UCSB Biochem 2017 Lecture 26: Biochemical mechanisms of chemical, drug toxicity in humans

Tricyclic antidepressants Pharmacology
1. Potentiates actions of norepinephrine, dopamine, or serotonin neurotransmitters in the brain

2. blocks reuptake of these compounds into the neuron

3. responsible for therapeutic effects

heent
head, eyes, ears, nose, throat

tricyclic antidepressant toxicity
1. overdose characterized by seizures, coma, and fatal cardiac arrhythmias

2. number one cause of fatality from drug ingestion until surpassed by analgesics

4 main pharmacologic properties of tricyclic toxicity
1. inhibition of norepinephrine and serotonin reuptake at nerve terminals

2. anticholinergic action

3. direct a-adrenergic blockade

4. Membrane-stabilizing effect on the the myocardium by blocking the cardiac myocyte fast sodium channels

TCA HEENT
1. mydriasis and nystagmus are common

2. Cardiovascular: tachycardia, ECG conduction disturbances, ventricular arrhythmias, hypotension

3. Respiratory depression, pulmonary edema, ARDS and hypoventialation may occur

4. Neurologic: lethargy, hallucinations, seizure, and coma

5. GI: decreased gastric motility (anticholinergic effect)

mydriasis
dilation of the pupul of the eye

miosis
contraction/constriction of pupil

nystagmus
rapid involuntary movements of the eyes

acute respiratory distress syndrome
ARDS
2. fluids builds up in the tiny, elastic air sacs (alveoli) in your lungs

3 symptoms of Iron toxicity
1. begins with acute gastroenteritis

2. followed by a quiescent period

3. then shock and liver failure

Diagnosis of Iron toxicity
1. measuring serum iron

2. detecting radiopaque iron tablets in the GI tract –> bezoars

3. detecting unexplained metabolic acidosis in patients with other findings suggesting iron poisoning

Treatment of iron toxicity
whole bowel irrigation and chelation therapy with IV deferoxamin

Deferoximine
iron chelator

Cocain, amphetamines
release of dompamine direcly at nerve terminal in nucleus accumbens

opioids, nicotine, alcohol, marijuana
release of DA indirectly via interneurons (GABAnergic neurons) in the nucleus accumbens and the VTA

what does dopamine act on?
glutamate receptors

ethyl alcohol treatment
disulfuram –> interferes with alcohol metabolism, results in build up of acetaldehyde which has negative side effects –> negative reinforcement

Fomepizol
used as an antidote in methanol, ethylene glycol poisoning

2. competitive inhibitor of alcohol dehydrogenase –> enzyme that catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites

Ethyl alcohol mech of toxic action
acidosis –> induced ketoacidosis

2. hypoglycemia because increase of conversion of pyruvate to lactate –> less pyruvate halts gluconeogenesis

3. hepatotoxicity due to excessive NADH production –> affects metabolism of lipids, carbs, proteins, purines

Benzodiazepine pharmacology
1. Anxiolytics. Enhances GABA receptor affinity

2. increase chloride channel opening

3. enhanced hyperpolarization and further inhibition of neuronal firing

4. “minor tranquilizers”

emesis
vomiting

Benzodiazepine mechanism of toxic action
1. Potentiation of neural inhibition mediated by GABA

Pharma intervention for benzo OD
Flumazenil: CNS benzodiazepine competitive antagonist (w/ partial agonist activity)

what should you not take with flumazenil and why
1. TCA’s
2. seizures

Barbiturates
1. CNS depressants

2. stimulate the inhibitory neuro system called y-aminobutyric acid GABA system (lets in Cl-)

3. no longer widely used as sedatives due to high abuse and dependence potential

4. to major uses –> to induce general anesthesia and may control seizures

Major toxicity of barbiturates
CNS depression with and without respiratory depression, hypotension, and hypothermia are most common

cardiovascular effect of barbiturates
peripheral vascular collapse and cardiac arrest may occur with OD

Antiemetics
used to prevent nausea and vomiting –> major tranquilizer

Opioids
1. major tranquilizer

2. operate on GPCR’s of CNS

Opioid examples
1. Heroin
2. Morphine
3. Oxycodone

methadone
can attenuate craving for heroin, and withdrawal rxn without causing significant reinforcement or exacerbating dependence

Actue opioid intoxication
1. euphoria and drowsiness
2. mast cell effects (eg, flushing, itching) common, particularly w/ morphine
3. GI effects include nausea, vomiting, decreased bowel sounds, constipation
4. miosis

opioid overdose identifiers
1. pinpoint pupils (miosis)
2. unconsciousness
3. respiratory depression –> death

naloxone
1. opioid antagonist –> reverses CNS, respiratory depression, hypotension

2. may be combined with opioids that are taken by mouth

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