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.

The effects of atropine on brain

 

The effects of atropine on brain

The evolution of the finest brain on the planet must have taken millions of years to reach its present complexity.

The brain functions as a single unit but is made up of closely knit “discrete” structures communicating with each other with mindboggling agility.

The “discrete” structures  are nothing but the cerebrum, cerebellum, brainstem, basal ganglia and others.

The neural processing within the “discrete” structures and the communication of neural information between them, are both dependent on neurotransmitters.

The balance between the two ubiquitous neurotransmitters- acetylcholine and dopamine is of paramount importance in maintaining CNS physiology.

Atropine, a non-selective muscarinic blocker (read acetylcholine receptor blocker) crosses the blood brain barrier and therefore, has widespread CNS effects.

Part of the brain	Effect of atropine	Possible explanation
Cerebral cortex	Cognitive impairment manifested as memory loss, inability to perform skilful mental tasks, indecision etc	Projections to the cerebrum from other parts of the brain and the inter-neuronal communication within the cerebrum for cognitive processing are mediated by acetylcholine. Atropine blocks the muscarinic receptors (M1)  in the CNS and therefore causes cognitive impairment.
Basal ganglia	Motor hyperactivity	Tone and movement of muscles depends on the delicate balance between acetylcholine and dopamine in the striatum. Atropine, by blocking acetylcholine action, promotes the unimpeded action of dopamine in the striatum, resulting in hyperkinesia and motor incoordination.
Mesolimbic pathway	Disorientation, hallucination, confusion, excitement	Tilting of balance towards dopaminergic transmission because of cholinergic blockade. Dopamine excess in the striatum has been shown to cause psychotic behaviour.
Vestibular Nuclei	Loss of balance and equilibrium at very high doses	Suppression of cholinergic transmission in the vestibular apparatus in inner ear. This action has therapeutic use in motion sickness.

 

Secondary adverse effects

 

Secondary adverse effects

·         Adverse effects are undesirable or unintended consequence of drug administration

·         In most cases, adverse effects are due to direct effects of drugs

·         In few cases, adverse effects can occur due to indirect effects of drugs

·         For example- tetracycline induced superinfection of gut

·         Explanation

·         Tetracycline is a broad spectrum antibiotic which is given orally

·         However, prolonged use can kill normal intestinal flora

·         In absence of normal intestinal flora, oppurtunistic bacteria like Clostridium difficile can proliferate and spread in the gut.

·         This is known as superinfection or pseudomembranous enterocolitis. In this condition, there is severe inflammation of the large gut. The patient presents with diarrhoea, pain abdomen and fever.

 

Ageing of acetylcholine esterase

 

Ageing of acetylcholine esterase

·         Acetylcholine is the endogenous cholinergic neurotransmitter.

·         Acetylcholine esterase is an enzyme present in the milieu of the synaptic cleft that degrades acetylcholine into acetyl and choline and terminates post synaptic muscarinic receptor stimulation.

·         Acetylcholine esterase inhibitors bind with acetylcholine esterase and prevent degradation of acetylcholine. So cholinergic transmission increases.

·         Acetylcholine inhibitors are of two types-Reversible and Irreversible

·         With reversible acetylcholine inhibitors, the enzyme is regenerated in reasonable time. So cholinergic stimulation is of short duration and shows time bound recovery

·         With irreversible acetylcholine inhibitors, the enzyme is regenerated very slowly. So cholinergic stimulation is prolonged and recovery depends upon synthesis of fresh enzyme.

·         Therefore, poisoning with irreversible inhibitors is much more dangerous than reversible inhibitors.

·         Among the irreversible inhibitors, the organophosphates may lose one of its alkyl groups and the enzyme-organophosphate becomes completely resistant to hydrolysis. The enzyme is not regenerated at all. This is known as “Ageing” of the enzyme. Recovery completely depends upon synthesis of fresh enzyme. Oximes, if administered as antidote, must be administered promptly because after “ageing”, even oximes cannot regenerate the enzymes.