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TOXICITY OF ALKALOIDS TAHAR ABDULAZIZ MD, PhD
DEFINITION OF PLANT ALKALOID A basic heterocyclic nitrogenous compound of plant origin that are physiologically active
Deviation from Definition • Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, • Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline. • Plant Origin: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals.
OTHER SOURCES . castoramine :--- from Canadian beaver
General Classification • True (Typical) alkaloids that are derived from amino acids and have nitrogen in a heterocyclic ring. e.gAtropine • Protoalkaloids that are derived from amino acids and do not have nitrogen in a heterocyclic ring. e.g Ephedrine • Pseudo alkaloids that are not derived from amino acids but have nitrogen in a heterocyclic ring. e.gCaffeine • False alkaloids are non alkaloids give false positive reaction with alkaloidal reagents.
They can be found in one or more parts of the plant (leaves, fruits, seeds, or whole plant). • Generally, non-soluble in water but can be extracted by organic solvents in alkaline media. • The most important alkaloids of toxicological interest are: opium, atropine, cocaine, strychnine, nicotine, aconite, ergot, digitalis, and cannabis.
OPIOIDS A group of narcotic analgesics that represent one of the most important groups of CNS depressants. • Classification: 1- Natural (Opiates) 2- Semi-synthetic 3- Synthetic
OPIATES & OPIOIDS • Opioids exert activity at opioid receptors & include opioid agonists, antagonists, and mixed agonist-antagonists. • Opiates are alkaloid extracts of the opium poppy. • Opiates are opioids but the reverse is not always true.
Opioid Receptors • Major receptors • Mu • Kappa • Delta • nociceptin receptor or NOP also known as the orphanin FQ receptor or kappa-type 3 opioid receptor • Minor receptors(undetermined role in humans) • Epsilon • Zeta
1- Natural Opium Alkaloids (OPIATES) • About 25 alkaloids are present naturally in opium. • Opium is the juice taken from the unripe capsule of poppy plant fruit (Papever somniferum). • Poppy plant is present mainly in Asia and South America, but can be cultivated anywhere either in hot or cold countries. • Fresh opium is plastic, moist, smooth, reddish-brown, then becomes hard, brittle, and dark-brown. • Dry-ripe poppy capsules contain a trace of opium.
Poppy seeds • Poppy seed or Maw seed is the dried seed of Papaversomniferum. • Poppy seeds contain no significant quantity of alkaloids contains 50% fixed oil. • Seed used as food and salad dressing.
Opium is used for sedative, antitussive, and constipating effects. • Opium alkaloids are combined with meconic acid, and divided into 2 groups: • Hypnotic (depressant) alkaloids: morphine (10%); codeine (0.5%); narceine (0.2%). • Convulsant (stimulant) alkaloids: papaverine (1%); narcotine (6%); thebaine (0.3%).
2- Semisynthetic Opium Derivatives: chemically and pharmacologically related to opium: • Heroin: diacetylmorphine (addictive drug). • Dionin: ethylmorphine hydrochloride (for corneal ulcer). • Apomorphine: central emetic agent. • Dilaudid: dihydroxymorphine (potent analgesic with short duration). • Metopan: methyldilaudid (potent analgesic with short duration).
3- Synthetic Opioids A group of chemically synthesized drugs, which are remote in chemical structure from that of opium but have similar pharmacologic effect.\ Examples: • Pethidine (Meperidine): potent analgesic usually used as postoperative analgesic and for labor pain. • Methadone: potent analgesic usually used to antagonize withdrawal manifestations during treatment of heroin and morphine dependence.
Stimulate • Pupillo-constrictor center (pin-point pupil) • Vagal center (slow full pulse & hypotension) • Medullary CTZ (vomiting). Inhibit • Sensory cortex (analgesia) • Medullary respiratory center (respiratory depression) • Cough center (suppression of cough).
Most opiates are agonists for mu and kappa receptors. • Opiate agonist – antagonist: • Synthetic drugs have both agonist and antagonist effects i.e. they oppose the effect of opiates when they are given simultaneously, but produce similar effects when given alone. • These drugs are used widely as potent analgesics. Examples: Pentazocine (Sosegone). Buprenorphine (Norphine). Nalbuphine (Nubain). • Pure opiate antagonist: • They block all opiate receptors. • They have reversal effect • They are used in the treatment of opiate toxicity Examples: Naloxone (Narcan); Naltroxone.
Acute Toxicity • Mainly accidental overdose among addicts or may be iatrogenic. • May be suicidal. • Rarely homicidal. • Hot-shoot phenomenon.
Clinical Manifestations • TRIAD (TOXIDROMES): 1- pin-point pupil 2- respiratory depression: slowing or irregularity of respiratory rate (not on the depth) due to direct effect on respiratory center. 3- coma.
Clinical Features (cont.) • Subnormal temperature or even hypothermia. • Decreased all body secretions except sweating leading to moist cold skin (cold sweat). • Cyanosis. • Rhabdomyolysis: elevated CPK. • Cardiac conduction defects including LBBB • Wide QRS (more with propoxyphene). • Noncardiogenic pulmonary edema, particularly with heroin, codeine, and methadone overdoses.
Treatment • Antidote: Naloxone IV in doses 0.2-4 mg, then observe for positive response (changes in respiratory rate & level of consciousness, and size of pupils). If the response is delayed give more Naloxone (up to 10 mg) until positive response occurs. • Naloxone plasma half-life (t½) is 30 – 80 minutes but its effect after IV bolus may last for 10 minutes only and relapse occurs, so, give repeated doses at frequent intervals as required. • Some cases may need IV infusion & NaHCO3 similar to effects in Tricyclic.
HEROIN (Diacetyl Morphine) • It was synthesized from morphine in 1874, but become popular after the discovery of Mexican heroin (black tea) in 1970, which is much more potent and cheaper than the first one. Heroin can be taken well absorbed by any route; this is because of its high lipid solubility. • Heroin distributes to all tissues and converted to morphine by hepatic enzymes and it is eliminated by kidneys as morphine in free and conjugated forms.
Heroin Body Packers Syndrome • Body Packers (mules) • Intentional swallowing or storing the packets in orifices to smuggle and avoid authorities. • Packets are well prepared • More quantity • Body Stuffers • Hastily conceal illicit packets in orifices just prior detection • Pakets are not well prepared • Less quantity
COCAINE • Cocaine is present in the leaves of Erythroxylon coca, which grows in South America. • Cocaine is a powerful CNS stimulant and sympathomimetic agent with local anesthetic effect but chemically related to atropine. • It inhibits reuptake of epinephrine & NE in peripheral ganglia & increase their secretion centrally • Its medical use is local anesthetic (paralysis of nerve endings by blocking fast Na channels) • Local vasoconstriction (N.B. xylocaine vasodilatation).
No specific finding in autopsy, except for nasal septal perforation
CANNABIS • From the group of hallucinogens • Psychological & Neurological: affects behavior, cognition, perception, and performance. • These effects are dose-dependent. • Disorientation in time and place. • Euphoric, talkative, joking and pleased with himself, may have fear of death and dysphoria. • Hallucinations , illusions, delusions • Accentuation of auditory perception. • Hyperphagia, especially to sweets.
Marijuana consists of the leaves and flowering parts of the plant Cannabis sativa and is usually smoked in cigarettes (“joints”). • Resin from the plant may be dried and compressed into blocks called hashish. • Marijuana contains a number of cannabinoids; the primary psychoactive one is delta-9-tetrahydrocannabinol (THC).
Mechanism of Toxicity THC binds to anandamide receptors in the brain, may have effectsdepending on the dose and time after consumption. • stimulant, • sedative, or • hallucinogenic
Nervous disorders such as: • Dilated reactive pupils (with conjunctival injection). • Ataxia. • Tinnitus. • Hyperreflexia. • Hypothermia. • With large doses, the effect varies from mild anxiety to paranoid behavior to acute psychosis with impaired complex motor functions. • Cardiovascular: tachycardia with blood pressure changes and increase in myocardial O2 demand (may be due to autonomic NS stimulation). • Respiratory: chronic bronchitis, rhinitis, pharyngitis, horsiness of voice (due to smoking).
Chronic users • 6 fold increase in schizophrenia • Mouth, jaw, lung cancers • Nonlymphoblastic leukemia in children from mother smokers • Decreased sperm activity and change in morphology
Urine Test • THC can be detected 3 – 8 weeks in chronic users & 3 days in sporadic users. • Passive inhalation ± give false-positive test • False positive: rarely brufen, naproxen. • False negative: diuretic use, vinegar
ANTICHOLINERGICS • Anticholinergics are antagonists for the neurotransmitter acetylcholine. • Acetylcholine receptors are the muscarinic & nicotininc receptors in the periphery and cholinergic receptors centrally. • Anticholinergics can be natural or synthetic compounds.
1- Natural Alkaloids (Tropane Group): A) Atropa belladonna; atropine B) Hyoscyamus; hyoscine, hyoscyamine C) Datura, hyoscine, hyoscyamine, atropine 2- Parmacological Preparations : a) Tricyclic antidepressants (imipramine). b) Antipsychotics (phenothiazines, haloperidol) c) Antihistaminics (chlorephenhydramine, Ipratropium (Atrovent)). d) Antiparkinsonism (benzotropine). e) Antispasmodics (propantheline, Oxybutinin (Ditropan)). f) Ophthalmic solutions (cyclopentolate).
