1. TOXICITY OF ALKALOIDS
TAHAR ABDULAZIZ MD, PhD

2. DEFINITION OF PLANT ALKALOID
A basic heterocyclic nitrogenous compound of plant origin that are physiologically active
heterocyclic compound has at least 2 types of atoms in coparison to homocyclic

3. 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.

4. . castoramine :--- from Canadian beaver
OTHER SOURCES
. castoramine :--- from Canadian beaver

5. Pyocyanine :-- from Pseudomonas aeruginosa (a bacteria).

6. Muscopyridine :--From Musk of an Deer.

7. General Classification
True (Typical) alkaloids that are derived from amino acids and have nitrogen in a heterocyclic ring. e.g Atropine
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.g Caffeine
False alkaloids are non alkaloids give false positive reaction with alkaloidal reagents.

8. 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.

9. 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

10. 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.

11. Opioid Receptors Major receptorsMu
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

12. MAJOR OPIATE RECEPTORS
Rector
Subtypes
Location
Functions
Delta
1, 2
brain
pontine nuclei
amygdala
olfactory bulbs
deep cortex
peripheral sensory neurons
analgesia
antidepressant effects
Convulsant effects
physical dependence
Perhaps of mu-opioid receptor-mediated respiratory depression
Kappa
1,2,3
hypothalamus
periaqueductal gray
claustrum
spinal cord
substantia gelatinosa
sedation
miosis
inhibition of ADH release
dysphoria

13. Mu anxiety depression appetite development of tolerance to μ agonists
1,2,3
brain
cortex (laminae III and IV)
thalamus
striosomes
periaqueductal gray
rostral ventromedial medulla
spinal cord
substantia gelatinosa
peripheral sensory neurons
intestinal tract
μ1: analgesia
physical dependence
μ2:
respiratory depression
miosis
euphoria
reduced GI motility
μ3:
possible vasodilation
nociceptin receptor (NOP)
(orphanin FQ receptor)
cortex
amygdala
hippocampus
septal nuclei
habenula
hypothalamus
anxiety
depression
appetite
development of tolerance to μ agonists

14. NOP Recptor

15. 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.

16. PAPEVER SOMNIFERUM

17. How to obtain Latex from Capsules?

18. Poppy seeds
Poppy seed or Maw seed is the dried seed of Papaver somniferum.
Poppy seeds contain no significant quantity of alkaloids contains 50% fixed oil.
Seed used as food and salad dressing.

19. 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%).

20. MORPHINE

21. 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).

23. 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.

24. Pharmacokinetics of opiates:
Well absorbed from GIT, nasal mucosa, pulmonary mucosa, subcutaneous and intramuscular routes.
Metabolism mainly in liver by conjugation with glucuronic acid, hydrolysis & oxidation.
Widely distributed into liver, kidneys, lungs, spleen, brain, placenta, intestinal mucosa, and skeletal muscles.
Excretion mainly by kidneys, where more than 50% are excreted within 8 hours, about 40% up to 24 hours, and traces are still detectable in urine after 48 hours by classic methods of detection and for longer periods by sophisticated techniques.
Small percentage is excreted in bile, saliva, sweat, & milk.

25. Stimulate Inhibit 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).

26. 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.

27. Acute Toxicity
Mainly accidental overdose among addicts or may be iatrogenic.
May be suicidal.
Rarely homicidal.
Hot-shoot phenomenon.

28. 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.

29. 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.

30. Treatment
Antidote: Naloxone IV in doses 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.

31. 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.

32. 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

34. 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).

35. Erythroxylon coca

36. Acute Cocaine Toxicity
Autonomic Effects: tachycardia, hypertension, hyperthermia, tachypnea, mydriasis.
CNS Effects: behavioral and psychiatric disorders such as irritability, hyperactivity, insomnia, agitation, psychosis (often paranoid), delirium, stupor, seizures, coma.
Heart: sympathetic stimulation of the heart may lead to tachyarrhythmias, myocardial ischemia, myocarditis, impaired cardiac conduction (local anesthetic effect).
Organ Ischemia: myocardial, renal, and/or intestinal infarction, and limb ischemia.
Shock: hypotension and shock
Pulmonary Effects: pulmonary edema (cardiogenic & noncardiogenic) , adult respiratory distress syndrome
Other Effects: rhabdomyolysis, coagulopathy.

37. No specific finding in autopsy, except for nasal septal perforation

38. 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.

39. 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).

42. HASHISH

43. 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

44. Dilated reactive pupils (with conjunctival injection). Ataxia.
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).

45. 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

46. 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

47. 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.

48. 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).

49. D. Stramonium Plant

50. D. Stramonium flower

51. D. Stramonium unripe seeds

52. Hyoscine (scopolamine) differs from atropine and hyoscyamine in that it has:
Depressant effect from the start.
Milder peripheral action
Toxidrome: Coma + Dry Skin + Hyperthermia + Cycloplegia + Absence Of Odor

53. CLINICAL PICTURE Diminish of body secretion lead to
PERIPHERAL EFFECTS:
Diminish of body secretion lead to
Dry mouth and throat cause hoarseness of voice, thirst and dysphagia.
Dry skin lead to fever.
Flushing of skin.
Dilated fixed pupil leading to blurring of vision, diplopia and photophobia.
Rapid pluse due to vagal block. Sinus tachycardia is the most sensitive sign of toxicity
Urinary retention and decrease intestinal motility.

54. CENTRAL EFFECTS Stage of stimulation
Occupational purposeless movement as (rolling cigarette, threading needles and catching flies).
Restlessness, anxiety, talkativeness and free laughing.
Convulsion
Stage of depression
Patient is drowsy, stupor and gradually become comatosed.
Coma characterized by :
Rise in temperature.
Dry flushed skin.
Dilated fixed pupil.
When depression in medulla occur pulse and respiration become slow weak and irregular.
Respiratory failure (Central asphyxia).

55. Postmortem Appearance
No specific findings

56. STRYCHNINE
It is the main alkaloid found in the seeds of Strychnos Nux vomica. The seeds are hard, flat biconcave discoid in shape, 1-2 cm in diameter, brownish-gray and covered with hair (velvet appearance).
Mainly accidental toxicity.
Fatal dose about 30 mg.
Fatal period: 2h.

57. Absorption through GIT & nasal mucosa.
After absorption, about half of the dose is distributed in all tissues in about 5 min.
Metabolized in the liver.
5-20% of dose excreted unchanged in urine within 24 hrs.
Action: causes stimulation of the spinal cord, brainstem, & thalamus by competitive inhibition of postsynaptic glycine receptors, which is an inhibitory neurotransmitter in the spinal cord.

58. Clinical Manifestations
TOXIDROME: Symmetrical generalized fits + Opisthotonus + Risus sardonicus + Full consciousness
Onset of symptoms after minutes.
Starting as restlessness, increased visual & auditory acuity, nausea, vomiting, and muscle twitching, then sudden onset of generalized, extremely painful tonic fits while patient is fully conscious.

59. Opisthotonus

60. Risus sardonicus

61. Strychnine fits are characterized by:
Sudden onset.
Generalized tonic convulsions.
Last min with min intervals of complete relaxation between fits.
Retraction of the jaw gives peculiar complexion called risus sardonicus (devil's laugh).
Body takes extensor position called opisthotonus.
During fits there may be apnea, bulging of eyeballs, cyanosis, bloody froth, dilated pupils, bradycardia, hypertension, hyperthermia, lactic acidosis, and rhabdomyolysis.
Patient cannot tolerate frequent fits; they die from exhaustion or asphyxia.

62. Differential Diagnoses 1-Tetanus. 2- Head injury. 3- Meningitis
Differential Diagnoses 1-Tetanus. 2- Head injury. 3- Meningitis. 4- Epilepsy. 5- Hysteria.
STRYCHNINE
TETANUS
HISTORY
Taking food with bitter taste
Wound
ONSET
Sudden
Gradual
CLINICAL FEATURES
Generalized fits with relaxation in between
Tonic contractions start at lower jaw
DEATH
Rapid (2hrs)
Delayed (24 hrs)
DIAGNOSIS
Chemical detection
Bacterial isolation

63. Antidote:
Mephenisine (20-30 mg IV)
Suxamethonium mg/kg IV.

64. Postmortem Appearance
No specific signs have been described
Early rigor mortis
Postmortem cooling

65. Toxicity of Cardiac glycoside plants

66. Digitalis lanata

67. Digitalis purpurea

68. Nerium Oleander

69. Nerium oleander

70. Sea onion

71. Strophanthus gratus