Antidotes & their MOAGROUP NO. 06CLINICAL PHARMACY (TOXICOLOGY)

FlumazenilASRA HAMEED

12859

Flumazenil (GABA Modulators)

• Imidazobenzodiazepine derivative• Antagonizes the actions of

benzodiazepines on the CNS• Competitively inhibits the activity at the

benzodiazepine recognition site on the GABA/benzodiazepine receptor complex

BenzodiazepineMechanism Of Action

symptoms of BZD overdose• Central nervous system depression• Ataxia• Slurred speech• Dizziness• Confusion• Drowsiness• Blurred vision• Unresponsiveness• Anxiety• Agitation

Severe symptoms include

coma and respiratory depression

Benzodiazepine Toxicity Differential Diagnoses

• Acute Hypoglycemia• Alcohol Toxicity• Antidepressant Toxicity• Encephalitis• Hypernatremia (rise in serum sodium concentration by

decrease in total body water)• Hyponatremia [abnormally low serum Sodium (helps regulate the amount of water in and around cells)]• Neuroleptic Agent Toxicity• Sedative-Hypnotic Toxicity• Stroke, Ischemic• Toxicity, Antihistamine

Tests and procedures depend on the presentation, as follows:

• Obtain a blood glucose level immediately if the patient has an altered mental status

• Obtain an arterial blood gas (ABG) if respiratory depression is present

• Obtain an electrocardiogram (ECG) to evaluate for co-ingestants, particularly cyclic antidepressants

• Obtain a chest radiograph if respiratory compromise is present

• Obtain a pregnancy test in women of childbearing age

In patients with an intentional overdose, measure the following:

• Serum electrolytes• Glucose• blood urea nitrogen (BUN)• Creatinine clearance• Ethanol• Acetaminophen level

Approach Considerations• As with any overdose, the first step is to

assess the patient's airway, breathing, and circulation and to address these rapidly as needed.

• The cornerstone of treatment in benzodiazepine (BZD) overdoses is good supportive care and monitoring.

activated charcoal

• Single-dose activated charcoal is not routinely recommended, as the risks far outweigh the benefit.

• BZD are very rarely fatal in overdoses, and the altered mental status from BZD overdose greatly increases the risk of aspiration following oral charcoal dosing.

Flumazenil• Flumazenil is a specific antidote for BZDs, but its use

in acute BZD overdose is controversial and its risks usually outweigh any possible benefit.

• It should be considered only in isolated iatrogenic BZD overdose in BZD-naive patients (e.g., during conscious sedation on BZD-naive patient).

• In long-term BZD users, flumazenil may precipitate withdrawal and seizures; in patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition.

Flumazenil• Common adverse events with flumazenil

include agitation and gastrointestinal symptoms

• Serious adverse events include supraventricular arrhythmia and convulsions

Vitamin C

Methemoglobinemia• Hemoglobin within red blood cells attaches (binds) to oxygen

molecules in the lungs, which it carries through the bloodstream, then releases in tissues throughout the body.

• Instead of normal hemoglobin, people with methemoglobinemia, have an abnormal form called methemoglobin, which is unable to efficiently deliver oxygen to the body's tissues.

It promote the heme iron to change from ferrous to ferric. The ferric iron cannot bind oxygen and causes cyanosis and the brown appearance of blood.

Cyanosis is a bluish discoloration, especially of the skin and mucous membranes, due to excessive concentration

of deoxyhemoglobin in the blood caused by deoxygenation.

Treatment andPatients with G6PD deficiency

• Methylene blue is the primary emergency treatment for methemoglobinemia

• Methylene blue should not be administered to patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency,

• MB may not only be ineffective but it is also potentially dangerous

• Pretreatment screening of G6PD deficiency is not usually possible in emergency.

• If methylene blue is contraindicated, only moderate doses of

ascorbic acid • Dose:300 to 1000 mg/day orally in divided doses

Repair the damaged hemoglobin

GlucagonNEELAM SHARIF

12886

Beta Blockers and CCBs Overdose Some beta blockers may antagonize sodium channel

blockage QRS widens and some beta blockers cause efflux blockade long QT

• Beta blockers overdose results in bradycardia and hypotension

CCBs prevent the opening of these voltage-gated calcium channels (myocardial cells, smooth muscle cells and β-islet cells of the pancreas) and reduce calcium entry into cells during phase 2 of an action potential.

In an overdose situation, receptor selectivity is lost, and effects not normally seen at therapeutic doses can occur.

Mechanism of Action of Toxicitya) Calcium enters open voltage-sensitive calcium channels to promote

the release of calcium from the sarcoplasmic reticulum. The released calcium combines with troponin to cause muscle contraction via actin and myosin fibers.

b) AC catalyzes the conversion of ATP to cAMP, which activates protein kinase A (PKA), which promotes the opening of dormant calcium channels, enhances release of calcium from the sarcoplasmic reticulum, and facilitates release of calcium by troponin during diastole.

c) Glucagon bypasses β-receptors and acts directly on Gs to stimulate conversion of ATP to cAMP.

d) Amrinone inhibits PDE(Phosphodiestrase) to prevent the degradation of cAMP.

e) Insulin promotes the uptake and use of carbohydrates as an energy source.

Mechanism of action of toxicity

Specific features and Symptomsof Beta Blockers Overdose

Specific Features and Symptoms Of CCBs Overdose

Antidote Glucagon• Glucagon is generally recognized as first-line therapy. • Glucagon is a hormone secreted by the α2 cells of the

pancreatic islets of Langerhans..• High-dose glucagon is recommended for cardiotoxicity

produced by β-blocker poisoning.

Mechanism of antidote glucagon

Glucose (Dextrose 50%)

AMMARAH UROOJ12852

MECHANISM OF INSULIN:

SYMPTOMS OF INSULIN TOXICITY:

High doses of insulin can lead to:• dyselectrolytemia.• Salt and water retention • hyponatremia• hypoglycemia • hypokalemia• dizziness and mild confusion• anxiety or nervousness• shakiness• rapid heartbeat• Hunger• Irritability

EMERGENCY TREATMENT : provide immediate attention to

patient before they lead to dangerously low blood sugar.  People who have low blood sugar levels are advised to consume 15 grams of a fast digesting carbohydrate, such as glucose tablets or a high-sugar food immediately. High-glucose foods include:

• raisins • soda • fruit juice • honey • candy

symptoms should improve within 15 minutes. If they don’t, or if a test shows your levels are still low, repeat the above steps until your blood sugar is above 70 mg/dL. If your symptoms still don’t improve, seek medical help immediately. Be sure to eat a meal after treating a low blood sugar reaction.

MANAGEMENT OF HYPOGLYCEMIA

 Management includes the

following steps:• Restoration of normal

plasma glucose levels• Prevention of relapse in the short term• Prevention of recurrent

episodes in the long term.

RESTORATION OF NORMAL PLASMA GLUCOSE LEVEL:

In non-severe hypoglycemia, the oral consumption of carbohydrates is usually adequate to restore plasma glucose levels above the lower limit of the normal range. Patients starting insulin for the treatment of their diabetes should be taught to recognize the symptoms of hypoglycemia and how to react in case of a hypoglycemic event. Self-monitoring blood glucose (SMBG) is strongly recommended for these patients If hypoglycemia is suspected, a blood glucose measurement using a portable glucose meter is recommended in order to confirm low plasma glucose

Prevention of relapse in the short term

Restoration of plasma glucose levels after an acute hypoglycemic event usually follows quickly after the administration of carbohydrates, either orally or intravenously, or after a glucagon injection. It is very important, however, to keep in mind that hypoglycemia tends to relapse in some cases, this tendency depending on the etiology of the initial decline in plasma glucose

Prevention of recurrent episodes in the long term

• Recurrent hypoglycemia requires a thorough evaluation of diabetes management A careful history is usually adequate to identify hypoglycemia unawareness. In other cases, careful follow-up with frequent SMBG or even the use of a glucose sensor for continuous subcutaneous glucose monitoring may be recommended

DEXTROSE 50% SOLUTION:

50% Dextrose Injection, USP is a sterile, nonpyrogenic, hypertonic solution of dextrose in water for injection for intravenous injection as a fluid and nutrient replenisher. Each mL of fluid contains 0.5 g dextrose, hydrous which delivers 3.4 kcal/gram

Mechanism of Action: • Provides immediate source of glucose for cellular metabolism. It provide free water that pass

through membrane pores both intracellular and extracellular spaces.its smaller size allow the molecule to pass more freely between compartment thus expanding both compatments simultaneously

Contraindications: • 1. There are no absolute contraindications to the IV administration of dextrose

50% in the emergency setting.2. Relative contraindication: Use with caution in patients with increasing Intracranial pressure as the added glucose may worsen the cerebral edema.

•

Side Effects: • 1. Patients may complain of warmth, pain or burning at the injection site.

2. Dextrose can cause severe neurologic symptoms (Wernicke's encephalopathy or Korsakoff's psychosis) if patient is thiamine deficient.

•

Routes of Administration: IV, IO.

Onset and Duration of Actions: • Onset will be 30-60 seconds but duration depends upon degree and

cause of hypoglycemia. Dosages:

• ADULT: 25 gm (50 ml solution preload) IVP/IOMay repeat once in 5 minutesOver 2 years: 1 ml/kg slow IVP/IO of a 50% solution (same solution as for the adult)May repeat once in 5 minutes.

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ThiamineSABIHA GUL

131027

INTRODUCTION

• also known as vitamin B1,• anti beriberi factor or antineuritic vitamin• It is an important water-soluble vitamin • is involved in carbohydrate, fat, amino acid,

glucose, and alcohol metabolism.• is required as a coenzyme in enzymatic reactions

that involve the transfer of an aldehyde group. • is essentially nontoxic

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CHEMISTRY

• Thiamine contains a substituted pyrimidine ring (dimethyl 6-amino pyrimidine) connected to a substituted thiazole ring (Methyl hydroxy ethyl thiazole) by means of Methylene bridge

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SYNTHESIS Thiamine can be synthesized by plants and some microorganisms, but not usually by animals. Human beings require thiamine from diet, though small amounts may be obtained from synthesis by intestinal bacteria. Whole wheat flour, unpolished rice, beans, nuts and yeast are the good sources of thiamine .It is also present in liver, meat and eggs. The body can only store up to 30 mg of thiamine in its tissues

• It is present in large amounts in skeletal muscle, heart, liver, kidney, and brain.

• It has a widespread distribution in foods, but there can be a substantial loss of thiamine during cooking above 100°C (212°F).

• The half-life of thiamine is 9-18 days. It is excreted by the kidney

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OCCURRENCE

RECOMMENDED DAILY ALLOWANCE:

•Depends on calorie intake (0.5 mg/1000 cals ) • RDA is 1-1.5 mg/day • Requirement increases with• increased carbohydrate intake •Pregnancy • Lactation • Smoking • Alcoholism •Prolonged antibiotic intake •Serious or prolonged illness

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METABOLISM• Thiamine has a central role in energy-yielding metabolism, and

especially the metabolism of carbohydrates • Thiamine pyrophosphate is an essential cofactor for enzymes that

catalyze the oxidative decarboxylation of α-keto acids to form an acylated coenzyme A (acyl CoA).

• These include pyruvate dehydrogenase , α -keto glutarate dehydrogenase and branched-chain α- keto acid dehydrogenase. These three enzymes operate by a similar catalytic mechanism

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THIAMINE AS AN ANTIDOTE

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Thiamine use a antidote :• Persons with alcoholism•Ethylene Glycol Poisoning•Wernicke–Korsakoff syndrome (WKS)

Wernicke–Korsakoff syndrome (WKS)

• Wernicke–Korsakoff syndrome (WKS) is the combined presence of Wernicke's encephalopathy (WE) and Korsakoff's syndrome. Due to the close relationship between these two disorders, people with both are usually diagnosed with WKS, as a single syndrome.

• It is due to thiamine (vitamin B1) deficiency, which can cause a range of disorders including beriberi, Wernicke's encephalopathy, and Korsakoff's psychosis.

SIGN AND SYMPTOMS • These disorders may manifest together or separately. WKS is usually secondary

to alcohol abuse, It mainly causes • vision changes, • ataxia • impaired memory.

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CAUSES• WKS is usually found in chronic alcoholics. Wernicke–Korsakoff syndrome

results from thiamine deficiency. It is generally agreed that Wernicke's encephalopathy results from severe acute deficiency of thiamine (vitamin B1)

Alcohol–thiamine interactionsStrong evidence suggests that ethanol interferes directly with thiamine uptake

in the gastrointestinal tract. Ethanol also disrupts thiamine storage in the liver and the transformation of thiamine into its active form. The role of alcohol consumption in the development of WKS has been experimentally confirmed through studies in which rats were subjected to alcohol exposure and lower levels thiamine through a low-thiamine diet

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TREATMENT

• Thiamine administration should be initiated immediately when the disease is suspected

• minimum dose of 500 mg of Thiamine hydrochloride

•  Such prompt administration of thiamine may be a life-saving measure. Banana bags, a bag of intravenous fluids containing vitamins and minerals, is one means of treatment.

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Persons with alcoholism

• It is well known that chronic alcoholics are at high risk for being deficient in vitamin B1 (thiamine), which is known to put the patient at an increased risk for Wernicke-Korsakoff Syndrome, cerebellar degeneration, and cardiovascular dysfunction.

TREATMENT• The current standard of treatment for such patients is to give them thiamine 100 mg

intravenously (IV) before administering glucose containing IV fluids and then to

continue this dose for several days.

Ethylene glycol poisoning• It is a sweet kiler• Ethylene glycol poisoning is caused by the ingestion of ethylene glycol the primary ingredient in

automotive antifreeze Ethylene glycol is a toxic, colorless, odorless, almost nonvolatile liquid with a sweet taste that is sometimes accidentally consumed by children and animals due to its sweetness.

• symptoms of poisoning• progress from signs similar to intoxication and vomiting to hyperventilation, metabolic acidosis

and cardiovascular dysfunction; and finally acute kidney failure

CAUSESThe major cause of toxicity is not the ethylene glycol itself but its metabolites,

mainly glycolic acid and oxalic acid. LETHAL DOSELethal dose is estimated as 1 -1.5 mls/kg or 100mls

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TREATMENT• Inhibit Absorption i.e Gastric lavage , syrup of ipecac and activated

charcoal• „ Correct Acidosis i.e Bicarp drip• „ Inhibition of Metabolism i.e • Thiamine • Fomepizole (4 -methylpyrazole) • Ethanol „ • Pyridoxine• „ Elimination of parent compound and the metabolites I,e remove

ethylene glycol and glycolate effectively

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TREATMENT

THIAMINE : MOA•–Prevents the formation of oxalic acid by facilitating the conversion of glycoxylic acid to alpha Hydroxy Beta ketoadipic acid.• DOSE•100 mg IV q6 until ethylene glycol can no longer be measured in the serum

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Hydroxocobalamin&

Sodium ThiosulphateNOSHEEN HAYAT

131018

CYANIDE POISONING

Cyanide poisoning occurs when a living organism is exposed to a compound that produces cyanide ions (CN−) when dissolved in water.

CYANIDE ANTIDOTES

Antidotes to cyanide include hydroxocobalamin and sodium nitrite and sodium thiosulfate. Sodium thiosulfate may be given in combination with sodium nitrite or hydroxocobalamin, or may be given alone. These agents are administered intravenously.

FomepizoleAISHA ABDULLAH

12850

Ethyiene glycol Toxicity & its Mechanism of Toxicity

Stages of Ethylene Glycol Intoxication

• Severe ethylene glycol poisoning may go through three stages:

1)CNS depression2) cardiopulmonary toxicity 3) renal toxicity

Stage 1

• At 4-12 hours after glycoaldehyde forms , these symptoms may appear:

• seizures• coma• cerebral edema (in some cases)• gastrointestinal irritation (nausea and

vomiting)

Stage 2• The following cardiorespiratory symptoms may appear 12-24 hours after ingestion• tachycardia,• tachypnea, and• hypertension or hypotension.• The following conditions may develop in this stage• pulmonary edema,• pneumonitis,• congestive cardiac failure, and• shock.• Formation of oxalic acid may lead to deposition of calcium oxalate crystals in• the meninges,• blood vessel walls,• lung, and• myocardium.

Stage 3• Kidney damage usually develops 24-72 hours after exposure.

Acidosis and acute renal failure may result from deposition of calcium oxalate crystals in the kidneys.

• The following conditions characterize the third phase• flank pain,• costovertebral angle tenderness, and• oliguric renal failure.

Diagnosis• It is most reliably diagnosed by the measurement of the blood ethylene

glycol concentration. Ethylene glycol in biological fluids can be determined by gas chromatography.

• Many hospital laboratories do not have the ability to perform this blood test and in the absence of this test the diagnosis must be made based on the clinical presentation of the patient.In this situation a helpful test to diagnose poisoning is the measurement of the osmolal gap.

• Large anion gap acidosis is usually present during the initial stage of poisoning. diagnosis of ethylene glycol poisoning should be considered in any patient with a severe acidosis.

• Urine microscopy can reveal needle or envelope-shaped calcium oxalate crystals in the urine which can suggest poisoning.

Treatment• The most important initial treatment for ethylene glycol poisoning is stabilizing

the patient. As ethylene glycol is rapidly absorbed, gastric decontamination is performed within 60 minutes of ingestion.

• Patients with significant poisoning often present in a critical condition. In this situation stabilization of the patient including airway management with intubation should be performed in preference to gastrointestinal decontamination.Patients presenting with metabolic acidosis or seizures require treatment with sodium bicarbonate and ticonvulsives such as a benzodiazepine respectively.Sodium bicarbonate should be used cautiously as it can worsen hypocalcemia by increasing the plasma protein binding of calcium. If hypocalcemia occurs it can be treated with calcium replacement although calcium supplementation can increase the precipitation of calcium oxalate crystals leading to tissue damage.

• Intubation and respiratory support may be required in severely intoxicated patients; patients with hypotension require treatment with intravenous fluids and possibly vasopressors.[

Fomepizole & its MOA

Dosing• The dosing and administrationof fomepizole is the same for children

and adults.• Loading dose :15 mg/kg IV maximum of 1500 mg• 12 hours later, give the 1st maintenance dose of 10 mg/kg IV.

Repeat every 12 hours• Continue treatment until EG or methanol levels are below 20 mg/dl

and the patient is asymptomatic with normal pH.

HeparinZABAB KHAN

131066

• Ergotamine is a naturally occurring ergot alkaloid

• Used for Preventing or treating acute migraine headache

• Partial agonist or antagonist activity against tryptaminergic, dopaminergic and α-adrenergic receptors

• Potent vasoconstrictor, analgesic, Oxytocics

• Ergotamine doses of more than 15

mg/24 hours or more than 40 mg

over a few days are likely to cause

toxicity.

• Death has been reported in a 14-

month-old toddler after an acute

ingestion of 12 mg

• vasospastic effects• nausea and vomiting• impaired mental function• confusion • depression • drowsiness• rapid and weak pulse• unconsciousness• spasms of the limbs

• Reverses hyper-coagulable state by interacting with anti-thrombin III to prevent local thrombosis and ischemia.

• Heparin binds to  antithrombin III (AT)• The activated AT then

inactivates thrombin, factor Xa and other proteases. 

• The conformational change in AT on heparin-binding mediates its inhibition of factor Xa.

• The formation of a  complex between AT, thrombin, and heparin results in the inactivation of thrombin.

Vitamin K

ZABAB KHAN131066

Most widely prescribed anticoagulant (a drug which reduces the risk of blood clots forming).  

decreases the clotting ability of the blood so reduces the risk of blood clots forming

Blood clots can be dangerous because they can lead to serious life-threatening conditions such as stroke.

It is very effective at significantly reducing the risk of stroke in people with atrial fibrillation(AF)

People taking warfarin need to have a regular blood test called an international normalised ratio (INR).

INR measures the time it takes your blood to clot.

It is increased by taking warfarin, which, in turn, increases the INR.

Patients on warfarin, their target INR is 2.5 If you’re not on warfarin your INR is around

1 The lowest toxic dose in humans ranges

from 10 mg/kg to 15 mg/kg The probable lethal oral dose in humans is

believed to be between 50 and 500 mg/kg

o Red spots on your skin that look like a rash

o Severe headache or dizzinesso Heavy bleeding after an injuryo Heavy bleeding during monthly period in

womeno You have severe stomach pain or you

vomit bloodo Pink, red, or dark brown urineo Black or bloody bowel movements

Vitamin K is a fat-soluble vitamin Vitamin K is known as the clotting vitamin,

because without it blood would not clot. Found in Green leafy vegetables, such as spinach

mustard greens, parsley and green leaf lettuce Vegetables such as broccoli, cauliflower, and

cabbage Fish, liver, meat, eggs, and cereals Vitamin K is also made by the bacteria in the lower

intestinal tract. Essential co-factor in the synthesis of blood

clotting factors ll, Vll, lX and X and proteins C and S

Antagonist of some oral anticoagulants (warfarin)

• Prothrombin time (PT) determinations    (The prothrombin test is sensitive to the levels of three of the vitamin K–dependent clotting factors (II, VII, and X)

• Rregular prothrombin level determinations are recommended to determine responsiveness to and need for additional vitamin K therapy .

• Allergic reactions, • Blue color or flushing or redness of skin• dizziness• fast and/or weak heartbeat

Leucovorin calciumMISHA MEHMOOD

INDICATION For the treatment of osteosarcoma (after high

dose methotrexate therapy). Used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anemias due to folic acid deficiency.

• Also used in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

MOA OF FOLATE ANATAGONIST

MECHANISM OF ACTIONLEUOCOVORIN

• As leucovorin is a derivative of folic acid, it can be used to increase levels of folic acid under conditions favoring folic acid inhibition (following treatment of folic acid antagonists such as methotrexate). Leucovorin enhances the activity of fluorouracil by stabilizing the bond of the active metabolite (5-FdUMP) to the enzyme thymidylate synthetase.

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