Poisoning of CNS

Question 1

CNS poisons

Answer 1

I. True alkaloids
I.1. Tropane alkaloids
I.2. Isoquinoline alkaloids
I.3. Piperidine alkaloids

II. Terpenoids
II.1. Diterpene derivatives
II.2. Triterpenoid derivatives (steroidal compounds)
II.3. Triterpenoid derivatives (non-steroidal compounds)

III. Thiaminase enzymes of plants

Question 2

Tropane alkaloids

Answer 2

Tropane rings are biosynthesis-ed from the amino acid, ornithine

Two types of tropane alkaloids:
• Solanaceous alkaloids
• Coca alkaloids

The basic compounds are: hyoscyamine (its two enantiomers together is called atropine), scopolamine, and cocaine

Question 3

Tropane mechanism

Answer 3

Inhibition of muscarinic cholinergic receptors

Site of action: smooth and cardiac muscle, gland cells, peripheral ganglia and CNS

Alkaloids bound reversibly to receptors

Solanaceous alkaloids are anticholinergics reducing the activity of the parasympathetic nervous system and promoting sympathetic predominance

Symptoms are developed in 30-60 minutes, last intensively for 2 hours and decrease for 10-12 hours (except in the eyes: 72 hours)

Alkaloids are excreted with urine

Question 4

Tropane symptoms

Answer 4

• Xerostomia (dry mouth)
• Mydriasis (dilated pupils)
• Tachycardia (high heart rate)
• Rapid breathing
• Spasms, seizures
• Death (respiratory failure)

Question 5

Isoquinoline alkaloid

Answer 5

Chemical origin: isoquinoline backbone from thyrosine amino acid

The most important derivatives are the opioids: morphine, codeine, papaverine, and rhoeadine

Question 6

Isoquinoline mechanism

Answer 6

In the brain, spinal cord, and digestive tract, opioids bound to the opioid receptors of neurons

Close Ca2+ channels and inhibit Ca2+ ions to enter the neuron
Open K+ channels K+ ion efflux

The efflux of many positive ions hyper-polarizes the neuron making it less likely to fire suppression of transmission of pain signals

Question 7

Isoquinoline symptoms

Answer 7

Pinpoint pupils
Spasms in the stomach and intestinal tract, vomiting
Paralysis of limbs  --> stumbling walk 
Slow and heavy breathing
Urinary retention, constipation 
Hallucinations, coma, death

Question 8

Piperidine alkaloid

Answer 8

Synthesis: piperidine ring biosynthesised from lysine amino acid, or from acetate ion

The most important derivatives are coniine, coniceine, and lobeline

Question 9

Coniine mechanism

Answer 9

In the peripheral nervous system, coniine blocks the nicotinic cholinergic receptors merged in the membrane of muscle cells in the neuromuscular junctions –> paralysis

Question 10

Coniine symptoms

Answer 10

• Trembling,movement disorders
• Uncontrolled urination
• Heart rate: first slow,later high
• Respiration rate become slow, respiration laboured, and irregular

• Persons with coniine poisoning remain conscious and aware; the major reason of death is respiratory paralysis

Question 11

Diterpene derivatives

Answer 11

Chemical origin: biosynthesised from(GGPP) –> pseudoalkaloid (with a C19 skeleton)

Major compounds are aconitine and Taxus alkaloids

Question 12

Aconitine mechanism

Answer 12

In the cardiac and skeletal muscle cell membranes, aconitine makes
the voltage-gated Na+ ion channels permanently open high Na+ levels in muscle cells inhibits Na+/Ca2+ exchangers –> higher Ca2+ and Na+ ion availability within the muscle neuromuscular junction cell –> cell membrane cannot be repolarized –> paralysis

In neurons, aconitine depolarizes both the membranes of presynaptic and postsynaptic cells by opening their voltage- gated Na+ ion channels.

Due to the strong depolarization, the permeability of the membrane for K+ and Ca2+ ions is increased. Ca2+ ions stimulate the release of Ach from vacuola into the synaptic gap.

Question 13

Aconitum poisoning

Answer 13

• Paresthesia (sensation of burning)
• Tingling and numbness in the mouth
• Vomiting
• Motoric weakness; slowing movements
• Heart and respiration failures (asphyxia)
• Ventricular arrhythmias, asystole, cardiac arrest, death

Question 14

Triterpenoid derivatives

Answer 14

Solanum alkaloids

Veratrum alkaloids

Question 15

Solanum alkaloid mechanism

Answer 15

If acetylcholinesterase enzime is inhibited by solanine, Ach content of synaptic gap will not be decreased –> Na+ channels (5) stay open –> no possibility of a new action potencial to be triggered –> no more muscle contractions –> paralysis

Solanine has a saponin effect: disruption of cell membranes

Veratridine inactivates the Na+ ion channels

Question 16

Solanine poisoning

Answer 16

Inhibition of acetylcholinesterase –> CNS symptoms
Disrupts cell membranes
Vomiting, salivation, mucosal inflammation, diarrhea
Dizziness
Paralysis of muscles, cardiac arrhythmia, death

Question 17

Triterpenoid derivative

non steroidal

Answer 17

Aglycons are biosynthesised from squalene

Saponin poisoning

Question 18

Saponins mechanism and symptoms

Answer 18

Amphipathic glycosides– emulsifying effect

• produce foam in the rumen
• can enter into the lipid bilayer of membranes –> disintegrated membranes
• red blood cells are affected –> haemolytic effect
• low conversion rate from digestive tract
• irritation of mucous membrane

Photosensitization

Question 19

Thiaminase enzyme mechanism and symptoms

Answer 19

Thiaminase enzymes cleave thiamine (vitamine B1) molecules and render them biologically inactive

Vitamine B1 is essential for many animals, as they are unable to biosynthesize it –> thiamine deficiency

Vitamine B1 has a pivotal role in carbohydrate and fatty acid metabolism acting as a coenzyme in the pyruvate dehydrogenase enzyme complex that produces acetyl-CoA from pyruvate

Low levels of acetyl-CoA can lead to metabolic coma and death