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Induction agents > Drugs > Flashcards

Drugs Flashcards

1
Q

Chemical structure of thiopentone

A

General: Derivative of barbituric acid (cyclic compound formed by condensation of urea and malonic acid) which itself lacks CNS activity.
Pharmacological activity derived by substitutes at the C2 atom
- oxybarbiturates (phenobarbitone) possess 02 on C2 atom - less lipid soluble which slows onset and decreases potency but prolongs duration of action
- thiobarbiturates (thiopentone) possess sulphur on C2 atom. More lipid soluble and increases potency + rate of onset and action

Thiopentone is a thiobarbiturate which contains sulphur at C2 atom. It has two isomers of which S is 2x more potent

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2
Q

Formulation of STP

A

Contains pale yellow, water soluble powder for reconstitution. Powder contains:

1) Na+ salt of STP as a racemic mixture - generally diluted to 2.5% (25mg/mL) in NaCL (higher conc causes pain on injection)
2) Sodium carbonate (Na2CO3) which reacts with H20 to produce NaHCO3 and NaOH to produce an alkaline solution (pH 10.5) that solubilises STP in water and makes it stable in solution. Alkalinity decreases solubility with other drugs though

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3
Q

Mechanism of action of STP

A

Potentiate the effects of GABA on GABA A receptors in the brain.

  • bind to the alpha subunit and directly activate the receptor
  • Also bind to the beta subunit and increase duration of GABA a receptor activated Cl- channel opening
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4
Q

Pharmacokinetics of STP

A

IV bolus has:

  • rapid onset due to high lipid solubility, rapid effect site equilibration and large portion of unionised drug at physiological pH.
  • Rapid offset mainly due to rapid redistribution to peripheral tissues

Absorption: Only IV
Distribution: Vd ~2.5L/kg. Highly lipid soluble due to sulphur on C2 atom. High protein binding. pKA 7.6 so about 60% unionised at physiological pH (increases in acidosis)
Metabolism and excretion: Low clearance rate 3-4mL/kg/min.
Metabolism - hepatic CYP450 to inactive metabolites.
Excretion - <1% excreted unchanged in the urine

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5
Q

Clinical uses of STP

A

Induction of anaesthesia (3-7mg/kg)
Treat increased ICP - NB CMR02 decreases more than perfusion so get cerebral protection
Anticonvulsant

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6
Q

Pharmacodynamics of STP

A

CNS:

  • Sedation to GA with rapid effects but residual CNS effects lasting hours (hangover)
  • Decreased CBF due to decreased CMR02. Leads to fall in ICP but CPP generally increased as ICP falls more than MAP
  • EEG - dose dependent decrease in EEG activity. Gradual change from alpha pattern (awake) to delta and omega waves then to burst suppression and finally isoelectric at high doses (can therefore be used as anti-convulsant)

CVS:

  • HR increase due to intact BRR and SNS output
  • CO - dose dependent decrease due to direct myocardial depression (negative inotrope)
  • -> at induction doses fall in CO is minimal due to intact BRR however this mechanism ineffective with b-blockers, hypovolaemia or IHD/CHF
  • BP - dose dependent decrease due to SVR (mild due to BRR)
  • CMR02 - increased demand / consumption

Resp:

  • Dose dependent decrease in MV (both TV and RR)
  • increase resting PaC02 and decreased ventilatory response to C02 and 02
  • UAW reflexes depressed only at higher doses
  • HPV intact

GI/GU/Other

  • reduced HBF (decreased CO)
  • Decreased RBF, GFR, UO
  • No effect on uterus
  • Does NOT trigger MH
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7
Q

Issues with injection of STP

A

Pain on injection (esp conc >2.5%)
Extravascular injection very painful and can cause nasty tissue necrosis.
Intra-arterial injection - STP can precipitate at physiological pH - if injected intra-arterial these crystals can block small vessels and cause severe pain and ischaemia

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8
Q

Adverse effects of STP

A

Acute porphyria crisis (barbituric acid enzyme induction can lead to increased haem production)
Allergic reactions + mild histamine release
Tolerance - to sedation occurs earlier than to anticonvulsant and toxic effects. Can decrease therapeutic index. Tolerance can increase required dose up to 6x.
Abuse potential - dependence and withdrawal can occur with prolonged use
Immunosuppression - can occur with prolonged use.

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9
Q

Propofol chemical and formulation

A

Alkyl phenyl derivative (2, 6 diisopropylphenol)
Formulation:
Propofol is highly lipid soluble and thus requires a lipid vehicle for emulsification in solution. As a result it is prepared as a white ‘oil-in-water’ solution.
1) Propofol (1 or 2%)
2) soybean oil (10%) (oil phase)
3) Emulsifying agents - glycerol (2.25%), purified egg phosphatide or egg lecithin
4) Preservative / anti-microbial
- either sodium metabisulfite (pH 4.5-6.5) with generic propofol or
- disodium edenate with NaOH (pH 7-8.5) with dripivam
5) Water

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10
Q

Mechanism of action of propofol

A

Potentiates the inhibitory effects of GABA on GABAa receptor in the CNS
- acts at a specific receptor separate from the binding site of GABA on the alpha subunit to decrease rate of dissociation of GABA from the receptor - prolonged opening of Cl- channel

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11
Q

Pharmacokinetics of propofol

A

When given as IV bolus:

  • rapid onset due to high lipid solubility, short effect site equilibration time, entirely unionised at physiological pH
  • rapid offset due to rapid redistribution
  • Short CSHT due to high clearance

Absoprtion: IV only
Distribution: large Vd (largest of all induction agents) (about 4L/Kg). 98% protein bound. Short distribution half life (1-4min)
Metabolism and excretion: Very high clearance (30-60mL/kg/min) which exceeds HBF (very high HER). Two routes of clearance
1) Hepatic clearance - oxidative metabolism by CYP450 to 4-hydroxy-propofol (33% active) which is then metabolised to inactive compounds
2) Extra hepatic clearance - pulmonary first pass metabolism (taken up and metabolised by pulmonary CYP450), renal metabolism via glucuronidate
- 0.3% renally excreted unchnaged, rest of inactive metabolites excreted in urine.
NB hepatic and renal dysfunction does not impair clearance

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12
Q

Clinical uses of propofol

A

1) Induction of GA - bolus 1.5-2.5mg/kg (higher for children due to increased clearance and large vd, lower for elderly due to decreased clearance and smaller vd)
2) Maintanence of GA - easily titratable. Short CSHT
3) IV sedation
4) anti-convulsant
5) Anti-emetic
6) Anti-puritic effect

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13
Q

Pharmacodynamic effects of propofol

A

CNS
- conscious sedation through to GA. Amnesic but no analgesia
- Decreased CBF due to decreased CMR02. Decreased ICP
- CPP may decrease due to hypotensive effects (decreased MAP > ICP
EEG dose dependent decrease. Can be used as anti-convulsant

CVS:
HR - generally unchanged due to depression of BRR. Can cause significant bradycardia and even asystole due to disinhibited vagal outflow (loss of BRR and SNS).
CO - dose dependent decrease (negative inotropy and myocardial depression due to decreased intracellular Calcium)
BP - dose dependent decrease due to fall in SVR and CO

Resp:

  • Dose dependent decrease in MV (decrease both TV and RR)
  • Increased resting PaC02 and decreased response to C02 and 02
  • AW - bronchodilation. Depresses UAW reflexes - risk of aspiration
  • HPV intact

GI/GU/other

  • anti-emetic
  • anti-pruritic
  • Not a trigger for MH or porphyric crisis
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14
Q

Adverse effects of propofol

A

1) Pain on injection (as a result of the emulsifying agents)
2) Low risk of allergic reactions and anaphylaxis - rarely due to additives. Mainly on first exposure to propofol due to previous sensitisation to phenyl and diisopropyl groups on other drugs
3) Propofol infusion syndrome - prolonged infusion. Fat overload syndrome, metabolic acidosis, rhabdo
4) Excitatory phenomena - can mimic seizures on induction or emergence
5) Addictive and abusive potential
6) Bacterial growth

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15
Q

Etomidate chemical and formulation

A

Carboxylated imidazole containing compound (allows it to be water soluble at acidic pH and lipid soluble at physiological pH).
Two isomers - R is 5x more potent

Formulation:
Clear, colourless solution of pH 6.9. Contains
- etomidate 0.2% (racemic mixture)
- either propylene glycol (35%) or fat emulsion
- water

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16
Q

Etomidate mechansim of action

A

Potentiates the inhibitory effects of GABA on GABAa receptors by enhancing the affinity of GABA for these receptors.

17
Q

Etomidate pharmacokinetics

A

IV bolus has rapid onset due to moderate lipid solubilitiy, ,moderate effect site equilibration time but entirely unionised at physiological pH.
Rapid offset due to rapid redistribution.

Absorption: IV only
Distribution: second largest Vd (2.5-4.5L/kg). pKA 4.2 (weak base) - 99% unionised at physiological pH. 75% protein bound. Short distribution half life
Metabolism and elimination: Clearance rate 10-20mL/Kg/min.
Metabolism - hydrolysis of ethyl ester side chains by hepatic and plasma esterases into inactive metabolites
Excretion - 97% excreted as inactive metabolites (85% urine, 12% bile). Only 3% excreted unchanged
- longer CSHT than propofol

18
Q

Clinical uses of etomidate

A

Alternate for induction and maintenance of GA for patient with unstable CVS. Induction dose 0.2-0.4mg/kg

  • benefits of being CVS stable with rapid onset and offset and relatively short CSHT
  • has some serious adverse effects though including suppression of adrenocortical function, increased PONV, proconvulsant and porphyric crisis
19
Q

Pharmacodynamic effects of etomidate

A

CNS

  • Conscious sedation and amnesia to GA. No analgesia
  • CBF decreased due to decreased CMR02. ICP decreased due to decreased CBF.
  • CPP maintained due to minimal fall in MAP
  • EEG - same as other agents. Dose-dependent decrease in EEG.

CVS

  • HR - minimal change at induction doses (BRR intact but minimal change in MAP anyway)
  • CO - minimal change at induction doses
  • BP - dose dependent decrease mainly due to decrease SVR
  • Does not blunt haemodynamic response to AW instrumentation
  • Cardiac MR02 and delivery stable

Resp:

  • Dose dependent decrease in MV (TV and RR)
  • Blunted response to PaC02 and 02 with increased resting PaC02
  • No effect on AW smooth muscle. UAW reflexes depressed
  • HPV intact
20
Q

Adverse effects of etomidate

A

1) Pain on injection (only with propylene glycol, not lipid solution)
2) Adrenocortical suppression:
- Dose dependent inhibition of 11-B hydroxylase and 17-A hydroxylase which blocks cholesterol conversion to cortisol and aldosterone. Single IV dose has little effect in a fit/healthy patient but poses an issue if unwell with suppressed cortical function (septic, shock etc) or wtih repeated dosing / infusion
3) Can precipitate porphryic crisis
4) Allergy and histamine rare
5) Increased PONV
6) Excitatory and proconvulsant activity

21
Q

Ketamine chemical and formulation

A

arylcyclohexamine which is a derivative pf phenylcyclidine. Two isomers R and S. The S isomer is:

  • 2-3x more potent, provides more intense analgesia
  • has more rapid metabolism (and hence recovery)
  • Has fewer side effects (esp cardiac depression, salivation, emergence)
  • possesses ischaemic preconditioning

Formulation:
Available as a clear, colourless solution (pH3.5-5.5)
Contains:
- Ketamine (10/50/100mg/mL) either racemic preparation or S+ enantiomer only
- preservative - bencethonium chloride (50/100mg solutions only)
- water

22
Q

Ketamine mechanism of action

A

Main mechanism = non-competitive antagonist at NMDA receptors
- NMDA receptor is an excitatory pentameric ligand gated receptor with a central cation channel. Receptor binding by glutamate (and glycine (a co-agonist)) activates the receptor displacing a magnesium plug and allowing influx of cations causing depolarisation of the neuron
- ketamine binds to the phenycyclidine site (therefore non-compeitive) and inhibits activation by glutamate
Minor mechanism - also acts on other receptors
- Potentiates effects of GABA on GABAa
- Antagonises mACHr
- acts on opioid receptors
- inhibits monoamine receptors
- acts via na+ channel and L=type calcium channel (LA effects)

23
Q

Pharmacokinetics of ketamine

A

When given as an IV bolus rapid onset due to very high lipid solubility and low portion of protein binding.
Rapid offset due to rapid redistribution

Absorption: PO oral bioavailability 20% (high first pass metabolism). IM - large doses need to be given due to first pass metabolism.
Distribution: Vd 2.5-3.5L/kg, pKA 7.5. Low protein binding (25%)
Metabolism and excretion: clearance rate 16-18mL/kg/min
- High HER (1.0) - hepatic CYP450 demethylates ketamine to norketamine (30% active) and has prolonged analgesic effects which is then metabolised to inactive metabolites.
Excretion - <4% excreted unchanged renally. 96% excreted as inactive metabolites

24
Q

Uses of ketamine

A

1) Induction and maintenance of GA
- produces dissociative anaesthesia characterised by apparent wakeful state with eyes open, slow nystagmus, purposeful movements but non-communicative. Rapid onset (slower IM 2-4min).
- dose 1-2mg/kg (IM 5-10mg/kg).
- Useful for certain cases where indirect CVS effects are beneficial in patients with compromised CVS function and can reduce inotropic support requirements. Asthmatic patients due to bronchodilatory effects - can be used in status asthmaticus (0.5mg/kg). Brief procedures where analgesia is required. Pre-med for children or special needs

2) Analgesia
- dissociates the thalamus from the limbic cortex and prevents relaying of pain sensation from RAS to the limbic cortex for proceessing. Also inhibits spinal cord sensitisation to pain by blocking activation of peripheral NMDA receptors.
- Useful for post op and chronic pain. Can help with tourniquet pain.
- Dose 0.2-0.5mg/kg +/- infusion

3) Pre-op sedative. Oral 6mg/kg, IM 5-10mg/kg. Peak effect 15-30min

25
Q

Ketamine pharmacodynamics

A

CNS
- dissociative anaesthesia, analgesia and amnesia
- CBF increased due to cerebral vasodilation, secondary to increased CMRO2. increaed ICP due to this.
EEG - dose related decrease in cortical EEG activity. Excitatory EEG activity only seen in thalamic and limbic systems

CVS
- Ketamine has indirect effects on CVS via
a) direct CNS stimulation of SNS outflow
b) Inhibition of n-adr reuptake (central and peripheral)
This leads to:
- increased HR, CO, BP and coronary metabolic demand and blood flow
- useful in patients with compromised CVS function eg shock, elderly etc but must be used in caution with those with uncontrolled HTN, pulmonary HTN, IHD, CHF
- NB ketamine itself is a negative inotrope as it has myocardial depressive effects

Resp:

  • Minimal effect on minute ventilation and resting PaC02
  • Potent bronchodilator
  • UAW reflexes maintained. Increased UAW secretions
  • HPV intact

GI/GU/other

  • NO hepatic/renal effects
  • increased salivation
  • increased PONV
  • Increased uterine tone
  • no MH, porphyria, histamine or allergic reaction
26
Q

Ketamine adverse effects

A

1) emergence delirium
- pyschomimetic effects (delirium, hallucinations etc). Generally occurs with increasing age (less common in children and elderly), increasing doses, known pysch/personality issues.
- Incidence reduced with midazolam pre-med
2) Addictive and subject to abuse
3) Tolerance with infusion / repeated doses
4) Hypertonia, hypersalivation

27
Q

Midazolam chemical and formulation

A

Imidazole ring structure that displays pH dependent opening.

  • pH <4 ring opens to form an ionised molecule that is water soluble
  • pH >4 ring closes to form an unionised molecule (lipid soluble) - this occurs at physiological pH.

Formulation:
Clear, colourless solution at pH 3.5. Conc 1,2 and 5mg/mL.

28
Q

Midazolam mechanism of action

A

Potentiate the effects of GABA on GABAa receptor. Acts via the alpha subunit (similar to GABA but different site on the subunit.

  • Alpha 1 subunit to cause sedation and alpha 2 to cause anxiolysis
  • Does not activate the receptor directly instead enhances the affinity of the receptor for GABA
29
Q

Midazolam pharmacokinetics

A

Rapid onset due to high lipid solubility, largely unionised at physiological pH and small vd.
Rapid offset due to redistribution and rapid clearance

Absorption: PO has 50% oral bioavailability (high first pass metabolism). IM 80-100% bioavailability
Distribution: Highly lipid soluble but low Vd (1-1.5L/kg)
Highly protein bound (98%). Long effect site equilibrium time.
Metabolism and excretion:
Clearance 6-8mL/kg/min
Metabolised via oxidative metabolism by hepatic and small intestine CYP450 3A4.
- Main metabolite = 1-hydroxymidazolam (50% activity) which is conjugated to hydroxymidazolam - has high activity at high conc.
- Minor metabolite - 4-hydroxymidazolam
NB metabolism slowed by liver disease, age and inhibitors of 3A4
Excretion - both inactive and active metabolites are excreted renally
Elimination t1/2 1-4hours. Short CSHT (can be infused)

30
Q

Uses of midazolam

A

1) Induction of anaesthesia (0.1-0.2mg/kg) -> rapid onset 30-60seconds. Delayed peak clinical effect (3-5min) that lasts 30min.
- causes minimal CVS depression
2) maintanence of GA - longer CSHT than propofol
3) Sedation 1-2.5mg (can cause resp depression)
4) pre-med
5) Anti-convulsant

31
Q

Pharmacodynamics of midazolam

A

CNS

  • Anxiolysis, sedation/hypnosis, anterograde amnesia
  • NO analgesia
  • CBF decreased due to decreased CMR02, ICP decreased
  • EEG same as other induction agents BUT unable to produce isoelectricity even at very high doses. Still a potent anti-convulsant

CVS

  • HR Increased due to preserved BRR and fall in BP
  • CO unchanged
  • BP decreased due to decreased SVR
  • does not blunt haemodynamic response to AW instrumentation

Resp:

  • Dose dependent decrease in MV (TV > RR)
  • No bronchodilatory effects. UAW reflexes depressed.
  • HPV intact

GI/GU/Other

  • Decreased HBF
  • Decreased RBF, GFR, UO
  • Decreased PONV
32
Q

Adverse effects of midazolam

A

Delayed awakening

lower potential for abuse than other benzos but tolerance and withdrawal can occur

33
Q

Flumazenil chemical and presentation

A

Imidazole benzodiazepine derivative indicated in the reversal of BDZ effects

Formulation:
clear, colourless solution 100mcg/mL

34
Q

Flumazenil mechanism of action

A

Competitive antagonist at BDZ receptor on GABAa receptor

35
Q

Pharmacokinetics of flumazenil

A

Absorption: significant first pass metabolism if given orally
Distribution: Small Vd 0.9L/kg. PB 50%. Moderate lipid solubility
Metabolism and excretion:
Hepatic metabolism to inactive metabolites
99% excreted in urine (0.1% unchanged).
High clearance of 10mL/kg/min.
Elimination half life of 53 minutes

36
Q

Flumazenil dosing

A

0.1mg (100-200mcg) increments up to 1mg.
Onset of action within 2min.
Duration of action 30-60 min. Therefore often needs repeat dosing or may need an infusion.

37
Q

Flumazenil pharmacodynamics

A

CNS - anxiety. May precipitate seizures, especially in higher doses.
CVS - increase HR and BP
Resp - reverses resp depression from bdz’s

Induction agents (1 decks)

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