Distribution) | 18-30L/kg | 12-30L/kg | ||||
| PK: Metabolism | extensively hepatically metabolized | extensively hepatically metabolized. At least 168 metabolites described, many of which are active | Hepatic metabolism. Smoking induces the CYP1A2 metabolism of olanzapine | CYP2D6 converts risperidone to paliperidone (active) | Hepatic metabolism | Active metabolite norquetiapine which has anticholinergic effects |
| PK: Excretion | Equal quantities in urine and faeces. | |||||
| - Clearance (PK: Excretion) | 11ml/min/kg | 6-11ml/min/kg | ||||
| - Half Life (PK: Excretion) | elimination T1/2 is 10-38hours | elimination T1/2 is 30 hours | Terminal T1/2 is 33 hours | Elimination T1/2 of 3-20 hours, paliperidone T1/2 is 24 hours | T1/2 elimination= 12 hours | Elimination t1/2 is 7 hours, active metabolite elimination T1/2 is 12 hours |
| SPECIAL POINTS |
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LOCAL ANAESTHETICS
Pharmacopeia - Local Anaesthetics
| LIGNOCAINE / LIDOCAINE AMIDE | BUPIVACAINE AMIDE | ROPIVACAINE AMIDE | COCAINE ESTER | |
|---|---|---|---|---|
| GROUP | Amide Local Anaesthetic | Amide Local Anaesthetic | Amide Local Anaesthetic | Ester Local Anaesthetic |
| CICM Level of Understanding | Level 1 | Level 1 | Level 1 | - |
| INTRODUCTION | ||||
| USES | 1. as a local anaesthetic 2. in the treatment of ventricular tachydysrhythmias, acting as a class Ib antiarrhythmic. | local anaesthetic | local anaesthetic | topical vasoconstrictor |
| PHARMACEUTICS (PC) | ||||
| PC: Chemical | tertiary amine which is an amide derivative of diethylaminacetic acid. | amide which is a structural homologue of mepivacaine | amino amide which is member of the pipecoloxylidide group of local anaesthetics | ester of benzoic acid (a naturally occurring alkaloid derived from the leaves of Erythroxylon coca). |
| PC: Presentation | Solution: clear, colourless solution in concentrations of 0.5/1/1.5/2% solution of lidocaine hydrochloride (with or without 1:200 000 adrenaline) Others: - - Gel: 21.4 mg/ml of lidocaine hydrochloride (with or without chlorhexidine gluconate) - a 5% ointment - 10% Spray - 4% aqueous solution for topical application - a cream/ suppositories (in combination with hydrocortisone) for rectal administration - 1% and 2% preparations are available with or without the preservatives methylhydroxybenzoate (1.7 mg/ml) and propylhydroxybenzoate (0.3 mg/ml). Hydrochloric acid and sodium hydroxide are also present in some formulations (the latter to a maximum of 1%). The pKa of lidocaine is 7.7 and is 25% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 2.9. | - clear, colourless solution containing racemic bupivacaine (s- and R-enantiomers) in concentrations of 0.25% (2.64 mg/ml equivalent to bupivacaine hydrochloride anhydrous 2.5 mg/ml) and 0.5% (5.28 mg/ml equivalent to bupivacaine hydrochloride anhydrous 5.0 mg/ml). - The 0.25/0.5% solutions are available combined with 1:200 000 adrenaline, which contain the preservative sodium metabisulfite. - A 0.5% (‘hyperbaric’ or ‘heavy’) solution containing 80 mg/ml of glucose (with a specific gravity of 1.026) is also available. - Bupivacaine 0.1% is available as a mixture with 2 micrograms/ml of fentanyl for epidural use. The s-enantiomer is available as levobupivacaine hydrochloride in the following concentrations: 2.5 mg/ml, 5 mg/ml, and 7.5 mg/ml. - Levobupivacaine is also available for epidural use in the following concentrations: 0.625 mg/ml and 1.25 mg/ml. The pKa of bupivacaine is 8.1, and it is 15% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 27.5. | - As a clear, colourless solution containing racemic ropivacaine hydrochloride monohydrate (s- and R-enantiomers) in concentrations of 0.2/0.75/1.0% equivalent to 2.0, 7.5, and 10 mg/ml, respectively, of ropivacaine hydrochloride. A pure s-ropivacaine preparation is also available. It is not available in combination with a vasoconstrictor, as this does not alter its tissue uptake or the duration of action. The pKa of ropivacaine is 8.1, and it is 15% unionized at pH 7.4. The heptane:buffer partition coefficient is 2.9. The preparation also contains sodium hydroxide equivalent to 3.7 mg of sodium per ml | 1–4% solutions and as a non-proprietary paste of varying concentration. |
| PHARMACODYNAMICS (PD) | ||||
| PD: Main Action | Local anaesthetic | Local anaesthetic | Local anaesthetic | Local anaesthesia, vasoconstriction, and euphoria. |
| PD: Mode of Action | Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane | Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channels, thereby decreasing Na+ conductance and preventing the depolarization of the cell membrane | Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane. s-ropivacaine is more potent and less cardiotoxic than R-ropivacaine. | Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane. Cocaine also produces blockade of the uptake-1 pathway of noradrenaline and dopamine, leading to vasoconstriction and CNS excitation. |
| PD: Route & Doses | Lidocaine may be administered topically, by infiltration, intrathecally, or epidurally; the toxic dose of lidocaine is 3 mg/kg (7 mg/kg with adrenaline). The maximum dose is 300 mg (500 mg with adrenaline). The adult intravenous dose for the treatment of acute ventricular dysrhythmias is a bolus injection of 1 mg/kg, administered over 2 minutes. A second dose may be administered according to the response of the patient. This is normally followed by an infusion at a rate of 20–50 micrograms/kg/min. Lidocaine acts in 2–20 minutes (dependent on the rate of administration and the presence of vasoconstrictors and the concentrations used). The speed of onset of lidocaine may be increased by the addition of bicarbonate to increase the pH of the solution, thereby increasing the unionized fraction of drug. The pH of the drug is approximately 6.4. | Bupivacaine may be administered topically, by infiltration, intrathecally, or epidurally; the toxic dose of bupivacaine is 2 mg/kg (with or without adrenaline). The maximum dose is 150 mg. The drug acts within 10–20 minutes and has a duration of action of 5–16 hours. | Ropivacaine may be administered topically, by infiltration, or epidurally; the drug is not currently intended for use in spinal anaesthesia. The maximum recommended dose of ropivacaine is 3 mg/kg. sensory blockade is similar in time course to that produced by bupivacaine; motor blockade is slower in onset and shorter in duration than that after an equivalent dose of bupivacaine. Alkalinization of 0.75% ropivacaine significantly increases the duration of action of epidural blockade. | topically; the toxic dose is 3 mg/kg. duration of action of 20– 30 minutes. |
| PD: Metrics (Onset/ Peak/ Duration) | ||||
| PD: Effects | CVS In low concentrations, lidocaine decreases the rate of rise of phase 0 of the cardiac action potential by blockade of inactivated sodium channels. This results in a rise in the threshold potential, with the duration of the action potential and effective refractory period being shortened. It has few haemodynamic effects when used in low doses, except to cause a slight increase in the systemic vascular resistance, leading to a mild increase in the blood pressure. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. RS The drug causes bronchodilatation at subtoxic concentrations. Respiratory depression occurs in the toxic dose range. CNS The principal effect of lidocaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNs. Initially, excitation (lightheadedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNs depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance. AS Local anaesthetics depress contraction of the intact bowel. Metabolic/other Lidocaine may have some anticholinergic and antihistaminergic activity | CVS Bupivacaine is markedly cardiotoxic; it binds specifically to myocardial proteins, in addition to blocking cardiac sodium channels and decreasing the rate of increase of phase 0 during the cardiac action potential. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. K+ and Ca2+ channels may also be affected at toxic doses. Levobupivacaine-induced cardiotoxicity requires a greater dose to be administered, compared with racemic bupivacaine. CNS The principal effect of bupivacaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNs. Initially, excitation (light-headedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNs depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance. Levobupivacaine produces less motor blockade, but longer sensory blockade, following epidural administration. | CVS Ropivacaine is less cardiotoxic than bupivacaine; in toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. Ropivacaine has a biphasic vascular effect, causing vasoconstriction at low, but not at high, concentrations. CNS The principal effect of ropivacaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNs. Initially, excitation (light-headedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNs depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance. GU Ropivacaine does not compromise uteroplacental circulation. | CVS The usual effect of cocaine is to produce hypertension and tachycardia due to a combination of central sympathetic stimulation and the blockade of noradrenaline reuptake at peripheral adrenergic nerve terminals, leading to intense peripheral vasoconstriction. Large doses produce myocardial depression and may precipitate ventricular fibrillation. RS Therapeutic concentrations of the drug cause stimulation of the respiratory centre and an increase in ventilation. CNS The principal effect of cocaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNs. Initially, excitation (euphoria, light-headedness, dizziness, visual and auditory disturbances, and fitting) occurs due to the blockade of inhibitory pathways in the cortex; with increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNs depression (drowsiness, disorientation, and coma). Cocaine may also cause hyperreflexia, mydriasis, and an increase in the intraocular pressure. AS The drug produces hyperdynamic bowel sounds and marked nausea and vomiting (a central effect). Metabolic/other Cocaine causes a marked increase in body temperature due to increased motor activity combined with cutaneous vasoconstriction and a direct effect of the drug on the hypothalamus. |
| PD: Side Effects / Toxicity | Lidocaine is intrinsically less toxic than bupivacaine. Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above. Methaemoglobinaemia may occur if doses in excess of 600 mg are used and is caused by the metabolite o-toluidine, although this condition may occur at lower doses in patients suffering from anaemia or a haemoglobinopathy or in patients receiving therapy known to also precipitate methaemoglobinaemia (sulfonamides). Use of lidocaine for paracervical block or pudendal nerve block in obstetric patients is not recommended, as this may give rise to methaemoglobinaemia in the neonate, as the erythrocytes are deficient in methaemoglobin reductase. | Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above. The use of the drug for intravenous regional blockade is no longer recommended, as refractory cardiac depression, leading to death, has been reported when it is used for this purpose. | Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above | Allergic phenomena occur occasionally with the use of cocaine. The side effects are predominantly correlated with excessive plasma concentrations of the drug. These include confusion, hallucinations, seizures, cerebral haemorrhage and infarction, and medullary depression leading to respiratory arrest. Chest pain is common; myocardial infarction, pulmonary oedema, gut infarction, rhabdomyolysis, and disseminated intravascular coagulation (DIC) may also occur. Cocaine is a drug of dependence; maternal use may result in neonatal dependence. Nasal septum necrosis is reported. |
| PHARMACOKINETICS (PK) | ||||
| PK: Absorption | The absorption of local anaesthetic agents is related to: 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous) 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved, and 3. the presence of vasoconstrictors which delay absorption. | The absorption of local anaesthetic agents is related to: 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous) 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved, and 3. the presence of vasoconstrictors which delay absorption. The addition of adrenaline to bupivacaine solutions does not influence the rate of systemic absorption, as: 1. the drug is highly lipid-soluble, and therefore its uptake into fat is rapid, and 2. the drug has a direct vasodilatory effect. | The absorption of local anaesthetic agents is related to: 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous) 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved and 3. the presence of vasoconstrictors which delay absorption. | well absorbed from mucosae, including that of the gut. BA Intranasally 0.5% |
| PK: Distribution | Demonstrates a biphasic absorption profile from the epidural space, with half-lives of 14 minutes and 4 hours in adults. | |||
| Protein binding (PK: Distribution) | 64–70% predominantly to alpha-1 acid glycoprotein | 95% albumin and alpha-1 acid glycoprotein; (Levo: >97%) | 94% predominantly to alpha-1 acid glycoprotein | 98% |
| Volume of distribution (PK: Distribution) | 0.7–1.5 l/kg. | 21–103 L | 52–66 L | 0.9–3.3 l/kg. |
| PK: Metabolism | Lidocaine is metabolized in the liver by N-dealkylation, with subsequent hydrolysis to monoethylglycine and xylidide. Monoethylglycine is further hydrolysed, whilst xylidide undergoes hydroxylation to 4-hydroxy- 2,6-xylidine which is the main metabolite and excreted in the urine. Metabolites of lidocaine may lower the fit threshold, thereby potentiating seizure activity, whilst others have some antiarrhythmic properties. | occurs in the liver by N-dealkylation, primarily to pipecoloxylidide. N-desbutyl bupivacaine and 4-hydroxy bupivacaine are also formed. There is no evidence of in vivo racemization of levobupivacaine. In vitro studies of levobupivacaine demonstrate that CYP3A4 and CYP1A2 are responsible for its metabolism to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively | Ropivacaine is metabolized in the liver by aromatic hydroxylation via cytochrome CYP1A2 to 3-hydroxy-ropivacaine, the major metabolite, 4-hydroxy-ropivacaine, and 4-hydroxy-dealkylated-ropivacaine. Co-administration of a CYP1A2 inhibitor (e.g. fluvoxamine, enoxacin) may reduce plasma clearance of the drug by up to 77% in vitro. The isoenzyme CYP3A4 is also involved in the metabolism of ropivacaine, as administration of a CYP3A4 inhibitor (e.g. fluconazole) reduces the plasma clearance of the drug by 15% in vitro, although this is unlikely to cause a clinically significant effect. Ropivacaine has an intermediate hepatic extraction ratio of approximately 0.4. There is no evidence of in vivo racemization of ropivacaine. | In common with the other ester-type local anaesthetic agents, cocaine is predominantly degraded by plasma esterases, predominantly to benzoylecgonine |
| PK: Excretion | Less than 10% of the dose is excreted unchanged in the urine. | 5% of the dose is excreted in the urine as pipecoloxylidide; 16% is excreted unchanged. | 86% of the dose is excreted in the urine, 1% unchanged; 37% of 3-hydroxy-ropivacaine is excreted in the urine, predominantly conjugated. | excreted in the urine, 10% unchanged. |
| - Clearance (PK: Excretion) | 6.8–11.6 ml/min/kg ↓ in the presence of cardiac and hepatic failure. | 0.47 l/min | 0.44–0.82 l/min | 26–44 ml/min/kg |
| - Half Life (PK: Excretion) | elimination half-life is 90– 110 minutes. | elimination halflife (after IV administration) is 0.31–0.61 hours. | terminal elimination half-life is 59–173 minutes. The elimination half-life is longer after epidural (4.2 hours) than after intravenous administration due to the biphasic absorption from the former, as described above. | elimination half-life is 25–60 minutes. |
| SPECIAL POINTS | The onset and duration of conduction blockade are related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants. Due to the narrow therapeutic index of lidocaine, the plasma concentrations of the drug need to be monitored in patients with cardiac and hepatic impairment. Lidocaine is not removed by haemodialysis. Intravenous administration of lidocaine decreases N 2o and halothane requirements by 10% and 28%, respectively. EMLA® (Eutectic Mixture of Local Anaesthetics) is a white cream used to provide topical anaesthesia prior to venepuncture and has also been used to provide anaesthesia for split skin grafting. It contains 2.5% prilocaine and 2.5% lidocaine in an oil–water emulsion. When applied topically under an occlusive dressing, local anaesthesia is achieved after 1–2 hours and lasts for up to 5 hours. The preparation causes temporary blanching and oedema of the skin; detectable methaemoglobinaemia may also occur in the presence of excessive o-toluidine plasma levels as a metabolite of prilocaine. | The onset and duration of conduction blockade are related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. In infants under 6 months of age, the low level of albumin and alpha-1 acid glycoprotein results in an increase in the free fraction of bupivacaine. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants. Levobupivacaine may precipitate if diluted in alkaline solutions. Clonidine (8.4 micrograms/ml), morphine (0.05 mg/ml), and fentanyl (4 micrograms/ml) have been shown to be compatible with levobupivacaine | The onset and duration of conduction blockade are related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants. |
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ANTICONVULSANTS
Pharmacopeia - Anticonvulsants
| PHENYTOIN | MIDAZOLAM | LEVETIRACETAM | NA VALPROATE | CARBAMAZEPINE | CLONAZEPAM | PHENOBARBITONE | LAMOTRIGINE | GABAPENTIN | |
|---|---|---|---|---|---|---|---|---|---|
| GROUP | Anticonvulsant | Anticonvulsant Sedative-Hypnotic | Anticonvulsant | Anticonvulsant | Anticonvulsant | Anticonvulsant | Anticonvulsant Sedative-Hypnotic | Anticonvulsant | Anticonvulsant |
| CICM Level of Understanding | Level 2 | Level 1 | Level 3 | Level 3 | - | - | Level 3 | Level 3 | - |
| INTRODUCTION | |||||||||
| USES | Anticonvulsant and antiarrhythmic (V-W class 1b) Epilepsy Trigeminal neuralgia TCA toxicity Digoxin-induced arrhythmias | Epilepsy in the case of partial seizures Adjunctive therapy for partial, myoclonic and tonic-clonic seizures | Anti-convulsant Epilepsy | Anti-convulsant Epilepsy Schizophrenia Trigeminal neuralgia | monotherapy or as an adjunct in the treatment of Lennox-Gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures. Alternative therapy for petit mal, panic disorder | - post-herpetic neuralgia - painful diabetic neuropathy - partial seizures with or without secondary generalization - neuropathic pain. | |||
| PHARMACEUTICS (PC) | |||||||||
| PC: Chemical | # Hydantoin derivative # Precipitates at pH < 7 ◦ → variable oral absorption ◦ → IM contraindicated | - Imidazole ring in its structure - Accounts for water solubility And rapid metabolism - 2-3x potent Diazepam | # Pyrrolidine # Highly lipid soluble | benzodiazepine | barbituric acid derivative | acetic acid derivate - structural analogue of GABA | |||
| PC: Presentation | Capsules, Syrups, Injections # Doses 15-20 mg/kg IV loading maintenance (plasma levels required aim 10-20µg/mL) # Rapidly achieves peak (<20mins after loading) # Duration 30mins-1hr but highly variable | Clear solution pH 3.5 (IV/IM), Tablet pKa 6.5 – 89% un-ionized | # Steady state after two days of a twice daily administration schedule. # Dose: PO/IV 1000 mg daily given as 500 mg 2 times a day | Tablets / Wafer 0.5,1,2 mg | Tablets. IV solution either 65mg or 130mg/1ml | Tablets 600/800mg Capsules 100/300/400mg | |||
| PHARMACODYNAMICS (PD) | |||||||||
| PD: Main Action | |||||||||
| PD: Mode of Action | # Slows inward Na and Ca ion flux during depolarisation and delays outward K flux. ◦ Stabilises the inactive state of V-gated Na channels limiting repetitive generation of APs. ▪ Limits spread of seizure ◦ Reduce glutamate release and thus attenuating Ca entry # Enhance action of GABA | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction | 1. Partial inhibition of N-type Ca2+ currents and reduced release of Ca2+ from intra-neuronal stores causing reduced intra-neuronal Ca. 2. Inhibition of synaptic vesicle protein 2A (SV2A) involved in vesicle fusion and neurotransmitter exocytosis # → membrane hyperpolarisation → ↓NT release. | Inhibits catabolism of γamino butyric acid(GABA) and inhibits voltage gated Na channels - Increased [GABA] in neuronal junctions - Increased Cl- conductance into neurons - Neuronal hyperpolarization - Increased threshold for depolarization - Increased seizure threshold | Inhibits voltage gate Na channels - Diffuses intracellularly and becomes ionized - Inhibits Na influx and therefore inhibits depolarization - Neurons become less excitable | increases the sensitivty GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction | acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal. | - does not interact with GABA receptors. - Binds to alpha-2 delta subunit of VGCC (voltage-gated calcium channels) - does not interact with sodium channels in vitro (cf. phenytoin, carbamazepine) May also: - partially ↓ NMDA response - ↓ release of monoamine neurotransmitters in vitro - stimulate glutamate decarboxylase (glutamate → GABA) - ↑ synaptic GABA release | |
| PD: Route & Doses | 2-2.5mg initially then 1mg boluses to eff¬ect | Status: Loading 15-20mg/kg Maintenance 2mg/kg/day in divided doses | PO. Titration. 300mg TDS usual Long term epilepsy dose: 900-3600mg/day Needs weaning on discontinuation ~1 week Reduce dose in renal impairment | ||||||
| PD: Metrics (Onset/ Peak/ Duration) | |||||||||
| PD: Effects | CNS: Sedative, reduces epileptiform activity, increases confusion and disorientation, amnesic properties more prominent than sedative eff¬ects CVS: minor hypotension has been reported Resp: respiratory depression - synergistic with opioids | - depresses the sensory cortex, decreases motor activity, and alters cerebellar function. - also capable of producing a dose-dependent respiratory depression | CNS - analgesic - anticonvulsant - improves sleep in patients with neuropathic pain | ||||||
| PD: Side Effects / Toxicity | Respiratory depression and excessive sedation with overdosage Same CYP as alfentanil (increases effect) | Drowsiness, ataxia, dysarthrias, nystagmus Overdose – areflexia, apnoea, hypotension, cardiorespiratory depression, coma | causes few systemic side effects, but its use is limited mainly due to the high rate of sedation and cognitive impairment. Toxicity: - CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation) - oliguria, tachycardia, hypotension, lowered body temperature, and coma. - Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. | - Dizziness, ataxia, nystagmus - somnolence, tremor, diplopia - N/V (>5%) - Leucopenia, erectile dysfunction, weight gain | |||||
| PHARMACOKINETICS (PK) | |||||||||
| PK: Absorption | IV, PO – variable 30-75% | A : IV,PO,In,IM poor oral bioavailability 45% | IV, PO Rapidly abs- BA 100%. | 100% Oral bioavailability | 100% Oral bioavailability | PO BA 90% | Variable rates of absorption | PO BA 60% Peak plasma levels 2-3hrs | |
| PK: Distribution | CSF concentration 20% of steady-state trough plasma | ||||||||
| Protein binding (PK: Distribution) | 90% protein bound | highly protein bound (95%) | <10% protein bound | 90% Protein binding, | 80% Protein binding, | 85% | 20 to 45% | no PB | |
| Volume of distribution (PK: Distribution) | Vd – 0.6-0.7 L/kg | small-mod Vd = 1-2 L/kg high lipid sol crosses BBB | Vd 0.4l/kg | Vd 1l/kg | 3 L/kg | not available | 0.85 L/kg | ||
| PK: Metabolism | # Hepatic to parahydroxyphenyl (inactive) ◦ hydroxylation by CYP450 2C9 ▪ Metabolism effected by inducers or inhibitors of CYP450 2C9 ◦ induces its own CYP450 # Mixed 1st and zero order kinetics as process is saturable ◦ 1st order at plasma [] < 10 µg/mL ▪ t1/2 ~ 24hr ◦ 0th order at plasma [] > 10 µg/mL ▪ t1/2 dose dependent | hepatic via CYP3A4, and glucuronidation active metabolite | # Enzymatic hydrolysis (24%) in a large number of tissues including whole blood but not plasma. | Hepatic β oxidation and conjugation | Hepatic phase 1 and 2 | Hepatic | Hepatic (mostly via CYP2C19). | not metabolized. | |
| PK: Excretion | < 3% unchanged in urine | excreted in urine (as glucuronide conjugated metabolites) | # 95% excreted in the urine # 65% unchanged | Renal | Renal | Metabolites: 70% urine 30% feces | 20-40% unchanged in urine | unchanged in urine | |
| - Clearance (PK: Excretion) | |||||||||
| - Half Life (PK: Excretion) | half life 1-4 hrs prolonged in cirrhosis, CRF, CCF, obesity, elderly | T1/2 7hrs | T1/2b 20 hours | T1/2b 24 hours | 30hrs | 50-160 hours | T1/2 5-7hrs. Clearance proportional to creat clearance | ||
| SPECIAL POINTS | - enchances morphine effect - removed by haemodialysis - BA dec with increasing dose - Antacids decrease BA |
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MISCELLANEOUS
Pharmacopeia - Neuro Misc
| LITHIUM | NIMODIPINE | FLUMAZENIL | INTRALIPID | |
|---|---|---|---|---|
| GROUP | Antipsychotic Mood stabilizer | (CCB) Ca channel blocker – Class II | Antidote | Antidote |
| CICM Level of Understanding | - | Level 2 | Level 3 | Level 3 |
| INTRODUCTION | Mood stabilizer, antipsychotic | Dihydropyridine calcium channel blocker | ||
| USES | 1. Mania and hypomania 2. Bipolar disorder 3. Recurrent affective disorders 4. Adjunct to non-malignant chronic pain therapy | Treatment and prevention of cerebral vasospasm after SAH Also used in migraine, CVA and drug resistant epilepsy can pass the blood-brain barrier | 1. as an aid to weaning and neurological assessment of ventilated patients who have received benzodiazepine sedation during intensive care 2. as part of the ‘wake-up’ test during scoliosis surgery 3. to reverse oversedation after endoscopy and 4. for diagnosis of, and assessment after, benzodiazepine overdose. | |
| PHARMACEUTICS (PC) | ||||
| PC: Chemical | imidazo-benzodiazepine | |||
| PC: Presentation | Oral tablets containing lithium carbonate Narrow therapeutic index. Levels should be checked within 1 week of starting and then regularly thereafter. Therapeutic level is 0.5-1.5mmol/L | IV 200mcg/ml with ethanol and macrogol PO 30mg tablets | clear, colourless solution containing 100 micrograms/ml of flumazenil | |
| PHARMACODYNAMICS (PD) | ||||
| PD: Main Action | Reversal of the actions of benzodiazepines | |||
| PD: Mode of Action | Mimics sodium ions in excitable cells to stabiles membrane potentials. | Binds to N binding site of L-type Ca channel on vascular smooth muscle to reduce intracellular Ca. | - competitive reversible antagonist at benzo site on GABA-A receptor - only intrinsic effect is slight anticonvulsant effect | |
| PD: Route & Doses | 60mg Q4h PO or 20mcg/kg/hr IV | IV Bolus: Titrated in 100mcg increments Total max adult dose: 1mg/5 mins, 3 mg/1 hr Infusion: 100-400mcg/hr question diagnosis if no response to repeated doses | ||
| PD: Metrics (Onset/ Peak/ Duration) | Onset: 30-60 sec Duration: 15-140 min need repeated doses to prevent relapse | |||
| PD: Effects | CVS: Reversible ECG changes, especially TWI CNS: Lowers seizure threshold in epileptic patients. May increase muscle tone. GU: Polyurea and polydipsia due to ADH antagonism develops in 30% of patients Metabolic: Hypothyroidism, hypercalcaemia, hypermagnasaemia | CVS: systolic and diastolic hypotension, 1mcg/kg/h → ↑CO+30% CNS: increases CBF+18% without steal, blunts cardiovascular responses to surgical stimulus/intubation | ||
| PD: Side Effects / Toxicity | 1. Hypothyroidism, weight gain, pretibial oedema, tremors develop 2. Nephrogenic diabetes insipidus in 20% long term 3. Toxicity involves N/V/D, ataxia, convulsions, coma, dysrhythmias and death | Decreases SVR and can increase CO (overall, May drop BP) | Minor: - headache/visual symptoms/↑anxiety/N&V Major: - can cause dangerous convulsions if: > benzo’s being taken for epilepsy > mixed ODs with CNS stimulants & antidepressants - seizures & severe withdrawal if taking benzo’s chronically | |
| PHARMACOKINETICS (PK) | ||||
| PK: Absorption | 100% bioavailability | PO/IV. BA 30% Well absorbed high first pass metabolism | Well absorbed orally (but significant first-pass hepatic metabolism, so not given by this route) | |
| PK: Distribution | Highly lipid sol – use cerebral vasospasm | |||
| Protein binding (PK: Distribution) | No protein binding. | 98% | 50% | |
| Volume of distribution (PK: Distribution) | Vd 0.5-1.3L/Kg | 1-2 L/kg | 0.9 L/kg | |
| PK: Metabolism | Demethylation and dehydrogenation to inactive pyridine analogue. | Liver Inert metabolites: carboxylic acid and glucuronide | ||
| PK: Excretion | 95% excreted in urine unchanged. Rest in sweat. | Inactive metabolites urine and faeces. | Urine: 95% Unchanged: 0.1% | |
| - Clearance (PK: Excretion) | 700-1100 ml/min | |||
| - Half Life (PK: Excretion) | T1/2= 14-30 hours | 2-4 hrs | 53 mins | |
| SPECIAL POINTS | improves the quality of emergence from anaesthesia reduces post-operative shivering |
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INDIVIDUAL TABLES
PROPOFOL
Pharmacopeia - Sedatives
| PROPOFOL | |
|---|---|
| GROUP | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 |
| INTRODUCTION | 2,6-di-isopropyl phenol Chemically inert phenolic derivative |
| USES | Short term sedation Induction and maintenance of anaesthesia Maintenance of sedation |
| PHARMACEUTICS (PC) | |
| PC: Chemical | |
| PC: Presentation | Milky white emulsion 1% Soya bean lipid/Egg phosphatide Sodium hydroxide Weak org acid pKa 11- unionised |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | selective modulation of GABA-A receptor (agonism) (distinct from modulatory site for barbiturates and benzos, and GABA itself) - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction |
| PD: Route & Doses | Induction: 2-2.5mg/kg Maintenance: 1-5mg/kg/hour Both sig. less in critically ill |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | CNS: Sedation and hypnosis (Rapid distribution across BBB) No analgesia Burst suppression Decreases cerebral VO2, blood flow and ICP CVS: signifi¬cant drop in BP due to decreased TPR, but without a reflex tachycardia (infusion rate dependent) Resp: Dose dependent resp depression, apnoea GIT: Anti-emetic |
| PD: Side Effects / Toxicity | Hypotension (baroreceptor sens. blunted, decreased sympathetic tone). Painful on injection. Propofol syndrome: Metabolic acidosis, hyperlipidaemia, myocardial failure, death- common in children |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | A: onset / duration 30 seconds / 3-10 minutes |
| PK: Distribution | pKa 11 very high lipid sol Crosses placenta |
| Protein binding (PK: Distribution) | 97-99% |
| Volume of distribution (PK: Distribution) | 2-10L/kg 60l/kg after 10 day infusion ↓ in elderly |
| PK: Metabolism | Hepatic to partially inactive metabolites (water soluble sulfate and glucuronide conjugates(~50%) Clearance > liver blood flow, ∴extrahepatic metabolism |
| PK: Excretion | Urine (~88% as metabolites,40% as glucuronide) |
| - Clearance (PK: Excretion) | |
| - Half Life (PK: Excretion) | half life Biphasic: Initial 40 min; Terminal 4-7 hrs (up to 60hrs) |
| SPECIAL POINTS |
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MIDAZOLAM
Pharmacopeia - Sedatives
| MIDAZOLAM (BENZODIAZEPINES) | |
|---|---|
| GROUP | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 |
| INTRODUCTION | - Benzodiazepine - Imidazole ring in its structure - Accounts for water solubility And rapid metabolism - 2-3x potent Diazepam |
| USES | Sedative, amnesic+ anxiolytic, antiepileptic |
| PHARMACEUTICS (PC) | |
| PC: Chemical | |
| PC: Presentation | Clear solution pH 3.5 (IV/IM), Tablet pKa 6.5 – 89% un-ionized |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction |
| PD: Route & Doses | 2-2.5mg initially then 1mg boluses to eff¬ect |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | CNS: Sedative, reduces epileptiform activity, increases confusion and disorientation, amnesic properties more prominent than sedative eff¬ects CVS: minor hypotension has been reported Resp: respiratory depression - synergistic with opioids |
| PD: Side Effects / Toxicity | Respiratory depression and excessive sedation with overdosage Same CYP as alfentanil (increases e¬ffect) |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | A : IV,PO,In,IM poor oral bioavailability 45% |
| PK: Distribution | lipid soluble at physiological pH (pKa 6.5). high lipid sol crosses BBB |
| Protein binding (PK: Distribution) | 95% |
| Volume of distribution (PK: Distribution) | 1-2 L/kg |
| PK: Metabolism | hepatic via CYP3A4, and glucuronidation active metabolite |
| PK: Excretion | excreted in urine (as glucuronide conjugated metabolites) |
| - Clearance (PK: Excretion) | |
| - Half Life (PK: Excretion) | half life 1-4 hrs prolonged in cirrhosis, CRF, CCF, obesity, elderly |
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PROPOFOL | MIDAZOLAM
Pharmacopeia - Sedatives
| PROPOFOL | MIDAZOLAM (BENZODIAZEPINES) | |
|---|---|---|
| GROUP | Sedative / Hypnotic | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | 2,6-di-isopropyl phenol Chemically inert phenolic derivative | - Benzodiazepine - Imidazole ring in its structure - Accounts for water solubility And rapid metabolism - 2-3x potent Diazepam |
| USES | Short term sedation Induction and maintenance of anaesthesia Maintenance of sedation | Sedative, amnesic+ anxiolytic, antiepileptic |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | Milky white emulsion 1% Soya bean lipid/Egg phosphatide Sodium hydroxide Weak org acid pKa 11- unionised | Clear solution pH 3.5 (IV/IM), Tablet pKa 6.5 – 89% un-ionized |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | selective modulation of GABA-A receptor (agonism) (distinct from modulatory site for barbiturates and benzos, and GABA itself) - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction |
| PD: Route & Doses | Induction: 2-2.5mg/kg Maintenance: 1-5mg/kg/hour Both sig. less in critically ill | 2-2.5mg initially then 1mg boluses to eff¬ect |
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | CNS: Sedation and hypnosis (Rapid distribution across BBB) No analgesia Burst suppression Decreases cerebral VO2, blood flow and ICP CVS: signifi¬cant drop in BP due to decreased TPR, but without a reflex tachycardia (infusion rate dependent) Resp: Dose dependent resp depression, apnoea GIT: Anti-emetic | CNS: Sedative, reduces epileptiform activity, increases confusion and disorientation, amnesic properties more prominent than sedative eff¬ects CVS: minor hypotension has been reported Resp: respiratory depression - synergistic with opioids |
| PD: Side Effects / Toxicity | Hypotension (baroreceptor sens. blunted, decreased sympathetic tone). Painful on injection. Propofol syndrome: Metabolic acidosis, hyperlipidaemia, myocardial failure, death- common in children | Respiratory depression and excessive sedation with overdosage Same CYP as alfentanil (increases e¬ffect) |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | A: onset / duration 30 seconds / 3-10 minutes | A : IV,PO,In,IM poor oral bioavailability 45% |
| PK: Distribution | pKa 11 very high lipid sol Crosses placenta | lipid soluble at physiological pH (pKa 6.5). high lipid sol crosses BBB |
| Protein binding (PK: Distribution) | 97-99% | 95% |
| Volume of distribution (PK: Distribution) | 2-10L/kg 60l/kg after 10 day infusion ↓ in elderly | 1-2 L/kg |
| PK: Metabolism | Hepatic to partially inactive metabolites (water soluble sulfate and glucuronide conjugates(~50%) Clearance > liver blood flow, ∴extrahepatic metabolism | hepatic via CYP3A4, and glucuronidation active metabolite |
| PK: Excretion | Urine (~88% as metabolites,40% as glucuronide) | excreted in urine (as glucuronide conjugated metabolites) |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | half life Biphasic: Initial 40 min; Terminal 4-7 hrs (up to 60hrs) | half life 1-4 hrs prolonged in cirrhosis, CRF, CCF, obesity, elderly |
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MIDAZOLAM | DEXMEDETOMIDINE
Pharmacopeia - Sedatives
| MIDAZOLAM (BENZODIAZEPINES) | DEXMEDETOMIDINE | |
|---|---|---|
| GROUP | Sedative / Hypnotic | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | - Benzodiazepine - Imidazole ring in its structure - Accounts for water solubility And rapid metabolism - 2-3x potent Diazepam | Central alpha2 agonist Greater selectivity for A2 than clonidine |
| USES | Sedative, amnesic+ anxiolytic, antiepileptic | Short term sedation Adjunct sedative when ventilator weaning in delirious and agitated patients |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | Clear solution pH 3.5 (IV/IM), Tablet pKa 6.5 – 89% un-ionized | Clear, colourless solution IV only in Aus (PO overseas) Comparitively expensive, D-stereoisomer |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction | Selective central α2 agonism Inhibition of noradrenaline release in locus ceruleus Peripherally at higher doses |
| PD: Route & Doses | 2-2.5mg initially then 1mg boluses to eff¬ect | 0.3-1mcg/kg/hr |
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | CNS: Sedative, reduces epileptiform activity, increases confusion and disorientation, amnesic properties more prominent than sedative eff¬ects CVS: minor hypotension has been reported Resp: respiratory depression - synergistic with opioids | CNS: sedation: REM sleep-like state,min respiratory depression Analgesia without as much confusion or disorientation as benzos. Pts easily aroused. Spinal cord analgesia Decreases cerebral VO2, blood flow and ICP No antiemesis CVS: Higher doses cause peripheral α2 effects – vasoconstriction, followed by hypotension and bradycardia (Decreased sympathetic output) Resp: Minimal Resp depression |
| PD: Side Effects / Toxicity | Respiratory depression and excessive sedation with overdosage Same CYP as alfentanil (increases e¬ffect) | Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia Later, hypotension and bradycardia. Rebound HTN on ceasing dose Dry mouth, nausea |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | A : IV,PO,In,IM poor oral bioavailability 45% | A: Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration |
| PK: Distribution | lipid soluble at physiological pH (pKa 6.5). high lipid sol crosses BBB | Lipid soluble (rapid distribution) |
| Protein binding (PK: Distribution) | 95% | 95% |
| Volume of distribution (PK: Distribution) | 1-2 L/kg | 2l/kg (steady state) |
| PK: Metabolism | hepatic via CYP3A4, and glucuronidation active metabolite | Hepatic via CYP and glucuronidation inactive metabolites |
| PK: Excretion | excreted in urine (as glucuronide conjugated metabolites) | Excreted in urine |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | half life 1-4 hrs prolonged in cirrhosis, CRF, CCF, obesity, elderly | Large variation in CSHT with infusion length (T1/2 5 minutes after 10 minutes IV, T1/2 240 minutes after 8 hour IV) |
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DEXMEDETOMIDINE | KETAMINE
Pharmacopeia - Sedatives
| DEXMEDETOMIDINE | KETAMINE | |
|---|---|---|
| GROUP | Sedative / Hypnotic | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | Central alpha2 agonist Greater selectivity for A2 than clonidine | Phencyclidine (remember the street drug name PCP) derivative that produces dissociative anesthesia |
| USES | Short term sedation Adjunct sedative when ventilator weaning in delirious and agitated patients | Induction of anaesthesia - Procedural sedation - Analgesia - ?Role in management of depression. - Recreational |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | Clear, colourless solution IV only in Aus (PO overseas) Comparitively expensive, D-stereoisomer | 10, 50 or 100mg/ml |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | Selective central α2 agonism Inhibition of noradrenaline release in locus ceruleus Peripherally at higher doses | NMDA receptor antagonism - Inhibits excitatory signaling within CNS - Also inhibits noradrenaline reuptake in sympathetic nerve terminals |
| PD: Route & Doses | 0.3-1mcg/kg/hr | - 1mg/kg induction dose - 10~20mg analgesia |
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | CNS: sedation: REM sleep-like state,min respiratory depression Analgesia without as much confusion or disorientation as benzos. Pts easily aroused. Spinal cord analgesia Decreases cerebral VO2, blood flow and ICP No antiemesis CVS: Higher doses cause peripheral α2 effects – vasoconstriction, followed by hypotension and bradycardia (Decreased sympathetic output) Resp: Minimal Resp depression | 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 | Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia Later, hypotension and bradycardia. Rebound HTN on ceasing dose Dry mouth, nausea | Increased salivation - Upper airway reflexes intact laryngospasm - Hypotension if given in shock states - Emergence delirium |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | A: Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration | A: 20% oral bioavailability |
| PK: Distribution | Lipid soluble (rapid distribution) | |
| Protein binding (PK: Distribution) | 95% | 25% |
| Volume of distribution (PK: Distribution) | 2l/kg (steady state) | 3l/kg |
| PK: Metabolism | Hepatic via CYP and glucuronidation inactive metabolites | Hepatic metabolism with active norketamine metabolite |
| PK: Excretion | Excreted in urine | Renal elimination |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | Large variation in CSHT with infusion length (T1/2 5 minutes after 10 minutes IV, T1/2 240 minutes after 8 hour IV) | T1/2a 15 mins, T1/2b 2~3 hours, CSHT 40mins at 5 hours |
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DEXMEDETOMIDINE | PROPOFOL
Pharmacopeia - Sedatives
| DEXMEDETOMIDINE | PROPOFOL | |
|---|---|---|
| GROUP | Sedative / Hypnotic | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | Central alpha2 agonist Greater selectivity for A2 than clonidine | 2,6-di-isopropyl phenol Chemically inert phenolic derivative |
| USES | Short term sedation Adjunct sedative when ventilator weaning in delirious and agitated patients | Short term sedation Induction and maintenance of anaesthesia Maintenance of sedation |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | Clear, colourless solution IV only in Aus (PO overseas) Comparitively expensive, D-stereoisomer | Milky white emulsion 1% Soya bean lipid/Egg phosphatide Sodium hydroxide Weak org acid pKa 11- unionised |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | Selective central α2 agonism Inhibition of noradrenaline release in locus ceruleus Peripherally at higher doses | selective modulation of GABA-A receptor (agonism) (distinct from modulatory site for barbiturates and benzos, and GABA itself) - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction |
| PD: Route & Doses | 0.3-1mcg/kg/hr | Induction: 2-2.5mg/kg Maintenance: 1-5mg/kg/hour Both sig. less in critically ill |
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | CNS: sedation: REM sleep-like state,min respiratory depression Analgesia without as much confusion or disorientation as benzos. Pts easily aroused. Spinal cord analgesia Decreases cerebral VO2, blood flow and ICP No antiemesis CVS: Higher doses cause peripheral α2 effects – vasoconstriction, followed by hypotension and bradycardia (Decreased sympathetic output) Resp: Minimal Resp depression | CNS: Sedation and hypnosis (Rapid distribution across BBB) No analgesia Burst suppression Decreases cerebral VO2, blood flow and ICP CVS: signifi¬cant drop in BP due to decreased TPR, but without a reflex tachycardia (infusion rate dependent) Resp: Dose dependent resp depression, apnoea GIT: Anti-emetic |
| PD: Side Effects / Toxicity | Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia Later, hypotension and bradycardia. Rebound HTN on ceasing dose Dry mouth, nausea | Hypotension (baroreceptor sens. blunted, decreased sympathetic tone). Painful on injection. Propofol syndrome: Metabolic acidosis, hyperlipidaemia, myocardial failure, death- common in children |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | A: Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration | A: onset / duration 30 seconds / 3-10 minutes |
| PK: Distribution | Lipid soluble (rapid distribution) | pKa 11 very high lipid sol Crosses placenta |
| Protein binding (PK: Distribution) | 95% | 97-99% |
| Volume of distribution (PK: Distribution) | 2l/kg (steady state) | 2-10L/kg 60l/kg after 10 day infusion ↓ in elderly |
| PK: Metabolism | Hepatic via CYP and glucuronidation inactive metabolites | Hepatic to partially inactive metabolites (water soluble sulfate and glucuronide conjugates(~50%) Clearance > liver blood flow, ∴extrahepatic metabolism |
| PK: Excretion | Excreted in urine | Urine (~88% as metabolites,40% as glucuronide) |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | Large variation in CSHT with infusion length (T1/2 5 minutes after 10 minutes IV, T1/2 240 minutes after 8 hour IV) | half life Biphasic: Initial 40 min; Terminal 4-7 hrs (up to 60hrs) |
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KETAMINE | MIDAZOLAM
Pharmacopeia - Sedatives
| KETAMINE | MIDAZOLAM (BENZODIAZEPINES) | |
|---|---|---|
| GROUP | Sedative / Hypnotic | Sedative / Hypnotic |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | Phencyclidine (remember the street drug name PCP) derivative that produces dissociative anesthesia | - Benzodiazepine - Imidazole ring in its structure - Accounts for water solubility And rapid metabolism - 2-3x potent Diazepam |
| USES | Induction of anaesthesia - Procedural sedation - Analgesia - ?Role in management of depression. - Recreational | Sedative, amnesic+ anxiolytic, antiepileptic |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | 10, 50 or 100mg/ml | Clear solution pH 3.5 (IV/IM), Tablet pKa 6.5 – 89% un-ionized |
| 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 | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction |
| PD: Route & Doses | - 1mg/kg induction dose - 10~20mg analgesia | 2-2.5mg initially then 1mg boluses to eff¬ect |
| 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 | CNS: Sedative, reduces epileptiform activity, increases confusion and disorientation, amnesic properties more prominent than sedative eff¬ects CVS: minor hypotension has been reported Resp: respiratory depression - synergistic with opioids |
| PD: Side Effects / Toxicity | Increased salivation - Upper airway reflexes intact laryngospasm - Hypotension if given in shock states - Emergence delirium | Respiratory depression and excessive sedation with overdosage Same CYP as alfentanil (increases e¬ffect) |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | A: 20% oral bioavailability | A : IV,PO,In,IM poor oral bioavailability 45% |
| PK: Distribution | lipid soluble at physiological pH (pKa 6.5). high lipid sol crosses BBB | |
| Protein binding (PK: Distribution) | 25% | 95% |
| Volume of distribution (PK: Distribution) | 3l/kg | 1-2 L/kg |
| PK: Metabolism | Hepatic metabolism with active norketamine metabolite | hepatic via CYP3A4, and glucuronidation active metabolite |
| PK: Excretion | Renal elimination | excreted in urine (as glucuronide conjugated metabolites) |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | T1/2a 15 mins, T1/2b 2~3 hours, CSHT 40mins at 5 hours | half life 1-4 hrs prolonged in cirrhosis, CRF, CCF, obesity, elderly |
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LIGNOCAINE / LIDOCAINE
Pharmacopeia - Local Anaesthetics
| LIGNOCAINE / LIDOCAINE AMIDE | |
|---|---|
| GROUP | Amide Local Anaesthetic |
| CICM Level of Understanding | Level 1 |
| INTRODUCTION | |
| USES | 1. as a local anaesthetic 2. in the treatment of ventricular tachydysrhythmias, acting as a class Ib antiarrhythmic. |
| PHARMACEUTICS (PC) | |
| PC: Chemical | tertiary amine which is an amide derivative of diethylaminacetic acid. |
| PC: Presentation | Solution: clear, colourless solution in concentrations of 0.5/1/1.5/2% solution of lidocaine hydrochloride (with or without 1:200 000 adrenaline) Others: - - Gel: 21.4 mg/ml of lidocaine hydrochloride (with or without chlorhexidine gluconate) - a 5% ointment - 10% Spray - 4% aqueous solution for topical application - a cream/ suppositories (in combination with hydrocortisone) for rectal administration - 1% and 2% preparations are available with or without the preservatives methylhydroxybenzoate (1.7 mg/ml) and propylhydroxybenzoate (0.3 mg/ml). Hydrochloric acid and sodium hydroxide are also present in some formulations (the latter to a maximum of 1%). The pKa of lidocaine is 7.7 and is 25% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 2.9. |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | Local anaesthetic |
| PD: Mode of Action | Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane |
| PD: Route & Doses | Lidocaine may be administered topically, by infiltration, intrathecally, or epidurally; the toxic dose of lidocaine is 3 mg/kg (7 mg/kg with adrenaline). The maximum dose is 300 mg (500 mg with adrenaline). The adult intravenous dose for the treatment of acute ventricular dysrhythmias is a bolus injection of 1 mg/kg, administered over 2 minutes. A second dose may be administered according to the response of the patient. This is normally followed by an infusion at a rate of 20–50 micrograms/kg/min. Lidocaine acts in 2–20 minutes (dependent on the rate of administration and the presence of vasoconstrictors and the concentrations used). The speed of onset of lidocaine may be increased by the addition of bicarbonate to increase the pH of the solution, thereby increasing the unionized fraction of drug. The pH of the drug is approximately 6.4. |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | CVS In low concentrations, lidocaine decreases the rate of rise of phase 0 of the cardiac action potential by blockade of inactivated sodium channels. This results in a rise in the threshold potential, with the duration of the action potential and effective refractory period being shortened. It has few haemodynamic effects when used in low doses, except to cause a slight increase in the systemic vascular resistance, leading to a mild increase in the blood pressure. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. RS The drug causes bronchodilatation at subtoxic concentrations. Respiratory depression occurs in the toxic dose range. CNS The principal effect of lidocaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNs. Initially, excitation (lightheadedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNs depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance. AS Local anaesthetics depress contraction of the intact bowel. Metabolic/other Lidocaine may have some anticholinergic and antihistaminergic activity |
| PD: Side Effects / Toxicity | Lidocaine is intrinsically less toxic than bupivacaine. Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above. Methaemoglobinaemia may occur if doses in excess of 600 mg are used and is caused by the metabolite o-toluidine, although this condition may occur at lower doses in patients suffering from anaemia or a haemoglobinopathy or in patients receiving therapy known to also precipitate methaemoglobinaemia (sulfonamides). Use of lidocaine for paracervical block or pudendal nerve block in obstetric patients is not recommended, as this may give rise to methaemoglobinaemia in the neonate, as the erythrocytes are deficient in methaemoglobin reductase. |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | The absorption of local anaesthetic agents is related to: 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous) 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved, and 3. the presence of vasoconstrictors which delay absorption. |
| PK: Distribution | |
| Protein binding (PK: Distribution) | 64–70% predominantly to alpha-1 acid glycoprotein |
| Volume of distribution (PK: Distribution) | 0.7–1.5 l/kg. |
| PK: Metabolism | Lidocaine is metabolized in the liver by N-dealkylation, with subsequent hydrolysis to monoethylglycine and xylidide. Monoethylglycine is further hydrolysed, whilst xylidide undergoes hydroxylation to 4-hydroxy- 2,6-xylidine which is the main metabolite and excreted in the urine. Metabolites of lidocaine may lower the fit threshold, thereby potentiating seizure activity, whilst others have some antiarrhythmic properties. |
| PK: Excretion | Less than 10% of the dose is excreted unchanged in the urine. |
| - Clearance (PK: Excretion) | 6.8–11.6 ml/min/kg ↓ in the presence of cardiac and hepatic failure. |
| - Half Life (PK: Excretion) | elimination half-life is 90– 110 minutes. |
| SPECIAL POINTS | The onset and duration of conduction blockade are related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants. Due to the narrow therapeutic index of lidocaine, the plasma concentrations of the drug need to be monitored in patients with cardiac and hepatic impairment. Lidocaine is not removed by haemodialysis. Intravenous administration of lidocaine decreases N 2o and halothane requirements by 10% and 28%, respectively. EMLA® (Eutectic Mixture of Local Anaesthetics) is a white cream used to provide topical anaesthesia prior to venepuncture and has also been used to provide anaesthesia for split skin grafting. It contains 2.5% prilocaine and 2.5% lidocaine in an oil–water emulsion. When applied topically under an occlusive dressing, local anaesthesia is achieved after 1–2 hours and lasts for up to 5 hours. The preparation causes temporary blanching and oedema of the skin; detectable methaemoglobinaemia may also occur in the presence of excessive o-toluidine plasma levels as a metabolite of prilocaine. |
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PHENYTOIN
Pharmacopeia - Anticonvulsants
| PHENYTOIN | |
|---|---|
| GROUP | Anticonvulsant |
| CICM Level of Understanding | Level 2 |
| INTRODUCTION | |
| USES | Anticonvulsant and antiarrhythmic (V-W class 1b) Epilepsy Trigeminal neuralgia TCA toxicity Digoxin-induced arrhythmias |
| PHARMACEUTICS (PC) | |
| PC: Chemical | # Hydantoin derivative # Precipitates at pH < 7 ◦ → variable oral absorption ◦ → IM contraindicated |
| PC: Presentation | Capsules, Syrups, Injections # Doses 15-20 mg/kg IV loading maintenance (plasma levels required aim 10-20µg/mL) # Rapidly achieves peak (<20mins after loading) # Duration 30mins-1hr but highly variable |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | # Slows inward Na and Ca ion flux during depolarisation and delays outward K flux. ◦ Stabilises the inactive state of V-gated Na channels limiting repetitive generation of APs. ▪ Limits spread of seizure ◦ Reduce glutamate release and thus attenuating Ca entry # Enhance action of GABA |
| PD: Route & Doses | |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | |
| PD: Side Effects / Toxicity | |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | IV, PO – variable 30-75% |
| PK: Distribution | |
| Protein binding (PK: Distribution) | 90% protein bound |
| Volume of distribution (PK: Distribution) | Vd – 0.6-0.7 L/kg |
| PK: Metabolism | # Hepatic to parahydroxyphenyl (inactive) ◦ hydroxylation by CYP450 2C9 ▪ Metabolism effected by inducers or inhibitors of CYP450 2C9 ◦ induces its own CYP450 # Mixed 1st and zero order kinetics as process is saturable ◦ 1st order at plasma [] < 10 µg/mL ▪ t1/2 ~ 24hr ◦ 0th order at plasma [] > 10 µg/mL ▪ t1/2 dose dependent |
| PK: Excretion | < 3% unchanged in urine |
| - Clearance (PK: Excretion) | |
| - Half Life (PK: Excretion) | |
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PHENYTOIN | LEVETIRACETAM
Pharmacopeia - Anticonvulsants
| PHENYTOIN | LEVETIRACETAM | |
|---|---|---|
| GROUP | Anticonvulsant | Anticonvulsant |
| CICM Level of Understanding | Level 2 | Level 3 |
| INTRODUCTION | ||
| USES | Anticonvulsant and antiarrhythmic (V-W class 1b) Epilepsy Trigeminal neuralgia TCA toxicity Digoxin-induced arrhythmias | Epilepsy in the case of partial seizures Adjunctive therapy for partial, myoclonic and tonic-clonic seizures |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | # Hydantoin derivative # Precipitates at pH < 7 ◦ → variable oral absorption ◦ → IM contraindicated | # Pyrrolidine # Highly lipid soluble |
| PC: Presentation | Capsules, Syrups, Injections # Doses 15-20 mg/kg IV loading maintenance (plasma levels required aim 10-20µg/mL) # Rapidly achieves peak (<20mins after loading) # Duration 30mins-1hr but highly variable | # Steady state after two days of a twice daily administration schedule. # Dose: PO/IV 1000 mg daily given as 500 mg 2 times a day |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | # Slows inward Na and Ca ion flux during depolarisation and delays outward K flux. ◦ Stabilises the inactive state of V-gated Na channels limiting repetitive generation of APs. ▪ Limits spread of seizure ◦ Reduce glutamate release and thus attenuating Ca entry # Enhance action of GABA | 1. Partial inhibition of N-type Ca2+ currents and reduced release of Ca2+ from intra-neuronal stores causing reduced intra-neuronal Ca. 2. Inhibition of synaptic vesicle protein 2A (SV2A) involved in vesicle fusion and neurotransmitter exocytosis # → membrane hyperpolarisation → ↓NT release. |
| PD: Route & Doses | ||
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | ||
| PD: Side Effects / Toxicity | ||
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | IV, PO – variable 30-75% | IV, PO Rapidly abs- BA 100%. |
| PK: Distribution | ||
| Protein binding (PK: Distribution) | 90% protein bound | <10% protein bound |
| Volume of distribution (PK: Distribution) | Vd – 0.6-0.7 L/kg | |
| PK: Metabolism | # Hepatic to parahydroxyphenyl (inactive) ◦ hydroxylation by CYP450 2C9 ▪ Metabolism effected by inducers or inhibitors of CYP450 2C9 ◦ induces its own CYP450 # Mixed 1st and zero order kinetics as process is saturable ◦ 1st order at plasma [] < 10 µg/mL ▪ t1/2 ~ 24hr ◦ 0th order at plasma [] > 10 µg/mL ▪ t1/2 dose dependent | # Enzymatic hydrolysis (24%) in a large number of tissues including whole blood but not plasma. |
| PK: Excretion | < 3% unchanged in urine | # 95% excreted in the urine # 65% unchanged |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | T1/2 7hrs | |
| SPECIAL POINTS |
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VALPROIC ACID | CARBAMAZEPINE
Pharmacopeia - Anticonvulsants
| NA VALPROATE | CARBAMAZEPINE | |
|---|---|---|
| GROUP | Anticonvulsant | Anticonvulsant |
| CICM Level of Understanding | Level 3 | - |
| INTRODUCTION | ||
| USES | Anti-convulsant Epilepsy | Anti-convulsant Epilepsy Schizophrenia Trigeminal neuralgia |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | ||
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | Inhibits catabolism of γamino butyric acid(GABA) and inhibits voltage gated Na channels - Increased [GABA] in neuronal junctions - Increased Cl- conductance into neurons - Neuronal hyperpolarization - Increased threshold for depolarization - Increased seizure threshold | Inhibits voltage gate Na channels - Diffuses intracellularly and becomes ionized - Inhibits Na influx and therefore inhibits depolarization - Neurons become less excitable |
| PD: Route & Doses | ||
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | ||
| PD: Side Effects / Toxicity | ||
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | 100% Oral bioavailability | 100% Oral bioavailability |
| PK: Distribution | ||
| Protein binding (PK: Distribution) | 90% Protein binding, | 80% Protein binding, |
| Volume of distribution (PK: Distribution) | Vd 0.4l/kg | Vd 1l/kg |
| PK: Metabolism | Hepatic β oxidation and conjugation | Hepatic phase 1 and 2 |
| PK: Excretion | Renal | Renal |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | T1/2b 20 hours | T1/2b 24 hours |
| SPECIAL POINTS |
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GABAPENTIN
Pharmacopeia - Anticonvulsants
| GABAPENTIN | |
|---|---|
| GROUP | Anticonvulsant |
| CICM Level of Understanding | - |
| INTRODUCTION | |
| USES | - post-herpetic neuralgia - painful diabetic neuropathy - partial seizures with or without secondary generalization - neuropathic pain. |
| PHARMACEUTICS (PC) | |
| PC: Chemical | acetic acid derivate - structural analogue of GABA |
| PC: Presentation | Tablets 600/800mg Capsules 100/300/400mg |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | - does not interact with GABA receptors. - Binds to alpha-2 delta subunit of VGCC (voltage-gated calcium channels) - does not interact with sodium channels in vitro (cf. phenytoin, carbamazepine) May also: - partially ↓ NMDA response - ↓ release of monoamine neurotransmitters in vitro - stimulate glutamate decarboxylase (glutamate → GABA) - ↑ synaptic GABA release |
| PD: Route & Doses | PO. Titration. 300mg TDS usual Long term epilepsy dose: 900-3600mg/day Needs weaning on discontinuation ~1 week Reduce dose in renal impairment |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | CNS - analgesic - anticonvulsant - improves sleep in patients with neuropathic pain |
| PD: Side Effects / Toxicity | - Dizziness, ataxia, nystagmus - somnolence, tremor, diplopia - N/V (>5%) - Leucopenia, erectile dysfunction, weight gain |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | PO BA 60% Peak plasma levels 2-3hrs |
| PK: Distribution | CSF concentration 20% of steady-state trough plasma |
| Protein binding (PK: Distribution) | no PB |
| Volume of distribution (PK: Distribution) | 0.85 L/kg |
| PK: Metabolism | not metabolized. |
| PK: Excretion | unchanged in urine |
| - Clearance (PK: Excretion) | |
| - Half Life (PK: Excretion) | T1/2 5-7hrs. Clearance proportional to creat clearance |
| SPECIAL POINTS | - enchances morphine effect - removed by haemodialysis - BA dec with increasing dose - Antacids decrease BA |
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HALOPERIDOL
Pharmacopeia - Antipsychotics
| HALOPERIDOL | |
|---|---|
| GROUP | First Generation Antipsychotics (D2-Antagonism) |
| CICM Level of Understanding | Level 3 |
| INTRODUCTION | |
| USES | - Schizophrenia - Nausea and vomiting - Motor tics and hiccupping - Acute confusional states and delirium in intensive care - Premedication - Palliative care |
| PHARMACEUTICS (PC) | |
| PC: Chemical | |
| PC: Presentation | Oral tablets, syrup and clear colourless solution for injection |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | Centrally acting D2 blockade and post-synaptic GABA antagonism |
| PD: Route & Doses | |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | CVS: Minimal cardiovascular effects but has antagonistic effects at alpha adrenergic receptors that may cause hypotension in the presence of hypovolaemia CNS: Induces neurolepsis, a state characterized by diminished motor activity, anxiolysis, and indifference to environment. Seizure threshold is raised GIT: Powerful antiemetic Metabolic/Other: Causes hyperprolactinaemia |
| PD: Side Effects / Toxicity | 1. Extrapyramidal Reactions - Tardive dyskinesia occurs in 20% of patients taking the drug for >1 year. Women and elderly are more susceptible - Acute dystonic reactions occur in 2% of patients in first 72 hour especially in young men. These include torticollis, oculogyric crisis and laryngospasm 2. Neuroleptic malignant syndrome - Typically develops over 24-72 hours ad is characterized by hyperthermia, generalized hypertonicity, autonomic instability and fluctuating LOC - Increased muscle tone may lead to chest wall rigidity and myonecrosis. Treatment includes dantrolene and bromocriptine 3. Cardiovascular - May prolong QTc - Hypotension in context of hypovolaemia but this is less pronounded in oral administration 4. Hyperprolactinaemia - Galactorrhoea and gynaecomastia - Hypothalamic effects may lead to increased weight gain |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | well absorbed orally with bioavailability of 60-80% orally |
| PK: Distribution | |
| Protein binding (PK: Distribution) | 92% |
| Volume of distribution (PK: Distribution) | 18-30L/kg |
| PK: Metabolism | extensively hepatically metabolized |
| PK: Excretion | |
| - Clearance (PK: Excretion) | 11ml/min/kg |
| - Half Life (PK: Excretion) | elimination T1/2 is 10-38hours |
| SPECIAL POINTS |
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HALOPERIDOL | DIAZEPAM
Pharmacopeia - Neuro
| HALOPERIDOL | DIAZEPAM | |
|---|---|---|
| GROUP | First Generation Antipsychotics (D2-Antagonism) | Sedative / Hypnotic Benzodiazepine |
| CICM Level of Understanding | Level 3 | Level 1 |
| INTRODUCTION | Benzodiazepine | |
| USES | - Schizophrenia - Nausea and vomiting - Motor tics and hiccupping - Acute confusional states and delirium in intensive care - Premedication - Palliative care | 1. in the short-term treatment of anxiety 2. in the treatment of status epilepticus 3. for muscle spasm in tetanus and other spastic conditions 4. for alcohol withdrawal, and for 5. premedication and 6. sedation during endoscopy and procedures performed under local anaesthesia. |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | Oral tablets, syrup and clear colourless solution for injection | Solution: Clear, yellow solution and as a white oil-in-water emulsion for injection containing 5 mg/ml. Tab: 2/5/10 mg Syrup: 0.4/1 mg/ml Supp: 10 mg |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | Centrally acting D2 blockade and post-synaptic GABA antagonism | increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx causing hyperpolarisation - Influx of Cl- into nerve cell - Hyperpolarised, preventing conduction Diazepam has kappa-opioid agonist activity in vitro, which may explain the mechanism of benzodiazepine-induced spinal analgesia |
| PD: Route & Doses | The adult oral dose is 2–60 mg/day in divided doses; the initial intravenous dose is 10–20 mg, increasing according to clinical effect. | |
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | CVS: Minimal cardiovascular effects but has antagonistic effects at alpha adrenergic receptors that may cause hypotension in the presence of hypovolaemia CNS: Induces neurolepsis, a state characterized by diminished motor activity, anxiolysis, and indifference to environment. Seizure threshold is raised GIT: Powerful antiemetic Metabolic/Other: Causes hyperprolactinaemia | CVS A transient decrease in the blood pressure and a slight decrease in the cardiac output may occur, following the intravenous administration of diazepam. The coronary blood flow is increased, secondary to coronary arterial vasodilation; a decrease in myocardial oxygen consumption has also been reported. RS Large doses cause respiratory depression; hypoxic drive is depressed to a greater degree than is hypercarbic drive.DIAzEPAM 101 CNS Diazepam is anxiolytic and decreases aggression, although paradoxical excitement may occur. sedation, hypnosis, and anterograde amnesia occur after the administration of diazepam. The drug has anticonvulsant and analgesic properties, and depresses spinal reflexes. |
| PD: Side Effects / Toxicity | 1. Extrapyramidal Reactions - Tardive dyskinesia occurs in 20% of patients taking the drug for >1 year. Women and elderly are more susceptible - Acute dystonic reactions occur in 2% of patients in first 72 hour especially in young men. These include torticollis, oculogyric crisis and laryngospasm 2. Neuroleptic malignant syndrome - Typically develops over 24-72 hours ad is characterized by hyperthermia, generalized hypertonicity, autonomic instability and fluctuating LOC - Increased muscle tone may lead to chest wall rigidity and myonecrosis. Treatment includes dantrolene and bromocriptine 3. Cardiovascular - May prolong QTc - Hypotension in context of hypovolaemia but this is less pronounded in oral administration 4. Hyperprolactinaemia - Galactorrhoea and gynaecomastia - Hypothalamic effects may lead to increased weight gain | Depression of the CNs, including drowsiness, ataxia, and headache, may complicate the use of diazepam. Rashes, gastrointestinal upsets, and urinary retention have also been reported. Tolerance and dependence may occur with prolonged use of benzodiazepines; acute withdrawal of benzodiazepines in these circumstances may produce insomnia, anxiety, confusion, psychosis, and perceptual disturbances. Intravenous diazepam is highly irritant to veins; the oil-in-water preparation is less so. |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | well absorbed orally with bioavailability of 60-80% orally | Diazepam is rapidly absorbed after oral administration; the bioavailability is 86–100%. Absorption after intramuscular administration is slow and erratic. |
| PK: Distribution | ||
| Protein binding (PK: Distribution) | 92% | 99% |
| Volume of distribution (PK: Distribution) | 18-30L/kg | 0.8–1.4 l/kg |
| PK: Metabolism | extensively hepatically metabolized | Hepatic to active metabolites. Major metabolite is desmethyldiazepam (half life 100hrs). other metabolites are oxazepam (which is further metabolized by glucuronidation) and temazepam. |
| PK: Excretion | mainly biliary, some urine | urine as oxidized and glucuronide derivatives; <1% is excreted unchanged. |
| - Clearance (PK: Excretion) | 11ml/min/kg | |
| - Half Life (PK: Excretion) | elimination T1/2 is 10-38hours | elimination half-life is 20–40 hours. |
| SPECIAL POINTS | - potentiates non-depolarizing muscle relaxants. - adsorbed onto plastic - not removed by dialysis. |
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BUPIVACAINE
Pharmacopeia - Local Anaesthetics
| BUPIVACAINE AMIDE | |
|---|---|
| GROUP | Amide Local Anaesthetic |
| CICM Level of Understanding | Level 1 |
| INTRODUCTION | |
| USES | local anaesthetic |
| PHARMACEUTICS (PC) | |
| PC: Chemical | amide which is a structural homologue of mepivacaine |
| PC: Presentation | - clear, colourless solution containing racemic bupivacaine (s- and R-enantiomers) in concentrations of 0.25% (2.64 mg/ml equivalent to bupivacaine hydrochloride anhydrous 2.5 mg/ml) and 0.5% (5.28 mg/ml equivalent to bupivacaine hydrochloride anhydrous 5.0 mg/ml). - The 0.25/0.5% solutions are available combined with 1:200 000 adrenaline, which contain the preservative sodium metabisulfite. - A 0.5% (‘hyperbaric’ or ‘heavy’) solution containing 80 mg/ml of glucose (with a specific gravity of 1.026) is also available. - Bupivacaine 0.1% is available as a mixture with 2 micrograms/ml of fentanyl for epidural use. The s-enantiomer is available as levobupivacaine hydrochloride in the following concentrations: 2.5 mg/ml, 5 mg/ml, and 7.5 mg/ml. - Levobupivacaine is also available for epidural use in the following concentrations: 0.625 mg/ml and 1.25 mg/ml. The pKa of bupivacaine is 8.1, and it is 15% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 27.5. |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | Local anaesthetic |
| PD: Mode of Action | Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channels, thereby decreasing Na+ conductance and preventing the depolarization of the cell membrane |
| PD: Route & Doses | Bupivacaine may be administered topically, by infiltration, intrathecally, or epidurally; the toxic dose of bupivacaine is 2 mg/kg (with or without adrenaline). The maximum dose is 150 mg. The drug acts within 10–20 minutes and has a duration of action of 5–16 hours. |
| PD: Metrics (Onset/ Peak/ Duration) | |
| PD: Effects | CVS Bupivacaine is markedly cardiotoxic; it binds specifically to myocardial proteins, in addition to blocking cardiac sodium channels and decreasing the rate of increase of phase 0 during the cardiac action potential. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. K+ and Ca2+ channels may also be affected at toxic doses. Levobupivacaine-induced cardiotoxicity requires a greater dose to be administered, compared with racemic bupivacaine. CNS The principal effect of bupivacaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNs. Initially, excitation (light-headedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNs depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance. Levobupivacaine produces less motor blockade, but longer sensory blockade, following epidural administration. |
| PD: Side Effects / Toxicity | Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above. The use of the drug for intravenous regional blockade is no longer recommended, as refractory cardiac depression, leading to death, has been reported when it is used for this purpose. |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | The absorption of local anaesthetic agents is related to: 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous) 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved, and 3. the presence of vasoconstrictors which delay absorption. The addition of adrenaline to bupivacaine solutions does not influence the rate of systemic absorption, as: 1. the drug is highly lipid-soluble, and therefore its uptake into fat is rapid, and 2. the drug has a direct vasodilatory effect. |
| PK: Distribution | |
| Protein binding (PK: Distribution) | 95% albumin and alpha-1 acid glycoprotein; (Levo: >97%) |
| Volume of distribution (PK: Distribution) | 21–103 L |
| PK: Metabolism | occurs in the liver by N-dealkylation, primarily to pipecoloxylidide. N-desbutyl bupivacaine and 4-hydroxy bupivacaine are also formed. There is no evidence of in vivo racemization of levobupivacaine. In vitro studies of levobupivacaine demonstrate that CYP3A4 and CYP1A2 are responsible for its metabolism to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively |
| PK: Excretion | 5% of the dose is excreted in the urine as pipecoloxylidide; 16% is excreted unchanged. |
| - Clearance (PK: Excretion) | 0.47 l/min |
| - Half Life (PK: Excretion) | elimination halflife (after IV administration) is 0.31–0.61 hours. |
| SPECIAL POINTS | The onset and duration of conduction blockade are related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. In infants under 6 months of age, the low level of albumin and alpha-1 acid glycoprotein results in an increase in the free fraction of bupivacaine. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants. Levobupivacaine may precipitate if diluted in alkaline solutions. Clonidine (8.4 micrograms/ml), morphine (0.05 mg/ml), and fentanyl (4 micrograms/ml) have been shown to be compatible with levobupivacaine |
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