Clinical pharmacology and toxicology

1. Domina Petric, MD
Drugs that activate Gio-
proteins receptors

2. Opioids
• Opioids are endogenous and exogenous agonists of three types of opioid
receptors: μ, κ and δ opioid receptors.
• All of these three types of receptors are associated with inhibitory
G-proteins (all of them inhibit adenylate cyclase).
• μ opioid receptors are in the VTA (ventral tegmental area) selectively
present on GABA neurons (which they inhibit).
• μ opioid receptors agonists cause euphoria.
• κ opioid receptors are present on dopaminergic neurons (so they inhibit
those neurons).
• κ opioid receptors agonists cause dysphoria.

3. Opioids
• The most common abuse substances are μ opioids MORPHINE, HEROINE,
CODEINE and OXYCODONE.
• All of these drugs cause severe tolerance and physical addiction.
Abstinence syndrome can be very severe:
• severe dysphoria
• nausea and vomit
• rhinorrhea
• mydriasis
• piloerection
• excessive sweating
• diarrhea
• fever

4. Treatment
Naloxone is opioid antagonist.
It is used for acute treatment.
For chronic opioids abuse treatment are
used opioids with long lasting effect like
METHADONE and BUPRENORPHINE.

5. Cannabinoids
• Endogenous cannabinoids are neurotransmitters:
2-arachidonoylglycerol (2-AG) and anandamide.
• Endogenous cannabionids are called retrograde transmitters
because they are released on the postsynaptic membrane
and affect on the presynaptic CB1 receptors.
• When they bind on the CB1 receptors, they inhibit glutamate
or GABA release.
• In the hippocampus endogenous cannabinoids release from
pyramidal cells selectively affect on the inhibitory
transmission and can be important for induction of synaptic
plasticity during learning and memorising processes.

6. Cannabinoids
• Exogenous cannabinoid that is very often abused is
tetrahydrocannabinol (THC).
• THC is strong psychoactive drug.
• THC causes disinhibition of dopaminergic neurons, especially
by presynaptic inhibition of GABA neurons in VTA.
• Half life of THC is 4 hours.
• Effect of THC after smoking starts after
several minutes and the maximum effects is
after 1-2 hours.

7. THC effects
• euphoria
• relaxation
• disturbed perception
of time
• memory disturbances
• sleepiness
• visual hallucinations
• depersonalisation
• psychotic episodes
increased apetite
nausea
decreased intraocular
pressure
chronic pain release
Potential for medical use!

8. Abstinence syndrome
It is usually mild and short lasting:
Nausea
• Agitation
• Cramps
• Iritability
• Insomnia

9. GHB
γ-Hydroxybutyric acid (GHB) can be
endogenous and exogenous.
Endogenous GHB is produced during GABA
metabolism.
Exogenous GHB, if abused, causes euphoria,
increased sensoric perception, feeling of
social intimacy and amnesia.
GHB is used as DRUG FOR RAPE.

10. Hallucinogenic drugs
• LSD, mescalin and psilocybe are hallucinogenic drugs.
• They induce perceptional symptoms like distortion of
colors and shapes.
• They can also induce psychotic symptoms like
depersonalisation, hallucinations and distortion of
time perception.
• These drugs also cause somatic symptoms like nausea,
dizziness, paresthesia and blurred vision.
• Some of the hallucinogenic drugs abusers can experience
flashbacks even years after last drug intake.

11. Hallucinogenic drugs
• Hallucinogenic drugs do not cause addiction, but they cause very fast
tolerance (tachyphylaxis).
• Hallucinogenics do not activate mesolimbic dopaminergic system like
most other drugs do.
• Instead they increase glutamate release in the cortex.
• LSD is ergot alkaloid and it is neurotoxic.
• Onset of psychoactive LSD effects is after 30 minutes and lasts 6-12
hours.
• LSD can cause spontaneous abortion.
• Main molecular target of hallucinogenics is 5-HT2A receptors that bind
with Gq-proteins and create inositol triphosphate (IP3) that causes
release of intracellular calcium.