Ketamine- The dissociative anaesthesia. "I see the colorful kites flying in the sky with no pain but with lots of excitement"

 

Ketamine is best described as "dissociative anaesthetic”.

 It “interrupts the communication” between the cerebral cortex and the limbic system.

 There is 

👉Profound analgesia 

👉Moderate hypnosis 

👉Marked sympathomimetic effect 

Hallucinations and hypersalivation also do occur.

Multiple mechanisms seem to modulate the wide responses of ketamine.

💥Antagonism of N-methyl-D-aspartate (NMDA)-receptor in the thalamus and reticular activating system is responsible for the analgesic effect.

💥Blockade of NMDA receptor in the cerebral cortex mediates the hallucinatory and hypnotic actions.

💥Sympathomimetic effects are due to direct CNS stimulation by enhanced central peripheral monoaminergic transmission.

Second Gas Effect and Diffusion Hypoxia

 

Second Gas Effect

For anaesthesia using inhalational agents, it is a common practice to use an anaesthetic inhalation mixture of 70% N2O + 25-30% O2 + 0.2- 2% other anaesthetic

Oxygen is used for maintaining blood oxygen levels while nitrous oxide (the first gas) and other anaesthetic gas (the second gas) are the anaesthetic agents

The lipid solubility of nitrous oxide is low and therefore, high concentration of nitrous oxide (70%) are required in the alveoli to achieve anaesthesia.

At such high concentration, a large amount of nitrous oxide is uptaken into the alveoli capillary at the rate of 1 litre/min

This creates a negative suction in the alveoli and the second gas is sucked into the alveoli. 

This speeds up the induction of anaesthesia because higher amount of the second gas is able to reach the brain. 

This is known as second gas effect

Diffusion Hypoxia

 Reverse of second gas effect occurs when N2O is discontinued after prolonged anaesthesia.

Large amount of nitrous oxide diffuses across alveolo-capillary wall into the alveoli.

Partial pressure of oxygen in alveoli falls. There is risk of hypoxia in the patient. This is known as Diffusion Hypoxia.

Diffusion Hypoxia is easily avoided by 100% oxygen inhalation in the first few minutes after discontinuing nitrous oxide.

Diffusion hypoxia is not significant with inhalation anaesthetics other than nitrous oxide because only nitrous oxide is required to be given at high concentration (70%), while other  inhalation anaesthtics are used at concentrations of 0.2 -2% 

Therapy in Parkinson's Disease. What is "End of Dose" phenomenon?

 

End of Dose Phenomenon

Parkinson’s disease is a progressive neuro-degenerative disease where the dopaminergic neurons in the substantia niagra and the nigro-striatal pathway degenerate gradually and irreversibly over a period of time.

Under normal physiology, dopamine is stored in vesicles in the pre-synaptic vesicle and released in the synaptic cleft upon arrival of an action potential. This event is highly “regulated” and exocytosis of neurotransmitter is “demand” based, occurring as and when required for the smooth execution of muscle action.

In early stages of Parkinson’s disease, exogenously administered dopamine as replacement therapy tend to get stored in the pre-synaptic vesicle and is released on “demand”, thus mimicking the normal physiology. The physiology of storage, release and re-uptake is still intact and dopamine replacement provides immense symptomatic relief to the patient.

As the diseases progresses, the number of dopaminergic neurons decreases due to degeneration. The capacity of the dopaminergic pathway to store the neurotransmitter and release on “demand” is impaired. Relief of symptoms becomes short lasting. Increase in amount and frequency of dose provide only limited benefit. Patient is alternately “well” and “not well”.  This is known as the “on-off” effect or “switch” phenomenon or “end of dose” phenomenon or the “all or none” response. In the terminal phase, when the majority of the neurons are destroyed, abnormal movements (dyskinesia) occurs with administration of dopamine and as soon as the effect of dopamine wanes, severe hypokinesia and rigidity returns.

Parkinson's disease and the neurotransmitter "duo"- DOPAMINE AND ACETYL CHOLINE

 

The smooth, co-ordinated movement of the human body is accomplished by the concerted action of neurones at multiple levels. The impulse for a movement begins in the cerebral cortex and travels to the lower motor neuron, but not before the impulse has been modulated through inputs at the level of striatum, Substantia Nigra and other parts of the brain. The inputs can be either excitatory or inhibitory. The objective is to achieve a smooth, graceful movement at the end.

The neuronal circuitry involves a lot of complexities.

However, the final simplification is-

In the striatum, dopaminergic pathway have a net inhibitory action and the cholinergic pathway have a net excitatory action.

In Parkinson’s disease, there is degeneration of the dopaminergic pathway.

So, Parkinson’s disease is a dopamine deficient state and therefore, treated with replacement of dopamine, or by inhibiting metabolism of dopamine or by administering dopamine agonist.