Opioid poisoning _Toxicology

1. Opioid poisoning
Dr. Sarita Sharma
Associate Professor
MMCP, MMDU

2. Opium a dark brown resinous material obtained
from poppy i.e Papaver somniferum capsule.
It contains two types of alkaloids
Phenanthrene derivatives
1) Morphine
2) Codeine
3) Thebaine
Benzo-isoquinoline derivatives
1) Papaverine
2) Noscapine both are non analgesics.

3. Morphine: it is principle alkaloid in opium & widely used.
Pharmacological actions:
1) Central nervous system: it is having depressant &
stimulant action on CNS.
1) Analgesia
2) Sedation
3) Mood & subjective effects
4) Respiratory center
5) Cough center
6) Temperature regulating center
7) CTZ (increases nausea & vomiting)
8) Edinger Westphal nucleus: III nerve is stimulated
produces miosis it is due to central action

4. 9) Vagal centre: it is stimulated bradycardia is a
result.
10) Cortical area & hippocampus cells: excitation is
seen,rigidity immobility.convulsions may occur.
11) Neuro-endocrine: FSH,ACTH, levels are
lowered, while prolactin & gonadotropine
hormone levels are raised. Sex hormone &
corticosteroids levels are low at early time.
12) CVS: vasodilation due to
a) Histamine release.
b) Depression of vasomotor Centre
c) Direct action decreasing tone of blood vessels.
13) GIT: constipation,spasm of ileococcal
region,decrease all GIT secretions.

5. Pharmacokinetics:
Orally unreliable bioavailability,largely used by
IM route,circulated in all body
tissues,metabolism is done by liver by
glucuronide conjugation….gives active
metabolite morphine 6 glucuronide.
Another metabolite morphine 3 glucuronide
has neuroexcitatory property.
Plasma half life is 2-3 hours.
Parenteral dose effect last for 4-6 hours.
Elimination is within 24 hours.

6. Adverse effects:
Sedation,mental confusion,clouding,lethargy,vomiting,
Idiosyncrasy,allergy,apnoea,acute morphine
poisoning,tolerance & dependence.

7. Treatment for opioid poisoning:
1) Naloxone: it is N-alylnor-oxymorphone & it
is competitive antagonist of all opioid receptors.
Block the µ receptor in very low doses.
it is injected intravenously (0.4-0.8mg) antagonize
all actions of morphine.
4-10mg dose also antagonize the
nalorphine,pentazocin & other opioid.
Actions of buprenorphine are prevented but not
fully reversed by naloxone.
Naloxone 0.4 mg IV precipitates morphine
withdrawal in dependent subjects
Naloxone blocks the actions of endogenous opioid
peptides

8. Pharmacokinetics:
It is inactive orally because of high first pass
metabolism in the liver.IV injected acts for 2-3
minutes. Metabolism is by glucurunidation.half life
in adult 1 hour & 3 hours in new born.
Adverse effects: rise in blood pressure,pulmonary
edema.

9. Use: in morphine poisoning,reversing neonatal
asphyxia.
To reverse respiratory depression due to
opioids.
In alcohol intoxication

10. 2) Naltrexone: it is chemically related to naloxone
& it is another important opioid antagonist. It is
more potent than naloxone.
Pharmacokinetics: it is orally active & having a long
duration of action (1-2 days) which makes it suitable
for opioid blockade therapy for post addicts
50mg/day is given orally.
Also used in alcohol withdrawal condition.
Side-effects: nausea,headache & high doses lead to
hepatotoxicity.
3) Nalmefene: it is having longer bioavailability & it is
long acting.
But hepatotoxic.

11. Heavy metal poisoning

12. Heavy metals exert their poisoning by combining
with & inactivating functional groups (ligands) of
enzymes or other critical biomolecules.
Following are the agents which are used to treat
heavy metal poisoning.
Chelating agents:
Dimercaprol (BAL)
Dimercaptosuccinic acid (succimer)
Disodium edetate.
Calcium disodium edetate
Calcium disodium DTPA
Penicillamine
Desferrioxamine
Deferiprone.

13. 1) Dimercaprol (British Anti Lewisite,BAL)
It is oily,pungent smelly,viscous liquid anti-dote for
arsenical war gas Lewisite. The two SH group of
dimercaprol bind to these metals which produce their
toxicity by interacting with sulfahydryl containing
enzymes,As,Hg,Au,Bi,Ni,Sb & Cu.
The ratio of binding dimercaprol is 2:1. This complex
dissociates slowly releasing metal at slow rate.
Dimercaprol is partly metabolized in the body.

14. Uses:
1) Poisoning of As,Hg,Au,Bi,Ni,Sb. It is
administered by IM route,5mg/kg
followed by 2-3mg/kg every 4-8 hours for
two days then once or twice daily for 10
days. It is oxidized by glucuronide
conjugation,during its therapy urine
should be alkalinized
2) Adjacent to calcium disodium edetate in
lead poisoning.
3) As an adjacent to penicillamine in Cu
poisoning & in Wilson’s disease

15.  Contraindications:
It is contraindicated in iron & cadmium poisoning,
because it forms toxic complex.
 Adverse effects:
It is dose related & distressing increase in Blood
pressure,tachycardia,vomiting,tingling & burning
sensation,inflammation of mucous
membrane,sweating,cramps,headache & anxiety.
Antihistaminics are given before dimercaprol
treatment to avoid it serious effects.

16. Dimercaptosuccinic acid (succimer)
It is having similar action as that of dimercaprol in
chelating properties. It is less toxic & orally effective.
It is effective against As,Hg & lead poisoning. For
lead toxicity it is marketed in US but till date not in
India.
Side-effects: Nausea,anorexia,loose motions.

17. Disodium Edetate:
It is disodium salt of ethylene diamine tetra-
acetic acid (EDTA). It is potent chelating agent
with calcium ions & causes tetany on IM
injections. It is used in emergency control of
hypercalcemia.
Dose: 50mg/kg I.V infusion over 2-4 hours.

18. Calcium disodium edetate:
It is calcium chelate of disodium edetate,
having good affinity for metals like
Pb,Zn,Cd,Mn,Cu & some radioactive metals.
Removal is done by exchanging calcium from
it. It is highly ionized & distributed only
extracellularly & rapidly excreted in the urine
by glomerular filtration (half life is 1 hr). It is
not metabolized & not absorbed from GIT. Its
preferred use is IV. It does not enter in to the
CSF or brain.

19. Uses:
1) Used in lead poisoning: 1gm + 200-300ml saline
solution or glucose solution & infused I.V over One hour
twice daily for 3-5 days.
Urinary excretion of lead is increased but declines
quickly as the metal is removed from accessible sites
(bones). Second therapy may be repeated after 5-7 days.
2) Useful in fe,Zn,Cu,Mn & radioactive metals but
not in Hg poisoning because its distribution site is
different .

20. Adverse effects:
kidney damage due to proximal tubular necrosis,acute fibrile
reaction with chills,body ache,malaise,tiredness,anaphylactoid
reactions,fall in Blood pressure, congetion of eyes & nose.

21. Calcium disodium DTPA:
Diethyl triamine penta acetic acid (DTPA,pentetic acid).
It is congener of EDTA,it is having higher affinity for
many heavy metals then EDTA.Its calcium chelate is use
for metal poisoning especially radioactive metals.

22. Penicillamines:
It is dimethyle cysteine,obtained from
degradation of penicillin. It is having strong
affinity for copper,also used in Wilson’s disease.
Forms chelates with Cu,Hg,Pb,Zn. Its D-isomer is
used therapeutically .L-isomer & the racemate
produce optic neuritis & more toxic in nature.
Pharmacokinetics:
oral administration is good but slow also slowly
metabolized & excreted in the urine & faeces.

23. Wilson’s disease:
(hepatolenticular degeneration):
It is due to genetic deficiency of ceruplasmin a protein
which binds & displace off Cu from the body. In absence
of this plasma concentration of Cu increases which lead
to cu diposition in liver,substantia nigra,basal ganglia &
causes local degeneration in this life long therapy is
needed.
Dose: 0.5 -1grm daily in divided doses or two hours after
the meals to avoid chelation of dietary meals.
Potassium sulfide 20-40mg may be given with meal to
decrease absorption of dietary copper.
In mercury & copper poisoning 1-1.5 gm/day is given.
Also used in chronic lead poisoning.

24. Cystinuria & cysteine stones:
It increases the excretion of cysteine & prevents
precipitation in urinary tract.
Used in disease modifying agent in RA.
Adverse effects:
Cutaneous reacting,itching,febrile
episodes,dermatological,renal,haematological &
collagen tissues toxicity.

25. Desferrioxamine:
It is long chain iron containing complex obtained
from actinomycete,its chemical removal of iron
lead to give desferrioxamine which has high
affinity for iron.
1grm is capable of chelating 85mg of elemental
iron. Straight chain desferrioxamine forms a
stable non-toxic complex which is excreted in
urine.
Having low affinity for calcium. It is less absorbed
orally & bind iron present in gut & prevents it’s
absorption.parenterally administered
desferrioxamine is partly metabolized & rapidly
excreted in urine.

26. Uses:
Used in children for acute iron poisoning.
Transfusion siderosis: it occurs in thalesemia
patients who receive blood repeatedly .
Dose: 0.5-1grm/day IM helps to excrete the
chronic iron overload.
Adverse-effects: it increases histamine
release,fall in blood
pressure,flushing,itching,urticaria,allergic
reactions,rashes,changes in lens of
retina,abdominal pain,loose motion,muscle
cramp,fever & dysuria.

27. Deferiprone:
It is orally active iron chelating agent used in
thalesemia patient
Also used in acute iron poisoning & for iron load in
cirrhosis.
Side-effects: anorexia,vomiting,altered taste,joint
pain,reversible neutropenia,agranulocytosis.

28. Trimetene (triethylene tetramine):
It is given in a dose of 400-800 mg TDS on empty
stomach. Used in Wilson’s disease. It is effective
then penicillamine & cause less iron deficiency.