Toxicology Lecture 4 PDF

Toxicology DR.MAMDOUH ORABY  Introduction Principles of management of toxicity  Arsenic 5- Enhance elimination of the toxins ❑ Enhance elimination of the toxic agent from the circulation should be done when the poison: 1) Is present at high...

Toxicology DR.MAMDOUH ORABY  Introduction Principles of management of toxicity  Arsenic 5- Enhance elimination of the toxins ❑ Enhance elimination of the toxic agent from the circulation should be done when the poison: 1) Is present at high concentration in plasma relative to its concentration in the organs (small distribution volume, Vd). 2) Is excreted in urine and its metabolite. 3) Dissociates rapidly from the plasma binding proteins 4) Has low molecular weight and size  Arsenic 5- Enhance elimination of the toxins I- Forced diuresis: ▪ Enhance the excretion of drugs/metabolites through the kidney. ✓N.B: Isn’t effective for chemicals that are reabsorbed by renal tubules (Conc. of these chemicals is low in the urine). a. Diuretics ▪ Diuretics are used to increase the urine output. ▪ Ex: Mannitol & furosemide.  Arsenic 5- Enhance elimination of the toxins b. Alkalinization of urine: ❑ Promotes the excretion of weak acids ❑ Increases their ionization “ion trapping“ in the renal tubules. ❑ Ex; Na bicarbonate & acetazolamide → alkalinize the urine (pH = 7.5-8). ❑ Ex; Weak acidic drugs (ex; salicylates, phenobarbitone, methotrexate) can be eliminated by alkalinization of urine.  Arsenic 5- Enhance elimination of the toxins c. Acidification of urine Promotes the excretion of weak bases Increases their ionization “ion trapping “ in the renal tubules. Ex; Ammonium chloride & ascorbic acid → acidify the urine (pH = 5.5-6). Ex; Weak basic drugs (ex; amphetamine, quinine, phencyclidine) can be eliminated by acidification of urine.  Arsenic Enhance elimination of the toxins II. Extracorporeal techniques: ❑ Dialysis is employed as an adjunct for the management of severely intoxicated patients. It is not necessary for toxins; ✓ Having specific antidotes; Ex: opioid toxicity (specific antidote, naloxone). ✓ Very rapidly toxic agents; Ex; cyanide (produces toxic effects within minutes).  Arsenic Enhance elimination of the toxins ❑ During dialysis, Chemicals diffuses through a semipermeable membrane from higher concentration area (blood & interstitial fluids) to lower concentration ones (dialyzing solution).  Arsenic Enhance elimination of the toxins a. Peritoneal dialysis: ▪ Patient’s peritoneum is used as in vivo semipermeable membrane ▪ Fluids & dissolved chemicals are exchanged from the blood into dialysis fluid down its concentration gradient through peritoneum.  Arsenic Enhance elimination of the toxins ❑ N.B: Adequate peritoneal blood flow is essential, so it is inefficient in patients with hypotension. ❑ Composition of dialysis solution: ✓Sodium chloride & lactate & bicarbonate ✓High glucose concentration to make the dialysis fluid hypertonic? ▪ N.B: For chemical toxins that are highly protein- bound, albumin is added to the dialysis solution.  Arsenic Enhance elimination of the toxins Complications: ❑ Abdominal pain ❑ Protein loss ❑ Intraperitoneal bleeding ❑ Water & electrolyte imbalance ❑ Intestinal, bladder, liver, spleen perforation.  Arsenic Enhance elimination of the toxins b. Hemodialysis: ▪ An in vitro semipermeable membrane (artificial kidney) is used for diffusion of chemicals from blood to the dialysis fluid.  Arsenic Enhance elimination of the toxins ❑Complications: ✓Infection ✓Hypotension ✓Bleeding & clotting ▪ N.B: Chemicals must have small molecular size ❑ N.B: Hemodialysis is less effective for highly protein-bound chemicals (can ҆t pass through the semipermeable membrane).  Enhance elimination of the toxins c. Hemoperfusion: ▪ The blood passes through a sterile column (or cartridge) containing activated charcoal, ion exchange resins to adsorb toxic chemicals from the blood. ▪ N.B: Hemoperfusion is more effective than peritoneal and hemodialysis? Due to the greater surface area offered by dialyzing membrane (column).  Enhance elimination of the toxins ❑ Advantages: Suitable for detoxifying: ▪ Lipid soluble substances ▪ High protein-bound chemicals ❑ Complications: ✓ Trapping of WBCs & Platelets ✓ Activation of the clotting system ▪ These complications are overcome by using newer adsorbent systems (such as charcoal + acrylic hydrogel).  Enhance elimination of the toxins d. Plasmapheresis: ▪ A method for separating red blood cells from the liquid plasma. ▪ RBCs are then mixed with a new fresh frozen plasma or treated plasma and returned to the body. ❑ Disadvantage: ✓ Some patient ҆s plasma proteins can be lost.  6- Antidote therapy A. Chemical antidote: ❑ Chemical antidotes react with the poison chemically to produce compounds with lower toxicity. ❑ Ex. 1: Calcium salts react with oxalic acid (causes renal damage) → poorly soluble Ca2+ oxalate (can ҆t be absorbed through the intestine). ❑ Ex. 2: Chelating agents (Ex; dimercaprol (BAL) & deferoxamine & EDTA & penicillamine) react with heavy metals → chemical chelates (water-soluble & readily excreted in urine).  6- Antidote therapy B. Receptor antidote: ▪ The antidote antagonizes the receptor of the poison. ▪ Ex. 1: Naloxone (μ receptor antagonist) is an antidote for opioids (ex; morphine)-induced respiratory depression. ▪ Ex. 2: Atropine (M-antagonist; has anticholinergic effects) is an antidote for organophosphates-induced cholinergic toxidrome. ▪ Ex. 3: Physostigmine (cholinesterase inhibitor; ↑ Ach) is an antidote for atropine toxicity  6- Antidote therapy C. Functional (physiologic) antagonism: The antidote produces physiological effects that oppose the effects of the poison. ❑ Ex 1: Epinephrine is used for severe anaphylactic reactions following administration of a drug (induce bronchodilation). ❑ Ex 2: Vitamin K (↑ synthesis of blood coagulation factors) is used to treat the hemorrhage caused by coumarin.  6- Antidote therapy D. Enzymatic antidote: ▪ Ex. 1: N-acetylcysteine acts as the endogenous GSH enzyme. ▪ Used to detoxify acetaminophen by forming a non-toxic intermediate conjugate ( ↓ liver toxicity). ▪ Ex. 2: Pralidoxime is used to reactivate acetylcholinesterase enzyme (breakdown of Ach) in case of organophosphorus toxicity. ▪ Ex. 3: Ethanol (10%) is used to detoxify methanol by reducing the formation of formic acid by inhibiting alcohol dehydrogenase (saturation of the enzyme).  7- Supportive treatment A. Hypertension: Can cause cerebral hemorrhage & pulmonary edema. Amphetamines & Cocaine & Corticosteroids can induce hypertension. ❑ Treatment 1. Sodium nitroprusside: used for treatment of hypertensive crises. 2. Other vasodilators: ex; Nitroglycerin & Ca+2 channel blockers.  7- Supportive treatment B. Anaphylaxis: ▪ A serious reactions with a rapid onset that can lead to death. ❑ Causes: ✓ Insect bites and stings ✓ Certain types of food such as seafood. ✓ Medications (ex, penicillin, NSAIDs). ❑ Treatment: 1. Epinephrine & I.V fluids (for circulatory failure & bronchospasm). 2. Antihistamines & Corticosteroids. 3. Bronchodilators  Supportive treatment C. Seizures: ❑ Seizures can be induced by various toxicants (ex; organophosphorus compounds) & drug abuse overdose (amphetamines & cocaine). ❑ Treatment: 1. Benzodiazepines ( ex; diazepam & midazolam). 2. Phenytoin as an anticonvulsant.  Supportive treatment D. Electrolyte disturbances: Hyperkalemia (serum K > 5.5 mEq/L) ❑ Causes: ACE inhibitors (captopril) & ARBs (losartan) ❑ Treatment: ▪ I.V. Ca2+ gluconate, Na bicarbonate, diuretics (↑ K+ excretion). ▪ Polystyrene sulfonate Na+ or Ca+2 (exchange resin in intestine)  Supportive treatment Hypokalemia: (serum K < 3.5 mEq/L) ✓ Causes: NSAIDs, Steroids, diuretics. ✓ Treatment: Oral or I.V. K+. Hypernatremia (↑ Na+): ✓ Causes: NSAIDs & Corticosteroids ✓Treatment: Diuretics Hyponatremia (↓ Na+): ✓ Causes: ex; desmopressin ✓ Treatment: hypertonic saline  Supportive treatment E. Hyperthermia: ❑ Severe hyperthermia (core temperature 42⁰C) is a devastating condition that causes: ✓Brain damage ✓Coagulopathy (Bleeding) ✓Denaturation of the enzymes ✓Death I. Malignant hyperthermia: ▪ Is a severe reaction to certain drugs used for anesthesia ▪ Ex; succinylcholine & general anesthetic gases such as halothane.  Supportive treatment ❑ During anesthesia, Ca2+ is released in large amounts muscles due to overstimulation of Ca2+ channels (ryanodine receptors) → Excessive muscle contraction → Hyperthermia ❑ Complications Severe muscle rigidity → Destruction of muscle fibers (rhabdomyolysis) ↑ Metabolic rate → ATP depletion. Muscle breakdown → ↑ myoglobin, K+, creatine, phosphate into the blood → renal failure  Supportive treatment ❑Treatment: Dantrolene, a ryanodine receptor antagonist → ↓ Ca+2 release from the sarcoplasmic reticulum → muscle relaxation.  Supportive treatment II. Exertional heat stroke: ▪ It is an excessive heat generation due to excessive muscle activity. ❑ Cause: ✓ Drugs; Ex; amphetamine & cocaine & strychnine. ❑ Treatment: ✓ Anticonvulsant ✓ Neuromuscular blocker ✓ Evaporative cooling  Supportive treatment IV. Anticholinergic syndrome: ❑ Cause: Agents: atropine & antihistamines → ↓ cholinergic (Ach)- mediated sweating → hyperthermia ❑ Treatment: ▪ Evaporative cooling ▪ Physostigmine (cholinesterase inhibitor → ↑ Ach→ sweating) Thank You