Antidotes | What is the Antidote | Drugs Overdose Treatment

ANTIDOTE TREATMENT AND DRUG THERAPY

 

01. Antidote of ANTICOAGULANTS

Heparin/Low-Molecular-Weight Heparin (LMWH)

I. Antidote For Heparin

PROTAMINE SULPHATE
Generally, Heparin has a half-life of almost 1-1.5 hours only. While Heparin Metabolism occurs in the Liver primarily. But if we talk about new Low molecular weight heparins like Enoxaparin, Dalteparin, Tinzaparin, these agents have a longer half-life as compared to Heparin.
Treatment:
If bleeding or bruising occurs with Heparin then stop administration of heparin for a few hours and then restart therapy with a reduced dose. In this way, we are able to reverse the over-anticoagulation effect if a mild overdose occurs. If a severe overdose occurs then we have to administer PROTAMINE to neutralize the effect of heparin by combining it with heparin.

Note: 1mg Protamine Neutralize 100U Heparin.

Mechanism of Action of Protamine Sulphate:
Protamine is a strong basic protein while Heparin is a strong acid. when protamine binds with heparin, they both form a complex and inactive complex. This stable complex leads to neutralizing the effect of Heparin.

II. Warfarin

The antidote of Warfarin:

Vitamin K (Phylloquinone)

Warfarin
It is an anticoagulant agent with a half-life of 35 Hours and strong protein binding of 99% while the duration of activity is 5 days. Chek instantly, Prothrombin Time (PT), and International normalized ratio and bleeding time after use of Warfarin. If PT and INR are slightly increased then stop the warfarin for 24 to 48 hours, after some time you can restart therapy by using a low dosage of warfarin. If PT & INR is elevated and bleeding observed then administer  Vitamin K as an antidote to stop the bleeding caused by Warfarin.
Vitamin K is a fat-soluble vitamin used as a blood-clotting agent.
1.    Vitamin K1 (Phytonadione)
2.    Vitamin K2 (Minaquinone)

02. The antidote of Tricyclic antidepressants (TCAs)

(Amitriptyline, Nortriptyline, Imipramine, Doxepin, Clomipramine)

Antidote: 

Sodium Bicarbonate

Mechanism of Action of Sodium Bicarbonate:

1.  Sodium carbonate for alkalinization to maintain an arterial PH of 7.47 to 7.55. Also, sodium carbonate can reverse cardiac abnormalities. Sodium Carbonate increases the PH of Blood and urine. it also regulates the acid-base balance and acts as a buffer. Sodium bicarbonate is also used as an Antacid for the treatment of Heartburn and indigestion.
2.   Phenytoin or benzodiazepines are required to stop the seizures but Phenytoin causes hypotensive side effects so we can use Fosphenytoin as an alternative drug to phenytoin because it has lower side effects of hypotension than phenytoin.
3.  Physostigmine is also used to reverse anticholinergic toxicity but because this drug caused asystole, its use for TCA toxicity is declining.

03. The antidote for Alcohol Poisoning

I. Ethylene glycol Antidote:

Ethylene Glycol Uses: 

Ethylene glycol MOA:

Metabolism of ethylene glycol in the liver is occurred by Alcohol dehydrogenase to Glycoaldehyde. Then this Glycoaldehyde is metabolized to Glycolic acid by Aldehyde dehydrogenase. Then the conversion of glycolic acid to the glyoxylic acid form occurred. Glyoxylic acid has a metabolite that is most toxic called Oxalic acid.

Mechanism of Action Of Fomepizole:

Fomepizole act by inhibiting the Alcohol dehydrogenase thus preventing the composition of methanol and ethylene glycol metabolites which are toxic.
In the case of Methanol Toxicity,
 Methanol is Converted into Formaldehyde with the help of Alcohol dehydrogenase. Formaldehyde is then converted to formic acid. Fomepizole inhibits alcohol dehydrogenase.

 4. The antidote of Calcium channel antagonists

Antidote:

Calcium chloride

Others Antidotes for CCBs:

Glucagon

Combine insulin and dextrose

Phosphodiesterase inhibitors: Inamrinone or milrinone (Inotropic effect)

Mechanism Of Action of Calcium Chloride:

Calcium chloride is used for hypocalcemia. It is used to increase intracellular calcium levels. Calcium chloride dissociates in the water in the form of Calcium and Chloride ions. Calcium levels lowered by the toxicity of Calcium channel blockers are maintained by giving Calcium chloride to increase the level of intracellular calcium which leads to an increase in heart rate. Calcium chloride is also used in hyperkalemic situations.

5. Beta receptor blockers (Adrenergic antagonists)

Antidote For Beta-Blockers: 

Glucagon

Others Antidote:

Epinephrine

Calcium salts

High dose Insulin dextrose

Mechanism Of Action of Glucagon:

Glucagon is released by Alpha-2 islets of Langerhans cells of the pancreas. Glucagon activates Gs-protein coupled receptors which stimulate adenylyl cyclase activation leading to cAMP production in Cardiac Muscles. cAMP (2nd Messenger) which is responsible for regulating Protein phosphorylation as well as Phospholipase C. This Phospholipase C is responsible for the activation of other 2nd messengers named as Inositol-1,4,5-Triphosphate and diacylglycerol. They are responsible for intracellular free calcium concentrations. Heart contraction is regulated by this free Calcium. In this way, Glucagon causes a positive Inotropic effect.

 

6. Benzodiazepines Antidote

(Chlordiazepoxide, Diazepam, Alprazolam, Triazolam)

1.    Antidote: 

• Flumazenil

2.    Activated Charcoal

Mechanism of Action of Flumazenil: 

Flumazenil is an imidazobenzodiazepine derivative. Flumazenil acts by inhibiting the binding of Benzodiazepines at the site of GABA receptors thus leading to antagonizing the effect of Benzodiazepines.

7. The antidote of Selective serotonin reuptake inhibitors

(Non-Tricyclic agents)

(Fluoxetine, Sertraline, Paroxetine)

1.    Adsorbent Antidote: Active Charcoal

2.    Serotonin Antagonist:

• Cyproheptadine

3.    Gastric lavage

4.    Supportive treatment

Mechanism of action of Cyproheptadine:

Cyproheptadine is an antihistamine that belongs to the piperidine group. It acts by competing for free histamine to bind with HA receptor sites. This results in a reduction of histamine's negative effects on the body. This antihistaminic drug Also antagonizes the serotonin receptors. Antagonizing serotonin at the hypothalamus on the appetite sites leads to stimulation of appetite. Cyproheptadine is a 1^st generation antihistamine drug for the treatment of allergic reactions.

SSRIs have a half-life of 8-30 hours.

8. Acetaminophen

Introduction
Acetaminophen has antipyretic and analgesic properties because it inhibits prostaglandin synthesis in the CNS leading to a decrease in body temperature. Acetaminophen lacks the property of anti-inflammatory or has a very less effect. Acetaminophen is an alternative therapy to aspirin. The patients who do not need anti-inflammatory effects acetaminophen is a perfect choice. It does not have antiplatelet activity so it's a good choice in patients who do not need prolongation of bleeding time.
Clinical Presentation
There are  3 phases of clinical presentation after acetaminophen toxicity.
1. Phase I ( 12 to 24 hours post-ingestion)

• Nausea, Vomiting, anorexia, diaphoresis

• Asymptomatic

• Nausea, abdominal pain, progressive evidence of hepatic failure, coma, and death

The antidote to Acetaminophen

N-Acetyl Cysteine

Acetaminophen Half-Life:
Acetaminophen has a half-life of 2-3 Hours and is well absorbed from the GIT.
Causes: 
Liver Failure, Coma, Diaphoresis

Acetaminophen USES:
Acetaminophen is an antipyretic and analgesic agent. Acetaminophen produces dangerous liver toxicity because of toxic metabolites.
NAC is an antioxidant. It’s a prodrug to L-cysteine. NAC provides cysteine for Glutathione synthesis. This glutathione reacts with N-Acetyl-P-Benzoquinone imine to protect tissues. NAPQI is a byproduct that is produced during the metabolism of Acetaminophen. Normally, When a drug is taken this NAPQI is Produced in small amounts. Then soon after its production quickly detoxified the Liver. But when acetaminophen is taken in large quantities or used excessively, then the reserved glutathione is not enough to deactivate this N-Acetyl-P-Benzoquinone imine. Thus the presence of NAPQI in large quantities reacts with the tissues of the liver and causes damage to the liver. This NAC maintains the quantity of glutathione in the body.
Adverse effects
With normal dose, 

1. Skin Rash

1. Minor allergic reaction

1. Minor alteration in leukocyte count

1. Hepatic necrosis

1. Renal Tubular necrosis

2. Phase II ( 1 to 4 days post-ingestion)

3. Phase III ( 2 to 3 days in untreated patients)

With a large dose,