Drug toxicity

ByDr.Mohamed Abd Almoneim Attia

• ANALGESICS Opiate and Non-opiate analgesics.

Non-opiates (aspirin) Opiates (morphine)

Low intensity pain (headache, toothache, muscle pain,..etc)

Any type of pain except itching Type of pain relieved

Subcortex (thalamus) Cortex and subcortex Site of action

No euphoria, narcosis or modified emotional reaction

Euphoria, narcosis and abnormal emotional reaction for pain

Relief of pain is accompanied by:

Never occurs Almost occur Addiction

MORPHINE Pharmacokinetics90% a given dose is excreted in the urine; the remaining 10% is excreted in the feces. Pharmacologic effects CNS effects:

Dose-related analgesia and increased tolerance of pain (sensory and emotional):are the most prominent effects of morphine. patients taking morphine become euphoric (feel freedom for anxiety). If morphine is given to a person who is pain-free, dysphoria, anxiety or mental clouding

may be produced. Morphine can treat all types of pain except itching. Morphine stimulates the chemoreceptor trigger zone, producing nausea and vomiting. Morphine produces miosis by stimulating the Edinger-Westphal nucleus and pinpoint

pupils are indicative of toxic dosage prior to asphyxia. Morphine is a powerful respiratory depressant, which acts by reducing the

responsiveness of the respiratory centers in the brain stem to blood levels of carbon dioxide. Due to the depressed respiration and increased arterial carbon dioxide retention, cerebral vasodilatation can occur, causing an increase in intracranial pressure

It is believed to stimulate the release of ADH, producing oliguria.Morphine is a potent cough suppressant.

Autonomic effects:Cardiovascular effects:Histamine release:Spasmogenic effects:

 • Uses: 3As

Adverse effects CNS:

Dysphoria, restlessness, hyperactivity and mental cloudiness can occur

Long-term chronic administration can result in physical dependence.

Increased intracranial tension.Tolerance and dependence: Tolerance may develop to the analgesia, euphoria and

respiratory depression.Tolerance to miosis and constipation occurs to a much

lesser extent.Physical dependence occurs within 24 hours if given /4

hours.

Respiratory: Depression is the most important effect and is dose dependent.Bronchoconstrictive action   Gastrointestinal:

Nausea and constipation.Increased biliary tract pressure can occur   Genitourinary: Urine retention.

Prolongation of labor.  Allergic reactions :

can occur and skin rashes are a common manifestation (due to histamine release).

Eye: Pinpoint pupils are a consistent finding in addiction.

CVS: Postural hypotension 

 A. Acute opioid (or morphine) toxicity:Symptoms and signs:

The patient is comatosed with depressed respiration, pin point pupils, hypotension , pulmonary oedema and shock may occur.

When death occurs, it is always due to respiratory failure. Treatment:

If large amounts are taken orally, gastric lavage is done with potassium permnganate solution.Establish a patent airway and ventilate the patient by positive pressure ventilation if pulmonary

oedema is present.Opioid antagonists as: Naloxone:

Naloxone is a pure antagonist to opiates.Can produce dramatic reversal of the respiratory depression.It is given in a dose of 0.4 - 0.8 mg and repeated every 2 - 3 minutes for 2 - 3 doses.Care should be taken as the antagonist may precipitate a severe withdrawal syndrome. Nalorphine:

Agonist-antagonist like nalorphine can be used only when the diagnosis of morphine poisoning is certain (its agonist effect aggravates respiratory depression).

The duration of opioid antagonists is shorter than many opioids, the patient should be watched carefully for he may go back into coma.

 

Chronic opioid (or morphine) toxicity (addiction)It results from addiction. The patient is emaciated,

constipated with frequent flushes and itching. The intellectual functions are also depressed.

• Withdrawal:It results in what is called the abstinence syndrome where

the patient becomes irritable, nervous, having tremors, hypertension, sweating, vomiting and with abdominal cramps.

These manifestations usually start 6-10 hours from last dose and peak effect are seen at 36-48 hours, after which manifestations gradually subside over 5-10 days.

• In severe cases cardiovascular collapse and death may occur.

Treatment of morphine addiction:• Hospitalization.• Gradual withdrawal is essential otherwise

acute abstinence syndrome may occur. This is with replacement by the synthetic morphine substitute methadone.

• Once the patient is stabilized on methadone, its dose should be gradually decreased to an end.

• Clonidine• Sedative can be used• Naltrexone (pure antagonist).

Classification of non opiate analgesics: (Acetaminophen). (Glafenine).Nefopam .Dipyron (Novalgin).Non-steroidal anti-inflammatory drugs

(NSAIDs).

N.BProstaglandins are derived from arachidonic acid by the action of cyclooxygenase

(COX) enzyme which has 3 isoforms: COX-1(physiological; constitutive):Is normally present in the tissues i.e. constitutive and it is involved in synthesis of

protective PGs (e.g. PGE2, PGI2) responsible for protection of stomach from HCl, regulation of RBF, regulation of platelet aggregation, etc.

COX-2 (pathological; inducible):is involved in synthesis of undesirable PGs included in the inflammatory reactions,

bronchoconstriction, etc., therefore COX-2 activity is markedly increased during these pathological conditions i.e. inducible

COX-3 (central):Found only in the brain and may be included in synthesis of PGs responsible for

fever and pain sensation. Acetaminophen and dipyrone, analgesic/antipyretic actions are assumed to be due to selective inhibition of COX-3 enzyme..

ACETAMINOPHEN (PARACETAMOL) PharmacokineticsAcetaminophen is completely and rapidly absorbed

from the gastrointestinal tract. 80%-90% is conjugated with glucuronic or sulfuric

acid in the liver and then excreted in the urine.At high doses, one of these metabolites undergoes

spontaneous dehydration to form N-acetyl-P-benzoquinone, the metabolite thought to be responsible for hepatotoxicity.

Pharmacologic effects:Acetaminophen is an effective analgesic and antipyretic

agent but it has no anti-inflammatory activity. It appears to be an inhibitor of prostaglandin synthesis

in the brain, and thus explaining its analgesic and antipyretic activity, but it is much less effective than aspirin as an inhibitor of the peripherally located prostaglandin biosynthetic enzyme system that plays such an important role in inflammation.

It exerts little or no pharmacologic effect on the cardiovascular, respiratory, or gastrointestinal systems, on acid-base regulation, or on platelet function as aspirin dose.

Therapeutic usesAcetaminophen provides an effective alternative as analgesic and

antipyretic when aspirin is contraindicated (e.g. in-patients with peptic ulcer or hemophilia) and when the anti-inflammatory action of aspirin is not required.

Preparations and administration Acetaminophen is available in tablet and liquid forms and is administered

orally in dose of 500 mg t.d.s. Adverse effects: A. At therapeutic doses, acetaminophen is well tolerated; however,

untoward effects include:*Skin rash and drug fever (an allergic reaction to the drug).*Rare instances of blood dyscrasias (haemolyticanaemia in with G6PD

deficiency, less than with phenacetin).*Renal tubular necrosis and renal failure (more with phenacetin).

B.An overdose of acetaminophen(about 15 gm in an adult; about 4 gm in a child)

can result in severe hepatotoxicity, resulting in centrilobular hepatic necrosis. Doses greater than 20 gm are potentially fatal.

The toxic metabolite of acetaminophen appears to be inactivated in the liver via glutathione.

It is thought that when glutathione stores are consumed, the N-acetyl-p-benzoquinone metabolite binds covalently to cellular constituents, producing hepatocellular damage.

Although clinical symptoms, such as nausea and vomiting, occur during the first 24 hours after toxic ingestion, signs of hepatic damage (e.g. enzyme abnormalities) may not occur for 2 - 6 days).

Treatment consists of:Emptying the stomach & administering activated

charcoalHemodialysis, if begun within the first 12 hours after

ingestion.Administration of sulfhydryl compounds (e.g.

acetylcysteine) which probably replenish hepatic stores of glutathione.

NSAID:Classification A.Non-selective COX inhibitors (inhibit COX-1 and COX-2): Salicylic acid derivatives: aspirin, aloxiprine, aminosalicylic acid,

diflunisal, methyl salicylate, etc.Acetic acid derivatives: indomethacin, sulindac, diclofenacPropionic acid derivatives:iboprufen, ketoprofen, fenoprufen,

naproxen.Fenamic acid derivatives:mefenamic acid, fulfenamic acid.Pyrazolonederivatives:phenylbutazone, azapropazoneOxicams:piroxicam, tinoxicam. B. Selective COX-2 inhibitors: Celecoxib, valdecoxib, meloxicam.

Acetylsalicylic acid (Aspirin) Chemistrywhite crystalline substance, stable in dry air but hydrolyses in moist air to

salicylic and acetic acids. Pharmacokinetics Absorption: Most of absorption occurs from the stomach and upper GIT. Distribution: Plasma protein binding is high. Metabolism and excretion:Metabolism of salicylates occurs by the hepatic microsomal enzymes.Excretion is increased by alkalinization of urine (pH 8) because in alkaline

urine, most of aspirin is ionized and less re-absorbable.

Mechanism of actionNon-selective COX inhibitor leading to inhibition of both PGs and TXs

synthesis.Acetyl salicylic acid(aspirin) produces permanent acetylation of COX enzymes

leading to irreversible inhibition of these enzymes. Non-acetylated salicylates and other NSAIDs produce reversible inhibition. Pharmacological effects Analgesic effect: For mild to moderate intensity pain (not severe pain).Mechanism:Peripheral effect: Decrease PGs synthesis in the peripheral inflamed tissues decrease

inflammation decrease of pain mediators.Central effect:Decrease PGs synthesis in the subcortical sites (thalamus and hypothalamus).

Antipyretic effect: Aspirin is antipyretic but NOT hypothermic agent i.e.

it can lower elevated body temperature but not normal body temperature.

Mechanism: …………………………………….Anti-inflammatory, anti-immunological and anti-

rheumatic effects:

Mechanism:• Decrease PGs synthesis and other inflammatory

mediators (e.g. kinins).• Analgesic and antipyretic effects.• Decrease Margination, emigration, and migration of

leucocytes from blood stream to the site of inflammation.

• Decrease capillary permeability.• Decrease synthesis of mucopolysaccharides that

form the ground substance.• Decrease hyaluronidase enzyme which is

responsible for spread of inflammation.• Stabilize lysosomal membranes.

Respiratory effects:• High therapeutic dose:Uncoupling of oxidative phosphorylation → CO2→initial

metabolic acidosis → compensated by hyperventilation to wash excess CO2.

• Low toxic doses:Stimulate respiratory center → hyperventilation→ CO2→

respiratory alkalosis compensated by renal mechanism.• High toxic doses:Inhibition of RC → respiratory acidosis.Inhibition of VMC → blood flow → excretion of acidic

metabolites →metabolic acidosisThis stage is stage of combined respiratory and metabolic

acidosis (Uncompensated).

CVS effects: Therapeutic doses: No significant effect on the CVS, decrease effectiveness of antihypertensive

drugs.• Large doses: cutaneous VD and sweating.• Toxic doses: inhibit VMC leading to circulatory failure. GIT effects: salicylates can produce 2 types of gastric ulcer:Acute gastric ulcer:Occurs as a result of acute ingestion of large doses of salicylates. The

pathogenesis is related to trapping of salicylate ions inside the gastric mucosal cells by the effect of pKa leading to acute, painful gastric bleeding.

Chronic gastric ulcer:Occurs as a result of chronic ingestion of therapeutic doses of salicylates. The

pathogenesis is related to chronic inhibition of the protective PGE1, PGE2 and PGI2 synthesis leading to chronic ulceration and chronic blood loss.

Hepatic effects: salicylates can produce 2 types of hepatic injury

Mild hepatic injury:It is dose-dependent, reversible and asymptomatic. There may be mild increase in serum transaminases (SGOT

and SGPT). Severe hepatic injury: “Reye’s syndrome”: it is a rare and fatal condition occurs if

aspirin is used to control fever of some viral infections (e.g. chicken pox, influenza, etc.) in children below 12 years old.

There is severe hepatic injury associated with encephalopathy. Theetiology is unknown.

Hematologic effects: Antiplatelet action: aspirin inhibit platelet aggregation by:Irreversible inhibition of COX enzyme → decrease TXA2 →

decrease platelet aggregation.Irreversible acetylation of platelet cell membranes →

decrease platelet adhesions.Decrease platelet ADP synthesis → decrease platelet

accumulation. Anticoagulant action:aspirin in high doses (> 6 gm /day) inhibits hepatic synthesis

of vit K dependent coagulation factors (treated by vitK).

Renal effects: Analgesic nephropathy:Salt and water retention:Antagonize diuretic effect of diuretics: due to

decrease synthesis of vasodilatorPGs. Metabolic effects:Uncoupling of oxidative phosphorylation in high

doses → metabolic rate leading to: Heat production. CO2 → metabolic acidosis.

Endocrinal effects: Prolongation of pregnancy and delay of labor: due

to decrease PGE1, PGE2, and PGF2α.

Reversible infertility in males: due to decrease PGs essential for normal sperm motility.

Local irritant action:Salicylic acid haskeratolytic action.Methylsalicylic acid has counter-irritant action for pain

relief.

Therapeutic uses of salicylatesAs analgesic:In headache, arthritis, rheumatic pain (mention the mechanism). As antipyretic: It should not be used routinely for this purpose because fever may be a normal

protective mechanism. As anti-inflammatory and anti-rheumatic:In rheumatic fever, rheumatoid arthritis, osteoarthritis, etc. As antithrombotic: in ischemic heart disease, deep vein thrombosis, AF, etc. Cancer colon and Alzheimer's disease: through COX inhibition. As keratolytic: Salicylic acid is used for treatment of warts. As a counter-irritant Methylsalicylic acid is used for local rheumatic pain.

Side effects Hypersensitivity (aspirin intolerance):Bronchospasm (aspirin asthma) in susceptible persons, urticaria, skin

rash, pruritus, hypotension and even shock.Actually these are not due to antigen-antibody reaction but mostly due

to shifting of arachidonic acid to lipo-oxygenase pathway leading to accumulation of LTs.

GIT: Epigastric pain, nausea and vomiting.Acute and chronic gastric ulcers (why?). Hepatic:Mild hepatic injury.Severe hepatic injury in children with viral infection: “Reye’s syndrome”.

Kidney:Blood:Increase bleeding tendency.Displacement of other drugs from plasma proteins. Male and female reproductive functions:Prolongation of pregnancy and delay of labor.Reversible infertility in males .

Salicylate toxicity1.Acute toxicity: Cause: ingestion of large doses of salicylates. Manifestations:• Nausea, vomiting, hematemesis.• Acidosis and dehydration.• Pulmonary edema and cardiovascular collapse.• Hyperpyrexia, hyperventilation, irritability, convulsions, coma.• Treatment:• Repeated gastric lavage with activated charcoal.• Cold fomentations for hyperpyrexia.• Vit K 10-30 mg i.m. to control hemorrhage.• i.v. fluids to correct dehydration.• i.v. sodium bicarbonate to correct acidosis.• Alkalinization of urine: to enhance salicylate excretion.• Hemodialysis in severe cases.

2.Chronic toxicity: (Salicylism): Cause:prolonged administration of salicylates.Manifestations:headache, tinnitus, tachypnea, respiratory alkalosis.Treatment: just stop salicylates. The condition is reversible.

Precautions and contraindications GIT disorders: peptic ulcer and gastritis Hemorrhagic disorders: hemophilia, thrombocytopenia, etc. Chronic renal diseases:

Renal artery stenosis: (aspirin may aggravate renal ischemia).Renal failure: (analgesic nephropathy).

Chronic liver diseases: (these patients have bleeding tendency). CVS diseases:

CHF (aspirin may cause fluid retention). Severe hypertension: (risk of fatal bleeding).

Gout:usual dose inhibits uric acid excretion. Pregnancy: long-term therapy may delay labor. Before surgery: aspirin must be stopped at least 7 days before surgery.Children <12 years old: Fear of Reye’s syndrome.

ADRENOCORTICAL STEROIDS The natural adrenocortical hormones are steroid

molecules produced and released by the adrenal cortex. Secretion of adrenocortical steroids is controlled by the pituitary release of ACTH.

• Metabolic Effects: On carbohydrate metabolism: leading to increase in serum glucose

levelsOn fat metabolism:They increase lipolysis, however, the increase in blood glucose level

lead to increase insulin release causing lipogenesis with redistribution of fat, e.g. In the face moon face. In the neck buffalo hump.

Catabolic and Antianabolic Effects:• Although glucocorticoids stimulate protein and RNA synthesis in the

liver, they have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, fat, and skin. Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing's syndrome and impose a major limitation in the long-term therapeutic use of glucocorticoids. In children, glucocorticoids reduce growth.

• Anti-inflammatory and Immunosuppressive Effects:

Glucocorticoids dramatically reduce the manifestations of inflammation.

On the electrolytes and water balance:On CVS: Anti-shock effects:Haematological effects:On CNS:

On growth: On bone: Hormonal effects: Glucocorticoids given chronically suppress the

pituitary release of ACTH, GH, TSH, and LH. Development of the fetal lungs: Enhance uric acid excretion:

DosesDosage requirements are variable and must be

individualized.: Short-term therapy: The patient needs duration less than 2 weeks.Alternate day therapy: The recommended dose is multiplied by 2 given every

other day (to give chance for the pituitary to release ACTH and prevent sudden withdrawal symptoms).

Long term therapy: The patient needs duration more than 3 weeks. Small and large dose therapy:

Uses:Replacement therapy:

A. Treatment of adrenocortical insufficiency:In chronic adrenocortical insufficiency (Addison’s disease) e.g. TB of suprarenal cortex.

B. In acute adrencortical insufficiency (Addisonian crisis), i.e. Prolonged corticosteroid therapy produce feed back inhibition of anterior pituitary which decrease ACTH secretion results in decrease corticosteroid release from adrenal cortex. When the exogenous corticosreoid therapy is stopped, its blood level markedly decrease leading to severe hypoadrenal function, severe hypotension and shock (adrenal crisis)

Treatment: Therapy consists of correction of fluid and electrolyte abnormalities Treatment of precipitating factors Large amounts of parenteral hydrocortisone. Hydrocortisone sodium

succinate or phosphate in doses of 100 mg intravenously is given every 8 hours until the patient is stable. The dose is then gradually reduced, achieving maintenance dosage within 5 days.

Hypothalamo-pituitary-adrenal axis suppression (addissonian crisis):

This can be avoided by:*Gradual withdrawal of the corticosteroids to give chance for the

pituitary to release ACTH and stimulate adrenal cortex to secrete endogenous corticosteroids.

*Alternate day therapy.*Avoid prolonged use.*Give long acting ACTH before stoping corticosteroids.

Side effects of glucocorticoids are related to large doses and/or prolonged administrations. When the glucocorticoids are used for short periods (less than 2 weeks), it is unusual to see serious adverse effects even with moderately large doses.

N.B. During stress (e.g. intercurrent infections or before

surgery) double the dose, because stress needs more corticosteroids

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