Exercise on Toxicology

Explain the mechanisms of toxic action of the following:

1. Garcinia cambogia
Also known as Malabar tamarind, the plant contains Hydroxycitric acid (HCA). (-)-HCA is a competitive
inhibitor of ATP citrate lyase, which converts citrate into oxaloacetate and acetyl CoA. The reverse of this
conversion is a step in the citric acid cycle.
Garcinia Cambogia fills the glycogen stores in the liver and other tissues, thereby reducing appetite while
increasing energy levels. Garcinia Cambogia lowers the production of triglycerides and cholesterol and may also
increase thermogenesis, the burning of calories. It is not recommended for diabetics.
2. Cannabis sativa
It appears that both cannabinoids and anandamides and their receptors reside within neuronal lipid
membranes and act as neuromodulators through intracellular G-proteins controlling cyclic adenosine
monophosphate formation and Ca2+ and K+ ion transport. In this role the system may have important interactions
with other neurotransmitters, including γ -aminobutyric acid, opioid systems and monoamines. In particular, THC
has been shown to increase the release of dopamine from the nucleus accumbens and prefrontal cortex (Tanda
et al, 1997). This effect, which is common to many drugs of misuse (including heroin, cocaine, amphetamine and
nicotine), may be the basis of its reinforcing properties and its recreational use. It is reversed by naloxone,
suggesting an opioid link.
Cannabis affects almost every body system. It combines many of the properties of alcohol, tranquillisers,
opiates and hallucinogens; it is anxiolytic, sedative, analgesic, psychedelic; it stimulates appetite and has many
systemic effects. In addition, its acute toxicity is extremely low: no deaths directly due to acute cannabis use have
ever been reported. Only a selection of cannabis effects are described in this review; other actions are reviewed
by Paton & Pertwee (1973), Pertwee (1995), Adams & Martin (1996) and many others.
3. Methanol
When methanol enters the body, it is converted to the toxic metabolites formaldehyde by aldehyde
dehydrogenase and formate by alcohol dehydrogenase. The most characteristic symptom in methanol poisoning—
visual disturbance—occurs along with anion gap metabolic acidosis. Since the conversion of methanol to its toxic
metabolites is relatively slow, there is often a delay of 6–30 hours before the appearance of severe toxicity.
4. Warfarin
Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates
vitamin phytonadione (K1). Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased
clotting ability. The anticlotting protein C and protein S are also inhibited but to a lesser degree.
Warfarin is very sensitive to drug-drug interactions involving its metabolism or function and great care must
be given to starting or stopping concurrent medications in patients on warfarin therapy. Severe bleeding episodes
can be caused by administration of another medication that prolongs its half-life or activity.
5. Phenobarbital
The sedative-hypnotic and anticonvulsant effects of barbiturates have been suggested to be related to their
ability to enhance and/or mimic the inhibitory synaptic action of gamma-aminobutyric acid (GABA). There is also
suggested that barbiturates have a particular effect at the level of the thalamus where they inhibit ascending
conduction in the reticular formation, thus interfering with the transmission of impulses to the cortex.
Serum bilirubin concentration is decreased by phenobarbital, probably by induction of
glucuronyl transferase, the enzyme which conjugates bilirubin. Also, Phenobarbital is a cytochrome P450 hepatic
enzyme inducer. Drugs that are metabolized by the CYP450 enzyme system will decrease effectiveness because
of faster clearance from the system. Phenobarbital intoxication may give the following symptoms: nystagmus,
dysarthria, ataxia, drowsiness, respiratory depression, and coma are commonly found.

Submitted by: Jorge Peter Tinaya