For Medical Professionals

Ketamine

Pharmacokinetic Review & Uses in the Anxiety Disorders

A Short History

Federal Regulatory Schedules Defined

Schedule Abuse Potential Legitimate Medical Use Safety Under Medical Supervision Dependency Potential Examples
I High None None Low-High LSD, MDMA, GHB, Heroin, Peyote, Mescaline
II High +++ High High Fentanyl, Morphine, Amphetamines, Dilaudid, PCP, Cocaine
III Low +++ High Low Ketamine, Cough Medicines, GHB, Xyrem, Anabolic Steroids, Cannabinoids
IV Low +++ High Low Lorazepam, Midazolam, Diazepam, Clonazepam, Phenobarbital, Tramadol, SOMA
V Low +++ High Low Cough and Appetite Suppressants, Anticonvulsants

Legal Classifications

State Drug Class Legal Penalty for inappropriate possession
A Worst
Mandatory jail
Heroine, GBH
B Moderate
Possible Jail
Cocaine, LSD, Amphetamines, Ecstasy, Oxycotin, Ketamine
C Moderate
Possible Jail
Ketamine
D Low
Possible Jail
Marijuana
*A state by state system, not used in California

Pregnancy & Teratogenicity

Category Effect on Pregnancy & Teratogenicity
  • No studies have ever been conducted in Humans
  • No teratogenicity shown in dog studies
  • Moderate teratogenicity in rats treated with 10X human general anesthetic doses over 8 days (organogenesis period) during embryonic development
  • No incidental clinical case reports of teratogenicity or effects on pregnancy in humans
  • Clinical case reports of Ketamine-Cocaine combination => significant teratogenicity
A None
Studies have shown no risk
B None-Low
Animal Studies = None
But no human studies done
C Low-Mod
Risk <Benefits
Ketamine
D Mod High
Risk ?<Benefits
X High
Risk >>Benefits
N Unknown or untested therefore no FDA Classification

Ketamine: Is a 50/50 mixture of both S & R enantiomers

ketamine-mixture

Chemistry:

Despite clinical similarities with other central neuro-modulators the differences are what is most important.

chemistry-page7
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Physiologic Behavior: Receptor Sensitivity

Many other locations in human body:

CNS locations including hippocampus: learning, cognition, memory centers

Skin, connective tissues, effects uncertain

 

Of significance is to note the cardiovascular, respiratory and cerebral effects of ketamine compared to other anesthetics. These effects make ketamine uniquely useful for specific medical purposes
(Source: Clinical Anesthesiology, Morgan and Mikhail, 5th Edition, 2013, McGraw Hill)
summary-nonvolatile-anesthetic-effects

Physiologic Behavior of Ketamine is very useful for…

Pharmacokinetics: A Quick Review

 

 

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Physiologic Behavior in-situ

Methods of Dose Administration  for an ED50 (general anesthesia):

Intra-Venous: Peak Blood levels 1min.
Intra-Muscular: Peak Blood levels 5min.
Intra-Nasal: 50% bioavailability
Oral: 10%-50% bioavailability
Rectal: 10%-50% bioavailability

Half-Lives: for a single injection

 

Metabolism:
– Mechanism: 99% is Hepatic p450 conjugation -> NorKetamine (20% potency), Hydroxy-Ketamines (inactive), etc.

– Excretion: Renal

Ketamine’s Clinical Margin of Safety

ketamine-clinical-margin-for-safety-page13

Blood Level & Clinical Effects

blood-level-clinical-effect-p14

Pharmacokinetics

Pharmacokinetics-p15

pharmacokinetics-page16

 

 

 

 

 

 

 

 

 

 

Continual Infusion Dosing achieves a constant therapeutic blood level

 

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A constant therapeutic blood level over a set amount of time is what is believed to achieve the NMDA Receptor Anti-Depressant effect.

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The Anti-Depression Therapeutic Window

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A Brief Review of the Anxiety Disorders

Incidence(1): 18.1% of adult population (~40M in USA)

Prevalence(1):
Age < 18: 12.5%
Age 18-29: 30.2%
Age 30-44: 35.1%
Age 45-59: 30.8%
Age 60+ : 15.3%

Societal Cost(2)
Lost Productivity and Disability: ~$217.5 Billion/year in USA
Medical Expenditures: ~$100.1 Billion/year in USA

Sources:
(1)National Institute of Mental Health, www.nimh.nih.gov/health/statistics/cost/index.shtml
(2)Am Journ Psychiatry 2008 Jun; 165(6):663-5

Incidence(1): in Adolescent Population in Guatemala City (1992) 35.1%

Sources:
(1) Berganza CE, Aguilar G.Adolescence. 1992 Winter;27(108):771-82.

Common Co-Morbidities Directly or Indirectly attributed to, or associated with, the Anxiety Disorders.

Sources:
(1)Anxiety and Depression Association of America

The Anti Depressant Mechanism of Ketamine

“We find that ketamine-mediated NMDAR blockade at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII) resulting in reduced eEF2 phosphorylation and desuppression of BDNF translation. Furthermore, we find inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. “

Nature. ; 475(7354): 91–95

Anita E. Autry1, Megumi Adachi1, Elena Nosyreva2, Elisa S. Na1, Maarten F. Los1, Peng-fei
Cheng1, Ege T. Kavalali2, and Lisa M. Monteggia

Department of Psychiatry, UT Southwestern Medical Center.

 

In other words: “…the underlying mechanism is unclear”
author-manuscript

Measurements of Validation & Progress

MADRS: Montgomery Asberg Depression Rating Scale/10 questions

Purpose: Severity of Depression, to measure baseline and long-term effectiveness

Reliability & Repeatability: Correlation Coefficient: 97%, p<.001

CADSS: Clinician Administered Dissociative State Scale/28 questions

Purpose: Dissociative Symptoms measurement
Pre vs. Post Ketamine Rx -> Ketamine Dosage Adequacy

Reliability/Repeatability: Correlation Coefficient: 94%, p<.0004

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CADSS: Clinician Administered Dissociative State Scale

clinician-administered-dissociative-state-p31

Other Usable Anxiety Testing Rating Scales & Surveys

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Depression, the Anxiety Disorders, Ketamine

The IOMI Collaborative

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Our Practice-Collaboration

page 34 – need to add screenshot

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Sunday Monday Tuesday Wednesday Thursday Friday Saturday
  1. Preliminary Psychiatric/Psychological Evaluation
  2. Baseline MADRS & Baseline CADSS
  3. Pre-Anesthetic general medical evaluation including additional CV studies and labs if deemed necessary
– CADSS
– Ketamine Infusion
– CADSS
MADRS – Ketamine Infusion
– CADSS
– Ketamine Infusion
– CADSS

Ketamine Infusion +-0.5mg/Kg x 50-60 mins

 

 

 

 

Related and Supportive Studies of note.

systematic-review-p42

Effective for Both Unipolar & Bipolar

Serial Infusion is better than a Single Dose
journal-of-psychopharmacology-p43

ketamine-cronic-treatment-p44

Post Traumatic Stress Disorder
(PTSD)

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Ketamine & Suicidal Ideation

rapid-antidepressant-effects-ketamine

Ketamine vs. Electro-Convulsive Therapy
(ECT)

effects-of-ketamine-OCD-p47

Ketamine & Obsessive Compulsive Disorder
(OCD)

Ketamine & Dissociative Side Effects

Journal of Affective Disorders, Apr;159:56-61, 2014

Exercise & Depression

page50

Summary:
Ketamine’s Use in the Anxiety Disorders