Pharmacology 5 Flashcards
List the potentially useful properties of benzodiazepines
Sedation Anxiolysis Anticonvulsant Muscle relaxation Amnesia
Where do benzodiazepine drugs act?
GABA-A receptor
Positive allosteric modulation through binding to BDZ site, increasing response to GABA activation.
This increases postsynaptic Cl- influx and hyperpolarisation, exerting a neuroinhibitory effect
How are benzodiazepines classified?
Short / medium / long acting
Short:
- Midazolam
- Triazolam
- Oxazepam
Medium:
- Lorazepam
- Temazepam
Long:
- Diazepam
- Clonazepam
- Flurazepam
What is a typical BDZ infusion regimen used for sedation in ICU?
Midazolam
- 02-0.08 mg/kg loading
- 04-0.2 mg/kg/h infusion
What are the IV BDZ regimens for use in status epilepticus?
Lorazepam:
- 4mg, repeated x1 for adult
- 100 μg/kg, max 4mg for child
Clonazepam:
- 1mg, repeated x1 for adult
- 500μg for child (all ages)
Diazepam (Diazemuls):
-5-10mg every 10 min
How long do the anticonvulsant effects of lorazepam last?
6-12h
How does baclofen exert its therapeutic effect?
Agonist at GABA-B receptor
What effect do BDZs have on memory?
Anterograde amnesia
What are the chemical features of the BDZs?
6-membered phenolic ring abutting a 7-membered ring, which has an attached phenolic group
Highly lipid soluble, mostly oral preparations
IV preparations are in lipid emulsion (diazemuls), propylene glycol (lorazepam, clonazepam) or in an acidic solution making use of tautomeric properties (midazolam)
How does an acidic solution render midazolam water soluble?
Tautomerism
Amine group of 7-membered ring becomes protonated, ‘opening’ the ring and conferring water-solubility.
At body pH, the ring closes and the functional BDZ group is active and very lipid soluble
Outline the pharmacokinetic properties of midazolam
- Short acting, t1/2: 2-4h
- Hydroxylated then glucuronidated
- Hydroxylation produces the active metabolite alpha-1-hydroxymidazolam but only produced at 1/10 the concentration of midazolam
- Duration prolonged in hepatic failure
Outline the pharmacokinetic properties of diazepam
- Long acting, t1/2: 43h
- Metabolised to several active compounds before excretion
Major pathway (>60%): -Diazepam -- [CYP3A4] -> Nordiazepam -- [CYP2C19] -> Oxazepam
Minor pathway:
-Diazepam – [CYP2C19] -> Temazepam – [CYP3A4] -> Oxazepam
Oxazepam is then glucuronidated for renal elimination
Outline the pharmacokinetic properties of lorazepam
- t1/2: 14h
- 75% hepatically conjugated with little metabolism
What are the common side effects of BDZ use?
Sedation
Cognitive impairment
Memory impairment
Excitation and aggression
Do BDZs cross the placenta?
Yes, readily
Also present in breast milk
What are the unwanted effects of long-term BDZ use?
- Impaired co-ordination + increased falls risk
- Drowsiness, dizziness, tremor
- Nausea
- Impaired operation of equipment/driving etc.
- Tolerance and physical dependence
Outline the features of the BDZ withdrawal syndrome
- Insomnia
- Anxiety/restlessness
- Impaired concentration
- Muscle cramps
- Headache
- Nausea
- Mood swings
- Seizures with abrupt withdrawal
Withdrawal from short acting BDZs will occur in 24-48h. Long acting withdrawal may not present until up to 3 weeks after cessation
The withdrawal syndrome may last several months
Outline the features of BDZ overdose
- Intoxication / impaired cognition
- Somnolence
- Impaired co-ordination
- Ataxia
- Anterograde amnesia
- Respiratory depression
- Hypotension
- Bradycardia
- Hypothermia
How is BDZ overdose managed?
Supportive treatment
Flumazenil is usually used only if respiratory depression is a significant feature
Outline the features of the non-BDZ sedative drugs
‘Z’ drugs:
- Eg. zopiclone, zolpidem
- Also acts at BDZ site on GABA-A receptor
- Mainly used for hypnosis
- Dose of all is 10mg nocte or 5mg in elderly
Chloral hydrate:
- Used historically for short-term treatment of insomnia
- MOA unknown
- SEs include D&V, drowsiness, pruritus, rash, dyspnoea, bradycardia
- May precipitate acute porphyria
Clomethiazole:
- Sedative used in treatment of alcohol withdrawal
- Structurally related to thiamine
- Acts at GABA-A receptor as a positive allosteric modulator but at different site to BDZs
Promethazine:
-Sedative H1 antagonist
Melatonin:
- Pineal hormone involved in sleep wake cycle
- Licensed for short term insomnia treatment >55 years
Which sedative agents are commonly used in ICU?
Midazolam
Propofol:
Pros - anxiolysis, anticonvulsant, amnesia, antiemetic, reduces ICP, rapid on/offset
Cons - Reduces CO + SVR + BP
Opioids:
Pros - Sedative, analgesic, anxiolytic
Cons - Venodilator, sympatholysis, bradycardia, hypotension
Morphine
Pros - Cheap
Cons - Accumulation, prolonged offset
Fentanyl
Pros - Short distribution t1/2, no active metabolites
Cons - Significant duration effect on CSHT
Remifentanil
Pros - Rapid on/offset, may shorten mechanical ventilation time, constant CSHT
Cons - Relatively expensive
Clonidine:
1-2 mcg/kg/h
Pros - Sedation, analgesia, no respiratory depression
Cons - Haemodynamic changes (initial 🠙MAP then 🠛), bradycardia, rebound hypertension
Summarise the pharmacology of propofol
- 2,6-diisopropylphenol is a phenol derivative
- MW 178.28, pKa 11
- Used for 1. Induction and maintenance of general anaesthesia 2. Sedation 3. Treatment of refractory N&V 4. Treatment of status epilepticus
- Presented in an isotonic lipid emulsion of pH 7-8.5 which is light and room temperature stable. Most commonly as a lipuro formulation of medium and long chain triglycerides. Some preparations contain EDTA, glycerol, egg phosphatide, soya bean oil and sodium hydroxide
- Can be mixed with 5% glucose, lidocaine or alfentanil
- Main action is hypnotic (?through GABA-A, ACh, α2R, D2)
- Administered intravenously at a dose of 1-2.5mg/kg for induction and as an infusion of rate 4-12mg/kg/h for maintenance of anaesthesia. Plasma concs of 0.5-1.5 and 2-6mcg/ml are associated with sedation and hypnosis respectively.
- Hypnosis produced 30-40 seconds from induction dosing and lasting up to 10 mins
- Causes up to 25% 🠛 MAP + SVR; 20% 🠛 CO; risk of bradycardia / asystole; apnoea; reduced laryngeal reflexes; 🠛TV 🠙RR; 🠛CO2/O2 response; bronchodilation; 🠛ICP/CPP/CMRO2; dystonic movements; anticonvulsant; 🠛IOP; antiemetic
- Causes pain on injection, green urine and risk of propofol infusion syndrome with prolonged use
- Contraindicated in peanut/soya allergy
- 98% protein bound, Vd 4L/kg
- Rapid glucuronidation and sulphation in the liver and lungs. No active metabolites known. Inhibits CYP450
- 98% eliminated in urine (1% unchanged); 2% in faeces; clearance 20-30ml/kg/min; CSHT (<8h) 40 mins
What are putative risk factors for propofol infusion syndrome?
- High dose (>4mg/kg/h) for >48h
- Concomitant vasopressor/glucocorticoid use
- Age <18 years
What are the possible clinical features of propofol infusion syndrome?
- Metabolic acidosis
- Rhabdomyolysis
- Multi-organ failure
What is the Bristol regimen for propofol infusion?
A commonly known manual controlled infusion
- 1 mg/kg loading dose
- 10mg/kg/h for 10 mins
- 8mg/kg/h for 10 mins
- 6mg/kg/h thereafter
What are some commonly used methods for determining depth of anaesthesia?
- Bispectral index
- Entropy
- Auditory evoked potentials
Define the concept of closed-loop anaesthesia
A computerised feedback loop including depth of anaesthesia monitoring which accordingly adjusts infusion rates for TCI
What are the most common barbiturates in anaesthesia and their primary uses?
Thiopental
-RSI + status epilepticus
Methohexital
-ECT + prehospital
Phenobarbital
-Anticonvulsant
Summarise the common production process for the barbiturates
Malonic acid + Urea -> Barbituric acid + water
Substituting a hydrogen ion on the barbituric acid ring with an alkyl or aryl group confers hypnotic activity
How are barbiturates classified?
Thiobarbiturates:
- eg. thiopental
- highly lipid soluble and protein bound
- Completely liver-metabolised
Oxybarbiturates:
- eg. phenobarbital
- Less lipid soluble / protein bound
How do barbiturates exert their pharmacodynamic effects?
- Facilitation of inhibitory synaptic transmission through enhanced GABA-A mediated Cl- influx
- Blocking of:
- non-NMDA glutamate receptors
- voltage-gated Na+ and Ca2+ channels
- K+ channels
- nAChRs
How is thiopental presented?
Pale yellow powder containing racemic thiopental with 6% Na2CO3
Dissolved in water to produce a 25mg/ml solution with pH 10.5 promoting formation of the soluble enol isomer
What is the pKa of thiopental?
7.6
What happens to thio after injection?
physiological pH promotes formation of lipid soluble keto-form
Summarise the pharmacokinetics of thiopentone
Rapid emergence following induction due to redistribution. Vd 2.2L/kg; 80% protein bound.
On emergence, only 18% of thio will have been metabolised
Metabolised by CYP450 to inactive metabolites but early saturation and reversion to zero-order kinetics
How is thiopental used in status epilepticus
Repeated 250mg boluses up to 5g
May be followed by infusion of 4-10mg/kg/h
Summarise the systemic effects of thiopental
CVS:
- 🠛MAP + CO
- Venodilatation but no change in SVR
- Reflex tachycardia
- Myocardial depression with rapid high doses
RS:
- Transient apnoea followed by 🠛RR + TV
- 🠛CO2/O2 response
- Laryngospasm / bronchospasm may occur as reflexes not depressed
CNS:
- 🠛ICP/CPP/CBF/CMRO2
- 🠛IOP
- Anticonvulsant
- Antanalgesic at low dose
- Myoclonus
IS:
-Anaphylaxis 1:20,000
Other:
- P450 inducer
- Crystals may precipitate if injected into joints
- May cause thrombosis if injected arterially
How is methohexital presented?
White powder containing racemic mixture of two (of four) optical methohexital isomers with 6% Na2CO3
Dissolved in water to produce 10mg/ml solution with pH 11 and shelf-life of 6 weeks
What is the pKa of methohexital?
7.9
What happens to methohexital after injection?
physiological pH increases unionised fraction, allowing methohexital to cross the BBB
Summarise the pharmacokinetics of methohexital
Vd 2L/kg 50-65% protein bound Main metabolite is hydroxymethohexitone, which has minimal hypnotic activity Lower accumulation than thiopental Elimination t1/2: 3-5h
Summarise the systemic effects of methohexital
CVS:
- 🠛MAP + CO (less than thio)
- Venodilatation but no change in SVR
- Reflex tachycardia (more than thio)
RS:
- Transient apnoea followed by 🠛RR + TV (more than thio)
- 🠛CO2/O2 response
- Laryngospasm / bronchospasm more common than thio
CNS:
- Rapid hypnosis lasting 3-4 mins from single dose
- Occasional excitatory phase
- Can precipitate seizures in epilepsy
Other:
- Pain on injection
- Precipitation on intraarticular injection
- Thrombosis on intraarterial injection (less than thio)
- Increased ADH secretion
How is phenobarbital presented?
Odourless white crystalline powder or in a 20% solution to be diluted to 2% before IV injection
Outline the pharmacokinetics of phenobarbital
Vd 0.7L/kg
50% protein-bound
25% excreted unchanged renally; 75% hepatically metabolised
Powerful P450 inducer
What are the uses of phenobarbital?
Anticonvulsant that can be used in all types of seizures except absence
Rarely used to treat status epilepticus
Summarise the systemic effects of phenobarbital
- Cardiovascular and respiratory depression
- Sedation and cognitive impairment, coma in overdose, hyperkinesia
- Megaloblastic anaemia, mild hypersensitivity and osteomalacia
Summarise the physiochemical properties of etomidate
Imidazole derivative MW 342 Two optical isomers, R(+) is active Highly lipid soluble Water soluble at low pH
How is etomidate formulated?
In solution with ethylene glycol
Summarise the pharmacokinetic features of etomidate
Hepatic metabolism with extraction ratio of 0.5 85% renally cleared, 13% in bile Vd 2.5-4.5L/kg 75% protein bound Et1/2 3-5h
Summarise the systemic effects of etomidate
CNS:
- Hypnosis through GABA-B2/3 receptors
- 🠛CBF/CMRO2
- 🠛IOP
- Lowers seizure threshold
- Myoclonus
CVS:
-No effect on MAP/HR/PAP/CO/SVR/coronary perfusion
RS:
- Minimal effects
- CO2 response reduced
- Hiccups on induction
Endo:
- Dose-dependent reversible inhibition of 11β-hydroxylase and minor inhibition of 17α-hydroxylase
- This causes accumulation of cortisol precursors and secondary inhibition of ascorbic acid re-synthesis (required for steroid production) and mineralocorticoid production
- Despite this, a single induction dose has not yet been associated with adverse endocrine outcomes
What are the adverse effects associated with etomidate?
- Pain on injection
- Haemolysis
- N&V
- Superficial thrombophlebitis
What is the induction dose of etomidate?
0.2-0.6 mg/kg
Summarise the physiochemical properties of ketamine
Phencyclidine derivative
MW 238
pKa 7.5
Two optical isomers - S(+) more potent
Highly lipid soluble
Racemic mixture contains benzethonium chloride which is potentially neurotoxic
S(+) enantiomer is preservative-free and thus can be used neuraxially
Summarise the pharmacokinetic characteristics of ketamine
Vd 3L/kg
Et1/2 2-3h
Clearance of 1L/min
Dependent on hepatic flow
Where does ketamine exert its pharmacodynamic action?
- NMDA receptor
- Thalamoneocortical projection system
- Opioid receptors
- AChRs and monoamine receptors
- Neuronal sodium channels
Outline ketamine’s action at the NMDA receptor
-Negative allosteric modulation of NMDAR activity, reducing Na+/Ca2+ influx
What is the mechanism for the ‘dissociative anaesthesia’ seen with ketamine?
-Functional and electrophysiological dissociation between the limbic and thalamoneocortical systems
What are the effects of ketamine on the CVS?
Stable patient:
-🠙HR / MAP / CO / MO2 / PVR
Shocked patient:
-🠛HR / MAP / CO / MO2 / PVR
What are the respiratory effects of ketamine?
- Respiratory depression with high dose
- Reflexes remain in tact
- Bronchodilatation
What are the CNS effects of ketamine?
- 🠙 CBF / CMRO2 / ICP
- Theta activity and abolition of alpha activity on EEG
- Purposeful movements and hypertonus can occur
What are the features of the emergence reactions seen with ketamine?
- Hallucinations, illusions, vivid dreaming
- Less prominent in children
- Occurence may be reduced with BDZs
What is known about the neuroprotective effects of ketamine?
- Rat studies suggest an anti-apoptotic effect following ischaemia
- No proven effect in humans yet
