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OPIOIDS AND DERIVATIVES

HISTORY and CLASSIFICATION

Opium -17th century --------heroin/morphine Classification

Snorting Skin popping Mainlining

Opioids - as a class it exert their pharmacological effects at

opioid receptor.

Opiates alkaloid extracts of the opium poppy.

Opium the parent crude from naturally occuring

compounds, derived from the milky exudates of the unripe

capsule of papaver somniferum.

MEDICINAL CHEMISTRY

Opioids are composed of six-membered saturatedheterocyclic rings forming the phenantrene nucleus to

which is attached a piperidine ring.Derivatives majority

have isoquinoline ring.

Esterification of the phenolic functions, such as in theformation of diacetylmorphine results in compound

with increased lipid solubility and increased potency

and toxicity.

MECHANISM OF TOXICITY

The mechanism of opiate toxicity is an extension of itspharmacology and is directly related to interaction with

stereospecific and saturable binding sites or receptors

in the CNS and other tissues.

Three receptor classes: mu-receptor Kappa-receptor Delta-receptor

TOXICOKINETICS

Morphine is rapidly absorbed from an oral dose, i.m.and sc injection.Thus, morphine levels rise slowly,

persist longer and decline slowly.

Heroin rapidly biotransformed. Codeine is extensively metabolized. SIGN AND SYMPTOMSHypothermia Mioisis CNS depression Respiratory depression Frothy,noncardiogenic,pulmonary edema Loss of consciousness Hypoventilation Bradycardia Hypotension Decreased GI motility Increased ADH secretion

CLINICAL MANAGEMENT OF ACUTE OVERDOSE

Maintenance of vital functions, including respiratoryand cardiovascular integrity is of paramount

importance in the clinical management of acute opioid

toxicity.

Gastric lavage and induction of emesis Opioid antagonist

Naloxone available as an inj. Only.a 2mgbolus rep every 5 min followed by 0.4 mg

every 2-3 minutes prn.up to 24mg total

Naltrexone available as oral tab only at50mg dose. It is also indicated for alcohol

dependence. It will induce hepatocellular

injury if given in excess.

Nalmefene available in 100 mcg/ml and1mg/ml ampule. Indicated for partial or

complete reversal of natural or synthetic

opioid effects.

Some antagonist of kappa,mu receptor Nalbuphine Butorphanol

- Pentazocine

TOLERANCE and WITHRAWAL

Addiction involves compulsive psychoactive drug usewith an overwhelming involvement in the securing and

using of such drug.

Compulsive drug use involves the psychological needto procure and use drugs,often referred as craving.

Habituation refers to psychological dependence. Physical dependence involves the need for repeated

administration in order to prevent withrawal

syndrome.

SPECIFIC OPIOID DERIVATIVES

Codeine ( methylmorphine ) In combination with other ingredients as an

analgesic and antitussive in prescription for

cough,cold, antihistaminic and expectorant.

About 120mg codeine is equivalent to 10mgmorphine. Diphenoxylate a synthetic opiate related to

mepiridine, is combined with atropine

( Lomotil ) for diarrhea. The toxicity of this combination

is due to the presence of anticholinergic.The narcotic toxicity

demonstrates as miosis, respiratory depression, severe cases is

coma.

Fentanyl marketed in the form of medicated patchesfor management of pain, the transdermal system can

release up to 200mcg/hr.

Meperidine first synthetic opioid, equianalgesic withMorphine.

Chronic oral ingestion of tablets is associatedwith CNS stimulation resulting in tremors,

muscle twitching, nystagmus,convulsion.

Naloxone for chronic meperidine use Pentazocine

Derivative of morphine with 3-4 times potencyand same addictive potential.

Continued injection resulted in seriouspulmonary artery occlusion, pulmonary

hypertension,neurologic complication

Tramadol centrally acting synthetic analog of codeine.In overdose, the effects are similar to those of otheropioids with convulsions.

Clonidine shares some pharmacological propertiesand clinical features with opioids. Overdose occurs

within 60-90 min after ingestion producing

bradycardia,hypotension, arrhythmias, CNS depression,

decreased respiration and miosis.

METHODS OF DETECTION

EMIT enzyme-linked immunoassay technique RIA - radioimmunoassays

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SYMPATHOMIMETICS

AMPHETAMINES AND AMPHETAMINE-LIKE AGENTSAmphetamine use in weight reduction and control of

obesity.The stimulant/euphoric effects improved their popularity

and gave rise to common street names : ups, bennies, dexies,

speed. Treatment for ADHD and short-term depression.

MEDICINAL CHEMISTRY

Beta-phenethylamine parent structure of thesympathomimetic amines, consisting of a benzene ring

and ethylamine side chain. Substitutions on the

aromatic ring and the side chain yield a variety of

compounds whose pharmacological and toxicological

profiles, and their relative potencies.

TOXICOKINETICS

Amphetamine compounds are weak bases that are wellabsorbed orally, predominantly throughout the length

of the basic environment of the small intestine.

TOLERANCE AND WITHRAWAL

Chronic use of amphetamine leads to psychologicaldependence.

Tolerance to the anorexic effect as well as to theimprovement of mood.

Withrawal syndrome depends on the extent ofhabituation but varies between several hours to severaldays after discontinuation of the drug.Characterized by

prolonged sleep,lassitude,drug craving

behavior,hyperphagia.Deep depression follows

interruption of chronic use.

METHODS OF DETECTION

Urine drug screening tests TLC RIA HPLC EMIT

XANTHINE DERIVATIVES

SOURCE AND MEDICINAL CHEMISTRY The compounds contain the purine nucleus. Caffeine most active component of coffee and

coffee beans of Coffea arabica also found in

Cola accuminata and Cola nitida (nuts).

Caffeine and Theophylline from the tea leavesof Thea sinensis and Theobroma cacao.

OCCURRENCE

Brewed coffee boast the highest amounts of caffeine (up to 100mg ).

Instant and decaffeinated coffees contain less ( up to 75and 5mg )

Cola beverage possesses dose of stimulant ( 55mg ) Cup of hot cocoa a dose of 200mg theobromine

TOXICOKINETICS

Xanthines are well absorbed orally, reaching peakdistribution within 2 hours.Metabolic variability among

different age group, smokers, and individuals with

pathologic complications is probably due to variable

levels of CYP450 and N-acetyltransferase systems. The

drug eliminated by the kidney with a half-life of 3-15

hours in nonsmokers, 4-5 hours in adult smokers

SIGN AND SYMPTOMS AND CLINICAL MANAGEMENT OF

CAFFEINE TOXICITY

Adverse effects of excessive caffeine intake ( LD is 510 g ) ( above 10mg/kg )

CNS stimulation Insomnia Restlessness Sensory disturbance Delirium Increased skeletal muscle tension Tachycardia PVCs Diarrhea Peptic ulcer GI bleeding

Caffeine can neutralize the desired therapeutic effects odiuretics, antihypertensive agents,beta-blockers and

sedative-hypnotics.

Short-acting beta-blocker ( esmolol ) useful inmanagement of myocardial tachyarrhythmias

Short-acting benzodiazepines (midazolam) Controlled the seizure in patient with an ingestion of 1g

or more of caffeine.

TOLERANCE AND WITHRAWAL

Caffeine withrawal is associated with chronic use and isdemonstrated abruptly within 12-24 hours after the last

dose.

Symptoms: headache,anxiety,fatigue,craving behaviorthat will last for about one week. There is demonstrated

tolerance to the diuretic action and the insomnia

produced with Theophylline, but no tolerance develops

to the CNS stimulation or bronchodilation.