Benzodiazepines PDF

Benzodiazepines Benzodiazepines (BZDs) are one of the most widely prescribed pharmacologic agents in the United States. Indications: anxiety, insomnia, muscle relaxation, relief from spasticity caused by central nervous system pathology, and epilepsy. Intraoperatively because of their amnesic and an...

Benzodiazepines Benzodiazepines (BZDs) are one of the most widely prescribed pharmacologic agents in the United States. Indications: anxiety, insomnia, muscle relaxation, relief from spasticity caused by central nervous system pathology, and epilepsy. Intraoperatively because of their amnesic and anxiolytic properties. Tolerance, dependence, age-related physiological changes, and drug-drug interactions are all important considerations. Pharmacology o BZDs act as positive allosteric modulators on the gamma amino butyric acid (GABA)-A receptor. o The GABA-A receptor is a ligand-gated chloride-selective ion channel. o GABA is inhibitory in nature and thus reduces the excitability of neurons. o The GABA-A receptor complex is composed of 5 glycoprotein subunits. o A major factor in predicting amnesia risk is lipid solubility; the greater the lipid solubility, the greater the risk of amnesia. Pharmacokinetics o Individuals respond differently to the same drug. o Pharmacokinetics (determination of the onset of action and the duration of drug effect) is affected by route of administration, absorption, and volume of distribution. o BZDs can be administered i.m., i.v., oral, sublingual, intranasal, rectal. o Lipid solubility, binding to plasma proteins, and molecular size— influence the volume of distribution. o Dose-response curves predict the effect of the drug on the patient as doses increase. o Preexisting disease processes and age-related changes affect elimination half-life. Pharmacokinetics o Elimination half-life is the time necessary for plasma concentration the elimination phase. o Half-life is directly proportional to the volume of distribution and clearance, renal and hepatic disease. o Elimination half-life does not reflect time to recovery from drug o Well absorbed by the gastrointestinal tract after oral administration o After intravenous administration, BZDs quickly distribute to the o Lorazepam is well absorbed after sublingual administration, reaching peak levels in 60 minutes. of a drug to decrease to 50% during inversely proportional to its effects. central nervous system. Metabolism o Oxidatively metabolized by the cytochrome P450 enzymes (phase I), conjugated with glucuronide (phase II), and excreted almost entirely in the urine. o Some BZDs exert additional action via production of active metabolites. o Midazolam, one of the short- acting BZDs, produces no active metabolites. o Diazepam, a long-acting BZD, produces the active metabolites oxazepam, desmethyldiazepam, and temazepam- increase the duration of drug action BZDs- Clinical aspects BZDs are classified in terms of their elimination half-life. Short-acting BZDs have a median elimination half-life of 1-12 hours. Intermediate-acting BZDs- elimination half-life of 12-40 hours. Long-acting BZDs- elimination half-life of 40-250 hours. BZDs- Clinical aspects o Increased potency leads to an increase in the risk of undesired effects o Common side effects among all BZDs include drowsiness, lethargy and fatigue. o At higher dosages, impaired motor coordination, dizziness, vertigo, slurred speech, blurry vision, mood swings, and euphoria can occur, as well as hostile or erratic behavior in some instances. o Repeated doses over a prolonged period- significant accumulation in fatty tissues. o Some symptoms of overmedication (impaired thinking, disorientation, confusion, slurred speech) can appear over time. o Tolerance, dependence, and withdrawal- adverse effects associated with long-term use.BZDs neurotoxicity o Anterograde amnesia, sedation, drowsiness, motor impairment, inattentiveness, and ataxia. o More prominent in elderly populations because of the metabolic changes associated with normal aging. o Loss of inhibition that can lead one to behave out of character, placing the patient in dangerous situations. o High-risk sexual behavior and reckless driving. o Delirium, an acute condition characterized by impaired attention and cognition. Increased morbidity, increased mortality, and longer hospital stays. Barbiturates o Sedative-hypnotic medications used for treating seizure disorders, neonatal withdrawal, insomnia, preoperative anxiety, and the induction of coma to address increased intracranial pressure (ICP) o Helpful for inducing anesthesia. Thiopental, introduced in 1934 for general anesthesia induction. o Cause postsynaptic enhancement of gamma-aminobutyric acid (GABA), interacting with alpha- and beta subunits of the GABA-A receptor. o Increase chloride ion flux, resulting in postsynaptic hyperpolarization. Classifications o Ultra-short-acting: methohexital and thiopental. o Short-acting: pentobarbital and secobarbital. o Intermediate-acting: amobarbital and butalbital. o Long-acting: phenobarbital and primidone. Pharmacokinetics o Absorption: Phenobarbital is rapidly absorbed with a time-to-peak concentration of 2 to 4 hours. The bioavailability of phenobarbital is approximately 90% in adults. o Distribution: Highly lipid-soluble barbiturates cross the blood-brain barrier rapidly, but rapid redistribution from the CNS to peripheral tissues occurs. o Metabolism: The oxidation of barbiturates is the most important biotransformation that terminates biological activity. Phenobarbital is metabolized extensively by the cytochrome P450. Repeated administration of phenobarbital decreases the half-life due to the induction of microsomal enzymes tolerance. Chronic administration- increase in aminolevulinic acid (ALA) synthetase enzyme- exacerbations in patients with porphyria. o Elimination: About 25% of phenobarbital is excreted unchanged in the urine. The renal excretion can be increased by osmotic diuresis or alkalinization of the urine. Adverse effects o For women taking phenobarbital as monotherapy, the drug correlates with congenital defects in exposed infants. o Thiopental and thiamylal release histamine. o Extravasation of thiopental may cause severe tissue necrosis. If extravasation occurs, treatment measures include hyaluronidase and phentolamine. o Mild liver injury. o Phenobarbital-induced severe adverse drug reactions are DRESS (drug reaction with eosinophilia and systemic symptoms), Stevens- Johnson syndrome, and toxic epidermal necrolysis. o Tolerance is a gradual loss of effectiveness such that the dose has to be increased to maintain the same effect. This effect is partly explained by enzyme induction in the liver. Overdose o CNS depression, respiratory failure, and hemodynamic instability. o No specific antidote exists for barbiturates, and overdose treatment includes supportive care and urinary alkalinization. o Efficacy of multiple-dose activated charcoal for phenobarbital and primidone overdose. Hemodialysis and haemoperfusion may be considered in patients with life-threatening barbiturate toxicity. o During recovery, patients with chronic barbiturate misuse can present with seizures and autonomic instability. Tricyclic antidepressants Tricyclics are rapidly absorbed from the gastrointestinal tract and undergo first pass metabolism. They are highly protein bound, large volume of distribution, resulting in a long half life of elimination that generally exceeds 24 and in the case of amitriptyline is 31 to 46 hours. The ingestion of large quantities of tricyclics in self poisoning causes altered pharmacokinetics. Gastrointestinal absorption may be delayed because of inhibition of gastric emptying and significant enterohepatic recirculation prolongs the final elimination. Toxicity The toxic effects of tricyclics- caused by four main pharmacological properties: 1. Inhibition of norepinephrine reuptake at nerve terminals. 2. Direct alpha adrenergic block. 3. A membrane stabilising or quinidine-like effect on the myocardium 4. Anticholinergic action. Clinical presentation Anticholinergic effects do not cause serious clinical problems. By impairing sweating heat dissipation is reduced and this can result in a fever, especially if seizures occur. Central cholinergic block can also alter thermoregulation. The commonest cardiovascular effect is a sinus tachycardia- inhibition of norepinephrine reuptake. The most important toxic effect of tricyclics is the slowing of depolarisation of the cardiac action potential. Prolongation of the QRS complex and the PR/QT intervals with a predisposition to cardiac arrhythmias. Coma, seizures. Management Gastric lavage- improved clinical outcome. Activated charcoal may reduce the absorption of tricyclics. Sodium bicarbonate in tricyclic poisoning has been shown to have beneficial effects. Antiarrhythmic drugs should be avoided and the correction of hypotension, hypoxia and acidosis will reduce the cardio- toxic effects of tricyclics. Avoid certain drugs that exacerbate the cardiac effects of tricyclics. Class 1a (quinidine, procainamide, disopyramide) and class 1c drugs such as flecainide, prolong depolarisation in a similar way to tricyclics Class 3 drugs (bretylium, amiodarone) also prolong the QT interval and may predispose to arrhythmias. Management Lignocaine (lidocaine) has been reported as being effective in the treatment of frequent ventricular ectopic beats. The use of beta blockers may further reduce myocardial contractility. Magnesium sulphate has been used successfully in an overdose patient with refractory ventricular fibrillation. Hypotension is thought to result from a combination of decreased myocardial contractility and peripheral vasodilatation. Norepinephrine has been found to be more effective than dopamine Seizures are usually self limiting but where treatment is necessary benzodiazepines are the treatment of choice. Neuroleptics The first, chlorpromazine, was developed as a surgical anesthetic. All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of the brain. Excess release of dopamine in the mesolimbic pathway has been to psychotic experiences. Haloperidol and chlorpromazine suppress dopamine. Antipsychotics have numerous side effects such as extrapyramidal symptoms. linkedStructural effects Chronic treatment with antipsychotics affects the brain at a structural level, increasing the volume of the basal ganglia (especially the caudate nucleus), and reducing cortical grey matter volume in different brain areas. Death of neurons in the cerebral cortex, especially in women, has been linked to the use of both typical and atypical antipsychotics for individuals with Alzheimer. Side effects Extrapyramidal reactions include acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, nightmares, hyperprolactinaemia. Antipsychotics, particularly atypicals, appear to cause changes in insulin levels by blocking the muscarinic M3 receptor. Altered insulin levels can lead to diabetes mellitus and fatal diabetic ketoacidosis. Some atypical antipsychotics (especially olanzapine and clozapine) are associated with body weight gain- changes to neurochemical signalling in regions of the brain that regulate appetite. Side effects Clozapine also has a risk of inducing agranulocytosis. Tardive dyskinesia- repetitive, involuntary, purposeless movements. Chlorpromazine and clozapine-relatively high seizurogenic potential. Neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency. Drug-induced Parkinsonism due to dopamine D2 receptor blockade. Sexual dysfunction. Dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements. prolactin in Hyperprolactinaemia. The breasts may enlarge and discharge milk, in both men and women due to abnormally- high levels of the blood. Prolactin secretion in the pituitary is normally suppressed by dopamine. Opioids Opioid overdose occurs when a person has excessive unopposed stimulation of the opiate pathway. Opioids are substances that act on the opiate receptors. Opioids work via the endogenous opioid system by acting as a potent agonist to the mu receptor. Complex cascade of intracellular signals resulting in dopamine release, blockade of pain signals, and a resulting sensation of euphoria. The typical symptoms seen in overdose are pinpoint pupils, respiratory depression, and a decreased level of consciousness. This is known as the “opioid overdose triad.” Opioids may be agonists, partial agonists, or agonist-antagonists of opioid receptors. Mu receptors mediate analgesia, euphoria, sedation, respiratory depression, gastrointestinal dysmotility, and physical dependence. Kappa receptors mediate analgesia, diuresis, miosis, and dysphoria. Delta receptors mediate analgesia, inhibition of dopamine release, and cough suppression. Receptors Sigma receptors are stimulated, the individual will develop hallucinations, dysphoria, and psychosis, whereas the delta receptors will produce analgesia, euphoria, and seizures. receptors are no longer considered opioids because naloxone does not antagonize them. Tolerance occurs rapidly with opioids. SigmaToxicokinetics Opiates can be administered intravenously (IV), topically, inhaled, intramuscularly (IM), and orally. Intravenous administration, the peak effects 5 to 10 minutes; 90 minutes after ingestion; nasal insufflation- 10 to 15 minutes. When administered orally, the majority of opiate absorption occurs in the small intestine. Opiates are broken down by the liver to inactive compounds that are excreted primarily by the kidneys. Highly lipid soluble and tend to redistribute into the fatty tissues and thus, have a prolonged half-life. Evaluation History is usually obtained from family, friends, bystanders, and emergency medical service providers. History are the amount of drug ingested, congestion, and time of ingestion. Opiate overdose will also cause respiratory depression, generalized central nervous system (CNS) depression, and miosis. Examination of the extremities may reveal needle track marks if intravenous opiates are abused. Most opiates are known to cause peripheral vasodilatation, which can result in moderate severe hypotension. Both nausea and vomiting are also seen in patients with opiate toxicity. The reason is that opiates can cause gastric aperistalsis and slow down intestine motility. toManagement If the patient is comatose and in respiratory distress, airway control must be obtained before doing anything else. Endotracheal intubation is highly recommended for all patients who are unable to protect their airways. Naloxone should be administered to reverse the respiratory depression. Naloxone can also cause agitation and aggression when it reverses the opiate- if the individual is a drug abuser, the lowest dose of naloxone to reverse respiratory apnea should be administered. Patient may become combative or violent, and the use of restraints may be an option. ABCDE protocol. Initial treatment of overdose begins with supportive care. Activated charcoal can be used to decontaminate the gastrointestinal tract in patients with opiate overdose. The role of whole bowel irrigation may be considered in people who have ingested drug. packets containing opiate. Naloxone Naloxone is a competitive antagonist of the opiate receptor. It can be administered by intravenous, intramuscular, subcutaneous, or intranasal routes. Whether naloxone is administered via the endotracheal tube or intravenously, the onset of action is within minutes. A second dose can be administered every 2 to 3 minutes. Besides naloxone, a new agent on the market to reverse opiate toxicity is Nalmefene. Nalmefene has a half-life of 4 to 8 hours. Antidiabetic drugs The sulfonylureas remain one of the mainstays in the management of type 2 diabetes. The primary pharmacologic effect of the sulfonylureas is a hyperinsulinemic state. Major clinical effects of overdose secondary to the subsequent hypoglycemia. Bind to the sulfonylurea receptor on the β-cells of the pancreatic islets- reduce conductance through the adenosine 5′-triphosphate. Overdose 2 key pharmacologic factors- onset of action and duration of action. Peak plasma concentrations of all the sulfonylureas occur within one to eight hours. The onset of hypoglycemia after acute overdose- occurs in less than eight hours. Risk factors for sulfonylurea-induced hypoglycemia include advanced age (over 65 years), inadequate caloric intake, concomitant drug use (e.g., β-blockers, insulin), recent initiation of sulfonylurea therapy. Overdose patient may prolong the duration of effect, but the onset will remain the same.Clinical findings Hypoglycemic state. Clinical response occurs for primarily two reasons: neuroglycopenic effects and counterregulatory hormonal response. Neurologic effects- direct reduction of intracellular ATP. Diaphoresis and tachycardia, occur as a result of the release of the counterregulatory hormones epinephrine, norepinephrine, cortisol, and growth hormone. The goal of sulfonylurea overdose management is the return of euglycemia. Activated charcoal is expected to bind the sulfonylureas to prevent. Absorption. Management I.v. dextrose should only be initiated if the patient becomes symptomatic or there is a measured blood glucose concentration below 60 mg/dL. Asymptomatic after eight hours- discharged. Octreotide is a synthetic somatostatin analogue, which binds the somatostatin subtype-2 receptor in the pancreatic β-cells. Several authors have argued that octreotide should be considered as first-line therapy in known sulfonylurea overdoses. Hypoglycemics- meglitinides Increase release of insulin from the β-cells in the pancreas. Short duration of action. Peak serum repaglinide and nateglinide concentrations occur in 30 minutes to one hour. Onset of hypoglycemia after acute overdose of the meglitinides occurs in less than two hours. Highly protein bound (>98%) and extensively metabolized in the liverprimarily by cytochrome P-450. The acute clinical effects from repaglinide and nateglinide overdose are similar to those of the sulfonylureas. Metformin (biguanides) Delayed glucose absorption, increased intestinal glucose utilization, increased intestinal lactate production, inhibition of hepatic gluconeogenesis, decreased lipid oxidation, decreased free fatty acid concentration, and increased peripheral insulin- related glucose uptake. Oral bio- availability is 40–60%. 90% of the absorbed metformin is eliminated through the kidneys within the first 24 hours. The major risk associated with metformin is that of metformin- associated lactic acidosis (MALA). Metformin overdose Metformin, which accumulates in much higher concentrations in the intestines- doubles the production of lactate in the intestines. Decreases the pH of the liver, causing a decrease in lactate metabolism due to suppression of pyruvate carboxylase. Accumulation due to renal failure. Promote increased nonoxidative metabolism- muscles. The primary risk factor for MALA is renal impairment. Metformin overdose- abdominal pain, vomiting, and diarrhea. Altered mental status, agitation, confusion, lethargy, and coma, may occur. Mild hypoglycemia has been reported. Management of metformin overdose Primarily supportive, with efforts to restore normal acid–base status, removal of the absorbed metformin, and support of cardiovascular function. No specific antidote. Activated charcoal is expected to absorb metformin. Initial correction of acidosis with infusions of sodium bicarbonate. Hemodialysis with a bicarbonate- buffered solution is recommended in severe cases of MALA. Iron intoxication Ingestion of less than 20 mg/kg of elemental iron is non-toxic. Ingestion of 20 mg/kg to 60 mg/kg results in moderate symptoms. Ingestion of more than 60 mg/kg can result in severe toxicity and lead to severe morbidity and mortality. Iron toxicity is classified as corrosive or cellular. Direct caustic injury to the gastrointestinal mucosa, resulting in nausea, vomiting, abdominal pain, and diarrhea. Significant fluid and blood loss can lead to hypovolemia. Hemorrhagic necrosis of gastrointestinal mucosa can lead to hematemesis, perforation, and peritonitis. Iron impairs cellular metabolism. Free iron enters cells and concentrates in the mitochondria. This disrupts oxidative phosphorylation, catalyzes lipid peroxidation, forms free radicals, and ultimately leads to cell death.Toxicokinetics Serum iron level peaks at 2 to 4 hours post-ingestion. Approximately 10% of ingested iron is absorbed from the intestine and is subsequently bound to transferrin. Excess iron will circulate in the blood as free iron, which is directly toxic to target organs. Management Patients who remain asymptomatic 4 to 6 hours after ingestion or those who have not ingested a potentially toxic amount do not require any treatment for iron toxicity. Patients who have GI symptoms that resolve after a short period of time and have normal vital signs require supportive care and an observation period, as it may represent the second stage of iron toxicity. Patients who are symptomatic or demonstrate signs of hemodynamic instability require aggressive management and admission to an intensive care unit Management 1.IV crystalloid infusion is administered to correct hypovolemia and hypoperfusion. 2.Deferoxamine, a chelating agent that can remove iron from tissues and free iron from plasma, is indicated in patients with systemic toxicity, metabolic acidosis, worsening symptoms, or a serum iron level predictive of moderate or severe toxicity. It is administered as a continuous infusion at 15 mg/kg/hr for up to 24 hours with a maximum dose of 35 mg/kg/hr if there is no rate-related hypotension. The maximum daily dose is 6 g. Clinical recovery guides the termination of deferoxamine therapy but the duration of therapy is typically 24 hours. 3.Whole-bowel irrigation with polyethylene glycol solution may clear the GI tract of iron pills before absorption and should be administered at 250 to 500 mL/h in children and 1.5 to 2 L/h in adults via nasogastric tube. 4.Coagulopathy can be corrected with vitamin K (5 to 10 mg subcutaneously) and fresh frozen plasma (10 to 25 mL/kg in adults; 10 mL/kg in children). 5.Gastric lavage with a large-bore orogastric tube is only indicated if abdominal x-ray demonstrates a large number of visible pills in the stomach. For most cases, the risks of gastric lavage outweigh the benefits. 6.Activated charcoal binds iron poorly and is not effective.Oral anticoagulants Warfarine- antidote Vitamin K1, Prothrombin complex concentrate (PCC). Heparin- antidote- protamine sulphate. Pradaxa (dabigatran) - antidote Praxbind (idarucizumab) Beta-blockers Beta-blockers antagonize beta-adrenergic receptors. Management of anxiety, migraine headache, glaucoma, tremor, hyperthyroidism, and various other disorders. Classified as selective and non-selective depending on the receptor specificity. Specificity is lost in cases involving overdose. Highly lipophilic beta-blockers can easily cross the blood-brain barrier and may cause various central nervous system (CNS) manifestations. Water-soluble beta-blockers, for example, atenolol, may also cause tiredness and fatigue. Propranolol, the most lipophilic beta-blocker, can easily cross the lipid cell and blood-brain barrier and may cause seizures in overdose cases. The liver excretes beta-blockers most frequently. Atenolol, carteolol, and nadolol are the only exceptions that undergo renal excretion. Co-ingestion involving calcium channel blockers (CCB) may cause profound hypotension and cardiotoxicity.Clinical aspects Bradycardia associated with hypotension may be the first clue to diagnose beta-blocker overdose. Hypoglycemia and altered mental status. The QTc prolongation secondary to sotalol may prolong up to three to four days and may warrant close observation in a unit setting. Vital signs should be monitored, continuously and 12 lead EKG should be done at frequent intervals. Management Certain beta-blockers may cause CNS depression. Prompt management of the airway is, therefore crucial. Premedication with atropine may be necessary especially in children since laryngeal manipulation during intubation may cause additive vagal stimulation and bradycardia. Bronchospasm due to beta-blockade may be treated with supplemental oxygen and inhaled bronchodilators like albuterol. Gastrointestinal decontamination with gastric lavage may be necessary. Administer activated charcoal- limit drug absorption. Consider whole bowel irrigation with polyethylene glycol sustained-release preparation. Benzodiazepines are the first line of treatment for seizures that may occur due to the high lipophilicity of certain beta-blockers. Sodium bicarbonate for QRS widening and magnesium sulphate for QTc prolongation. Glucagon is considered as a useful treatment of choice- antidote. Possible side effects of glucagon include hypocalcemia and hyperglycemia. Management Treatment with calcium salts- for hypotensive patients who overdosed on beta-blockers alone or in combination with a calcium channel blocker. Cases refractory to fluids, atropine, and glucagon should be considered candidates for high-dose insulin euglycemia (HIE) treatment- augment cardiac contractility. Calcium blockers Calcium channel blockers in all their subtypes target the L-type voltage-gated calcium channels. Contraction strength is directly proportional to intracellular calcium concentration, allowing actin and myosin to interact. Extensive hepatic first-pass metabolism. Are lipophilic. Bind to plasma proteins. Have a large volume of distribution ( > 2 liters/kg). Elimination by hemodialysis or hemofiltration is ineffective. At higher doses clearance slows, because hepatic clearance changes from first-order to zero-order kinetics. Calcium blockers Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Dihydropyridines (nifedipine, amlodipine, isradipine, nicardipine, nimodipine). Verapamil has a strong affinity for both myocardium and vascular smooth muscle. It suppresses cardiac contractility, SA nodal automaticity, AV nodal conduction and causes potent vasodilation. Diltiazem has a similar range of effects as verapamil with less vasodilation; its effect is more potent on chronotropic action. Clinical aspects Hypotension and bradycardia, when progressive, can lead to cardiogenic shock. Hyperglycemia is common with all subclasses of CCBs. Metabolic acidosis. Mild hypokalemia and mild to severe hypocalcemia. Seizures, myocardial infarction, acute respiratory distress syndrome (ARDS), renal failure, bowel infarction and ischemia, and stroke. Management Consider endotracheal intubation in patients with worsening signs and symptoms of toxicity due to the risk of rapid hemodynamic deterioration. Atropine is mostly ineffective in severe CCB toxicity. Use intravenous crystalloids during initial resuscitation while remaining cognizant of the risk of fluid overload with drug-induced inotropic failure. Conventional decontamination measures like urinary alkalinization, hemodialysis, or hemofiltration are ineffective in CCB toxicity. Calcium may improve hypotension and conduction disturbances but is less effective in the management of bradycardia. Hyperinsulinemic euglycemia (HIE)- improvement in cardiac function and survival rate. Methylene can counteract post coronary artery bypass vasoplegia- inhibiting guanylate cyclase. Lipid emulsion infusion can sequester intensely lipophilic drugs like verapamil and diltiazem and thus reduce their volume of distribution. Management Glucagon secreted from alpha cells of the pancreas act through activation of adenylate cyclase via G proteins resulting in a positive chronotropic and inotropic effect. Improvement in heart rate, cardiac output, and reversal of AV blocks in animal models of CCB overdose using glucagon. Refractory hypotension and shock may result- catecholamine infusion may become necessary. Phosphodiesterase inhibitors like milrinone may provide inotropic support. Levosimendan is an inotropic agent that enhances myofilament response to calcium and increases myocardial contraction. Antihypertensive Antihypertensive overdose can lead to shock refractory to catecholamine and vasopressin therapy. In overdose, antihypertensives can be both vasodilatory and cardiotoxic. Intravenous AG II has been used successfully to treat shock. AG II is an octapeptide with a half-life of seconds to minutes in vivo. Effect- increase aldosterone secretion. AG II raises blood pressure by multiple additional mechanisms, including antidiuretic hormone secretion, vasoconstriction via a G-protein coupled receptor, and enhanced catecholamine release. Digoxin Digoxin is a cardiac glycoside derived from the foxglove plant (digitalis species). Digoxin toxicity can present acutely after an overdose or chronically, as is often seen in patients on digoxin that develop acute kidney injury. Increased intracellular calcium from the poisoning of the Na-K transporter and AV nodal blockade from increased vagal tone are the primary causes of digoxin toxicity. Digoxin's therapeutic half-life is between 30 to 40 hours. Digoxin excretion is primarily renal. Cardiovascular toxicity may have delayed manifestation of up to 8 to 12 hours ingestion. post-Toxicity and treatment Gastrointestinal upset is the most common symptom of digoxin toxicity. Visual symptoms, which classically present as a yellow-green discoloration. Cardiovascular symptoms- palpitations, dyspnea, and syncope. It is critical to obtain an ECG, a basic metabolic panel, and digoxin levels on arrival. These tests should be repeated at 6 hours post-ingestion. ”Pathognomonic" ECG finding is bidirectional ventricular tachycardia. Digoxin-specific antibody antigen-binding fragments (DSFab) are an effective antidote directly binds digoxin. thatDSFab DSFab is indicated for life-threatening toxicity, including: Ventricular arrhythmias. High-grade heart blocks. Hypotension. Symptomatic bradycardia. Potassium greater than five meq/L in acute overdose.  Acute ingestions greater than 10 mg in an adult or greater than 4 mg in a child. Digoxin Concentration greater than 15 ng/mL measured at any time. Digoxin Concentration greater than 10 ng/mL measured 6 hours post-ingestion. If DSFab is not available, then treatments such as multidose-activated charcoal, atropine, and antidysrhythmics such as phenytoin or lidocaine may be employed. Cardioversion and pacing may induce dysrhythmias and are typically not used. Dialysis also may be indicated in patients with acute renal failure or refractory hyperkalemia; however, it is not useful as a treatment for digoxin toxicity itself.