Belladonna alkaloids

Source:

The three alkaloids (atropine, hyoscyamine and hyoscine) are present in every part of the
following plants with highest concentration in roots and seeds:

1- Atropa belladonna:
 This plant has small berries containing poisonous brown mammillated kidney shaped
small seeds.
2- Hyoscymus muticus:
 Grows in Upper Egypt.
 Its seeds similar to those of atropa belladonna.
3- Datura plant (thorn apple):
 Common in Egypt.
 Its seeds are capsulated and the capsule is covered by many thorns.
 It has two subtypes:
- Datura fastuosa.
- Datura stramonium.

Datura Stramonium (S= ‫) أﺳﻮد‬ Datura Fastuosa (F= ‫) ﻓﺎﺗﺢ‬

Shape Kidney shaped Kidney shaped
Color Black Brown
Size Small (2 mm) Large (4 mm)
Surface Mammillated with no groove on convex Mammillated with groove on convex
border border
D.D. Onion seed: black, irregular, non- Capsicum: thinner, lighter, whiter.
mammillated
Pharmacology:

- Absorption:
 Lipophilic: (absorbed by all routes).
 Cross BBB.
- Metabolism:
 70% in the liver
- Excretion:
 30% excreted by kidney.

Mechanism of action:

 Anticholinergic action.
 Competitive inhibition to acetylcholine at its receptors:
 Nicotinic receptors: NMJ, autonomic ganglia and suprarenal medulla
 Muscarinic receptors: Heart, Exocrine glands.
 It acts centrally and peripherally.
 N.B. acetylcholine is an inhibitory neurotransmitter.

Pathophysiology:

I- Atropine and hyoscyamine:

a- Central effect:
 CNS stimulation from above downwards (block A.Ch. release at central pathways
leading to ↑↑ CNS excitability).
Followed by
 CNS depression from above downwards (due to exhaustion of the neurons).
b- Peripheral effects:
 Blockade of A.Ch. release at the muscarinic sites of neurons either sympathetic or
parasympathetic. Which lead to:
1- ↓↓ All body secretions except (milk, pancreatic and bile).
2- Eye:
 Paralysis of constrictor pupillary muscle lead to:
o Passive mydriasis.
o Closure of space of Fontana → ↑ I.O.P.
 Paralysis of ciliary muscle lead to:
o Loss of accommodation (cycloplagia).
o Closure of canal of Schlem → ↑ I.O.P.
 ↓↓ Lacrimal secretions → dry eye.
3- GIT:
 ↓↓ Secretions.
 ↓↓ Motility and contraction of the sphincters → constipation and delayed
gastric emptying.
4- Bronchi:
 ↓↓ Secretions and mucociliary movements.
 Bronchodilatation.
5- GUT:
 Relaxation of the wall and contraction of the sphincters → urine
retention.
6- Heart:
 Tachycardia.
7- Bl.V.:
 V.D. in cutaneous Bl.V. → Red skin (atropine flush)
8- Atropine fever.
II- Hyoscine:
a- Central effects: CNS depression without initial stimulation.
b- Peripheral effects: is mild.
Therapeutic uses:

I- Of Atropine:
 Preanaesthetic medication (↓↓ secretions, ↓↓ incidence of laryngeospasm
and prevent vomiting).
 Treatment of peptic ulcer (↓↓ secretions and antispasmodic effect).
 Antispasmodic.
 Ophthalmoplagia (in fundus examination).
 Antidote:
o Organophosphorus, Aconite.
o B-blockers, CCB and Digitalis (as they cause bradycardia).
II- Of Hyoscine:
 Preanaesthetic medication (better than atropine due to rapid onset, short
duration, less CVS effects and more CNS effect).
 Motion sickness.
 Parkinsonism.
 Treatment of mania.

Mode of poisoning:

I- Accidental:
 Overdose poisoning.
 Manzool: (mixture of cannabis, nutmeg, Datura seeds and honey) used as
aphrodiasic.
II- Homicidal:

Fatal dose:

1- Of Atropine and hyoscyamine: 2 grains (120 mg).

2- Of hyoscine: 1/2 grain (30 mg).

N.B. Toxic dose of Datura seeds is more than 100 seeds.

Fatal period: 12-24h

Cause of death: R.C. depression → respiratory failure.

Management a case of atropine toxicity:

I- Diagnosis:
1- Clinical picture:
a- Central effects:
 Stage of stimulation:-
 Agitation, restlessness, irritability
 Purposeless movement.
 Hallucinations.
 Slurred speech, impaired short memory.
 Drunken gait.
  Convulsions.
 Stage on depression:-
 Drowsiness, sleepy, stupor and then coma.
 Slow then irregular respiration (due to R.C. inhibition).
 Asphyxia, cyanosis.
b- Peripheral effects: (Atropinism)
 ↓↓ All body secretions (dry eye, mouth and skin).
 Tachycardia.
 Dilated fixed pupil.
 Atropine flush (red skin).
 Atropine fever (-- of sweat & alternation of thermoregulatory center).
 ↓↓ Gastric emptying, constipation and paralytic ileus.
 Urine retention.
2- Investigations:
a- Routine investigations:
 CBC, electrolytes, RBG, renal functions,………etc
 ECG: sinus tachycardia
b- No specific investigations for atropine.
3- Differential diagnosis:
a- Other anticholinergics: antihistaminic, phenothiazines and TCA.
b- Delirium state of encephalitis.
c- Drunken gait of atropinism with alcoholic gait:
Atropine Alcohol
Skin Hot, red and dry Cold and moist
Smell No smell Alcoholic smell
Temp. Atropine fever Hypothermia
Vomiting No Possible
Purposeless
Present Absent
movements
+ve McEwen's sign
Pupil Dilated fixed (constricted & on pinching the
skin of cheek dilated)

d- Atropine coma with barbiturate coma:

Atropine coma Barbiturate coma
Skin Red, hot and dry Cyanosis, cold and clammy
Temp. Atropine fever Hypothermia
e- With other agents that causes dilated pupil:
 Dilated fixed: with other pure anticholinergic intoxications and death.
 Dilated reactive: amphetamines, cocaine.
II- Treatment:
1- Emergency measures:
 A.B.C.
2- Decontamination:
 Gastric lavage may be done up to 18-24 h post ingestion (delayed
gastric emptying).
 Alkaloid antidote may be used as K+ permanganate.
3- Specific antidote:
a- Pilocarpine:
 Antagonize only the peripheral actions (not pass BBB)
 10 mg IV.
b- Physostigmine:
 It is a physiologic antidote.
 Action:
o Competitive inhibition of the action of atropine both
peripherally and centrally.
o It has short duration of action (1-2 h) due to its rapid
metabolism
 Dose:
o 1-4 mg in adult, 0.02 mg/kg in children.
o IV infusion over 10 min (to avoid adverse effects) and
the dose may be repeated every 10 min.
 Side effects:
o Precipitation of seizures, cholinergic crisis,
bradyarrythmias and asystole.
 Indications:
o Pronounced hallucination & agitations.
o Supraventricular tachycardia causes hemodynamic
instability or precipitate HF
o Intractable seizures or deep coma not respond to
standard measures.
 Contraindication:
o Asthma, gangrene, IHD and peripheral vascular disease.
o Mechanical obstruction of GIT or GUT.
 Precautions:
o Give very slowly IV over 5-10 min.
o Use only when central & peripheral symptoms present.
o Use only in absence of any cardiac abnormality.
o Always be preceded and followed by proper supportive
care
4- Supportive treatment:
 IV diazepam for convulsions: 2-10 mg.
 Care of coma.
 Control of fever.
 Opiate & Opioids toxicity Therapeutic uses:
- Analgesic for: sever pain, MI, Sever renal colic.
- Acute pulmonary edema: sedative, Anxiolytic, ↓↓ peripheral resistance.
Opiates: naturally alkaloid derived from opium.
- Treatment of morphine & other Opioids addiction.
Opioids: synthetic drugs with morphine like action.
- Anti-cough: not used nowadays. But (codeine) used.
- Anti-diarrheal: not used nowadays. But (diphenoxylate) used.
Source:
- Anesthesia: not used nowadays due to: (--RC, miosis, vomiting), but now it
• Opium poppy (papaver somniferum).
used for CVS surgery & regional anesthesia.
• Opium contains about 20 different compounds include morphine (10%),
codeine (0.5%), papaverine, and thebiane. Mode of poisoning:
• Opium 1000 gm → morphine 100gm → heroin 10 gm. - Mainly accidental.
- Suicidal: - not common
Ph.k. - Homicidal: rare. (doctors of mercy)
- Well absorbed orally and parentrally.
- Large Vd: - > 5L/kg Fatal dose: - opium 2 gm, morphine 100 mg (FD increase in addicts)
- Metabolized in liver mainly by conjugation, little by demethylation.
- Excretion: Fatal peroid: - within 6-12 h the main caus of death is respiratory depression
o Mainly by the kidney (metabolites can be detected.
o Milk, bile (entero-hepatic circulation), saliva, stomach. Clinical picture:
1- CNS:
Mechanism of action: o Early: euphoria, relieve of distress.
It acts on specific type of receptors. o Then: dysphoria, restlessness, anxiety.
- Mu receptors → supraspinal analgesia, respiratory depression, euphoria, o Finally: drowsiness, sleep, & coma
physical dependence. 2- Slow stertorous respiration.
- Delta receptor → modulate the action of Mu receptor. 3- Slow full pulse.
- Kappa receptor → spinal analgesia, sedation, miosis. 4- Hypothermia.
- Sigma receptor → Vasomotor and respiratory stimulation, mydriasis, 5- Vomiting.
dysphoria. 6- Bilateral, Symmetrical, non-reactive, pin point pupil.
This lead to: 7- Skin: moist & cyanosis.
8- Terminally:
CNS: o Irregular respiration (cheyne stock respiration).
• Cerebral cortex: analgesia, sedation, euphoria. o Deep cyanosis.
• Centers: o Circulatory collapse.
Stimulation Depression o Dilated irreactive pupil
- Vagus. - Cough center. o Death. (central respiratory failure)
- Occulomotor. - Respiratory center. 9- DD: of pin point pupil:
- CTZ - Heat regulatory center. ▪ Organophosphorous.
GIT: ↓↓ motility & ↑↑ tone of sphincters → constipation ▪ Phenothiazines.
Urinary tract: ↓↓ Motility & ↑↑ tone of sphincters→ urine retention. ▪ Pontine Hge.
 Morphine poisoning Pontine Hge Naloxone Naltrexone
History Of poisoning Head trauma or HTN Kinetics: - - Well absorbed orally.
Age Any Old - Poor absorbed orally. - Lon duration of action 36-48h
Sex Common in male Common in male - Short duration of action1-4h - Metabolized mainly hepatic &
Temperature Hypothermia Hyperthermia - Metabolized mainly hepatic there is 1st pass metabolism.
BL.P. Normal Hypertension Uses: -
Reflexes Sluggish Exaggerated - Therapeutic & diagnostic of - ttt of Opiate addiction.
Paralysis No Usually quadriplegia Opioids toxicity. - ttt of Cerebrovascular strokes.
Diagnostic test Naloxone test No test - Clonidine toxicity.
- Reversal of ethanol coma.
Investigations: - ttt of shock.
- Routine: ABG, electrolytes - ttt of Cerebrovascular strokes
- Specific: detection of drug level in blood, urine (after 3 days). - coma with unknown cause
- Chest x ray: showing pulmonary edema. o Nalmefene (Revex):
- ECG: diagnose arrhythmias results from hypoxia. ▪ As Naloxone but
• 4 times potent than naloxone
Treatment: • Has longer t1/2 (longer duration of action).
1- Emergency: A, B, 3C. ▪ Metabolized maily in liver
2- Decontamination: emesis, gastric wash (even IV administration), MDAC, ▪ 0.25 mg / 2-5 min to a total dose 1-2 mg IV
WBI in body packer. II- Agonist – antagonist: as Nalorphine.
3- Specific antidote: physiologic antidotes. ▪ Not used nowadays
▪ May lead to respiratory depression.
I- Pure antagonist: To all Opioids receptors, with high affinity to Mu 4- Symptomatic & supportive:
receptors - Care of coma.
o Naloxone (Narcan): - Keep body arm by blanket.
▪ Drug of choice. - Treatment of shock if present
▪ Used as diagnostic & therapeutic agent.
▪ Dose: 0.1-0.4mg IV may be repeated without ceiling level
▪ Duration of action: 1-4 h If the patient doesn’t get awake after naloxone administration, why?
▪ It may be used IM, SC, indo-tracheal. Associations
Diagnosis Antidote
▪ Treat coma & respiratory depression of opiate & non opiate Non-toxicological Toxicological
drugs. *Misdiagnosed *Head injury *Multiple *Expired
▪ Effects: *Brain edema intoxications *Inappropriate
• In normal person → no effect *Post-anoxic damage dose
• In addict → withdrawal symptoms. *Metabolic disorder
• In acute intoxicated person → dramatic response. *Sytemic disorder
o Naltrexone (Trexan):
▪ Pure antagonist.
▪ Used orally 50mg/day or 350 mg/week divided on 2-3 doses.
▪ Duration of action: 36-48 h.
▪ Used mainly in treatment of chronic cases.
 Acute cocaine toxicity: • Neurological:
o Ischemic cerebral stroke.
Source: leaves of erythroxylone coca plant. o Subarachnoid, intracranial Hge.
Absorption: by all routes. • Rhabdomyolysis & renal failure.
Metabolized in liver & excreted by kidney.
Investigation:
Mechanism of action: - Routine: CBC, electrolytes, ABG, renal & liver functions.
1- Sympathomimetic & CNS stimulant: - Specific: detection of metabolites in urine (benzolecgonine) by GC, TLC,
• -- Reuptake & ++ release of E, NE, D, 5HT. HPLC
ttt:
• ++ Release of excitatory amino acid (glutamate, aspartate).
2- Local anesthetic effect: 1- Emergency: A, B, C.
2- Decontamination: emesis, gastric wash, AC, WBI in body packers.
• By blocking the fast inward Na channels.
3- No specific antidote.
3- Gold frank-Hoffman model of toxicity:
4- Supportive measures:
o Cocaine ++ CNS (↑ E, NE. & -- reuptake)
▪ Convulsions: barbiturate & BZ. In refractory cases
o ↑ E, NE, 5HT → cardiac effect.
pancromium bromide & anesthesia.
▪ Blocking of cardiac effect → E, NE act on CNS → more
▪ Treatment of shock.
toxicity. (enhancement of CNS toxicity)
▪ Cold fomentation & ice enema for hyperthermia.
▪ Blocking of CNS effects →↓↓ both central & peripheral
effects.
Body Packers and Stuffers:
Uses:
Medical: local anesthetic, nasal packing & anti-arrhythmic.
Non medical: sport doping, anorexogenic, drug abuse. Body Packers Body Stuffers
internal concealment of illicit drugs swallows drugs in an attempt to conceal
Mode of poisoning: mainly accidental among addicts. for transportation across international contraband on arrest
Cause of death: borders
- Hyperthermia in stimulation stage. usually in large quantities Up to 1 kg Small amounts
- Central respiratory & circulatory collapse. of drug, divided into 50-100 packets
drug is usually of a single type Single or more than one type
Clinical picture: meticulously packaged in plastic, loosely packaged drugs, or the raw drug
a. Stimulation stage: latex, condoms or balloons itself
▪ Euphoria, talkativeness, headache, confusion & agitation. Many hours have usually elapsed Presented early
▪ Tingling numbness in limbs.
before presentation to the emergency
▪ Exaggerated reflexes, convulsions, and status epilepticus.
▪ ↑Bl.p, ↑ HR, ↑RR, dilated reactive pupil. department
▪ Hyperthermia.
b. Depression stage (due to depletion of neurotransmitters.)
▪ ↓Bl.p, ↓ HR, ↓RR.
c. Others:
• CVS:
o Chest pain: sympathetic ++ → coronary spasm → angina or MI.
o Arrhythmias: ST, VE, VT.
 Cannabis toxicity

Source: cannabis plant : c.sativa (C. indica, C. Americana)

Active principle: tetrahydrocannabinol (THC), cannabinol, cannabidol)
Forms:
- Hashish or marijuana. (flower of the plant)
- Bango. (leaves of the plant)
How used?
- Smoked, inhalation.
- Ingestion (manzol): it is composed of (Datura, nutmeg, hashish, spices, honey)
- Tablet: Marinal as antiemetic in cancer.
Ph.k.
- Rapid absorption by inhalation.
- Metabolized in liver & lung
- Excreted by stool 80% & kidney 20%.
Mechanism of action:
• ++ THC receptors in basal ganglia, cortex, cerebellum.
• ++ Sympathetic rec. & -- parasympathetic rec.
Uses:
Medical:
1- Anti-emetic in cancers.
2- Appetizer in AIDS.
Non-medical:
- Addiction.
- Manufacture of ropes and paints.
Mode of toxicity
Mainly acciddental
FD
Not reported in human, exprimental 25gm/kg
FP: not reported in human, expected in 1st 24 h
Cause of death:
- Central asphyxia.
- Overeating → over distension of the stomach → reflex coronary spasm.
Clinical picture:
• Psychiatric manifestation.
- Euphoria.
- Accentuation of special senses especially hearing.
- Disorientation of time, place, & persons.
- Loss of recent memory.
- Anxiety agitation.
- Delusion.
- Dysphoria, agitation, psychosis and sense of impeding death
• CNS:
- Tremor, hyperreflexia, confusion, coma.
• CVS:
- ↑Bl.p. &↑HR.
- Dysrrhythmias: - rare
• Others:
- Dilated reactive pupil, tinnitus, Fatal respiratory depression
 Investigations:
Routine investigations:
- Urine analysis.
- Stool analysis.
- CBC. - ABG.
- Serum electrolytes.
- Coagulation profile.
- ECG. - X-Ray (chest, abdomen).
- Renal Functions: bl. Urea, serum creatinine..etc.
- Liver functions: SGOT, SGPT, bilirubin, …etc.
Specific investigations:
(1) Beam’s test: Positive when there is violet color.
(2) T.L.C.: - Scarlet color THC.
- Violet color Cannabinol
N.B. Detection in urine:
o Infrequent users: 5-8 days.
o Frequent users: 6-8 weeks (up to 60 days).
Treatment
1- Emergency: A, B, 3C.
2- Decontamination: emesis, gastric wash, AC.
3- No specific antidote.
4- Symptomatic & supportive.
o Reassurance.
o O2
o Diazepam: if needed