18B04: Exam Report

Compare and contrast ketamine and midazolam.

62% of candidates passed this question.

In addition to the key PK and PD properties of each drug, a clear comparison was required to score well (why choose one drug over the other?). When a table was used the addition of a comparison column was helpful.

A good answer covered the following: ketamine has analgesic properties whilst midazolam does not; ketamine preserves airway reflexes and does not cause respiratory depression unlike midazolam; whilst ketamine increases cerebral blood flow and CMRO2, midazolam decreases it; ketamine has a direct myocardial depressant effect which is often offset by an increase in sympathetic tone, whilst midazolam has no direct cardiac depressant effects but may reduce BP due to reduced SVR; midazolam has anticonvulsant properties, ketamine does not; ketamine is a bronchodilator; both drug effects are offset by redistribution; midazolam is lipophillic at body
pH and will accumulate with prolonged infusions, ketamine will not; both are metabolised in the liver; midazolam can be reliably reversed by flumazenil, whereas there is no reliable complete reversal of ketamine; midazolam exhibits tolerance, dependence and withdrawal, whereas patients will only experience tolerance to the analgesic properties of ketamine.

“Drugs in Anaesthesia and Intensive care” chapters on midazolam and ketamine outline the key facts to include in this answer; interpretation and comparison of these facts will help achieve a good mark.

K2i / 18B04: Compare and contrast Ketamine and Midazolam

Chemical

Ketamine

Midazolam

Use

Ketamine

  1. Induction GA
  2. Conscious sedation
  3. Analgesia
  4. Severe asthma

Midazolam

  1. Sedation
  2. Hypnosis
  3. Anxiolysis
  4. Anticonvulsant
  5. Anterograde amnesia

Ketamine can be used as a cardiostable induction agent and has analgesic properties

 Midazolam is great for amnesia and as anticonvulsant – both absent in ketamine

Route

Ketamine

IV/IM/PO/PR

But poor OBA 16% due to high 1st pass metabolism

Midazolam

IM, IV, SC, CNB (intrathecal/epidural)

Both have good alternative routes of administration

Onset

Ketamine

30 – 60sec IV →3 – 8mins IM

Midazolam

2-3mins

MoA

Ketamine

  1. NMDA Antagonism
  2. Voltage sensitive Ca2+ channel inhibition
  3. Muscarinic antagonist
  4. Facilitates descending inhibitory monoaminergic pathways →inhibits reuptake of CA →INDIRECT SYMPATHOMIMETIC

Weak opioid receptor agonism

Midazolam

  • Bind BZD receptor which are closely linked with GABA receptors
  • Facilitates GABAergic inhibition
  • ↑frequency of Cl channel opening

PD

Ketamine

CNS

  • Dissociative anaesthesia with slow nystagmic gaze
    • Dissociates thalamus (relays sensory info from RAS to C. Cortex) from Limbic Cortex (awareness & sensation)
  • Amnesia →anterograde
  • Analgesia
  • Emergence delirium →visual, auditory, illusion & delirium
  • Cerebral protection →↑CMRO2 & ↑CBF

(Directly dilates cerebral arteries)

RESP

  • ↑airway secretions →anticholinergic
  • Preserves laryngeal reflexes
  • Bronchodilation →↑symp & Ca2+ channel inhibition
  • PAP →↑symp NS

CVS

  • ↑MAP, PAP, CVP, HR, CO, myocardial O2 requirements
    • Actually a Direct – ve Inotrope
    • But with ↑symp NS & adequate catecholamine stores, therefore CVS stimulating effects predominate

NB: can be unmasked in ICU patients with ↓catecholamine stores

GI

  • Salivation = antimuscarinic

↑BSL = ↑symp

Midazolam

CNS

  • Anterograde amnesia
  • Dose related ↓CMRO2 & CBF
  • Potent anticonvulsant
  • Sedation
  • Anti-nociceptic in SC/Epidural

CVS

  • Blunts CV response to intubation
  • Small ↓SVR

RESP

  • Stable MV
  • Dose dependent resp depression

↓response to ↑PaCO2

Ketamine increases cerebral BF and CMRO@ whereas midazolam is more neuroprotective

Ketamine is a bronchodilator and preserves laryngeal reflexes.  Midazolam depresses respiratory drive

Ketamine is a direct myocardial depressant, although offset by increase in symp tone

Although midazolam does not depress myocardium it may reduce BP by SVR

PK

Ketamine

A

Lipid soluble →absorbed, but poor poor OBA 16%

Due to high 1st pass metabolism

D

  • Large →5L/kg
  • PPB small 12%
  • Rapidly crosses placenta
  • *HIGH LIPID SOLUBILITY *

M

High hepatic ER

  • Clearance 18mL/kg/min

E

H2O soluble metabolites excreted by kidney

<5% unchanged

Faecal excretion <5% dose

Midazolam

A

OBA 40% (large 1st pass)

IM availability 80%

D

95% PPB (albumin-base)

VD 1.5L/kg

High lipid solubility

Short DoA 2° redistribution (because lipophilic)

M

Hepatic 3A4 hydroxylation →same as Alfentanil

∴ together have ↑DoA

Then glucuronidation for renal excretion

5% to OXAZEPAM = active metabolite

E

Metabolites renally cleared

Clearance 7mL/kg/min

 

Midazolam’s high lipophilicity give it longer CSHT

Both offset by redistribution

Both require liver metabolism

Adverse Effects

Ketamine

Tolerance (enzyme induction

IHD/HTN/CCF = Increases myocardial work

Increases ICP, CBF and CMRO2

Pregnancy = reduces uterine BF

Prolongs SUX activity

Unmasks myocardial depression when given w sympatholutic

Enhances NDMR block

Midazolam

  • May have pain on injection
  • Apnoea

Flumazenil = antagonist

Midazolam reliably reversed by Flumazenil

No reliable reversal agent for ketamine

Ketamine has AE of hallucinations and should not be used w PMH PTSD

Both drugs of abuse.  Ketamine as a hallucinogen and midazolam due to withdrawal