Additional information

Bioavailability of different routes of drug administration

First pass metabolism is avoided in all except orally administered drugs.

Succinylcholine

It is metabolised by the enzyme cholinesterase or pseudocholinesterase in plasma to inactive forms. Inherited differences in the enzyme may slow down the breakdown of succinylcholine resulting in prolonged neuromuscular paralysis in some patients. Involved gene is located on chromosome 3 on gene E1. Most common mutation is a substitution of aspartic acid to glycine which reduces the binding of enzyme to succinylcholine. Slow and fast acetylators: Drugs like isoniazid, dapsone, hydralazine, sulfa drugs and procainamide are metabolized by acetylation reactions catalysed by enzyme acetyltransferases. Gene is NAT2. Rate of acetylation is determined by ethnicity due to polymorphisms in the enzyme. 50% of Caucasians and African Americans are slow acetylators while most Asians are fast acetylators. Slow acetylators are at risk of adverse effects while rapid acetylators are at risk of low blood levels leading to decreased response to drug therapy.

Acetaminophen toxicity

It is a common cause of liver transplantation. Large doses of acetaminophen, especially in people suffering from chronic liver disorders and in alcoholics, saturates the usual hepatic detoxification mechanisms, leading to excessive formation of a toxic metabolite called NAPQI or N-acetyl-p-benzoquinone imine. Normally, NAPQI is detoxified by glutathione. In acetaminophen overdose, glutathione stores are depleted which causes NAPQI to bind to hepatocytes causing necrosis. Chronic alcoholism induces hepatic microsomal enzymes resulting in increased formation of NAPQI. Alcohol also causes glutathione depletion. Patients may be asymptomatic up to 24 hours, presenting later on with vomiting, RUQ pain, hypotension, liver failure, renal failure, coagulopathies, metabolic acidosis and encephalopathy. Microscopically, the liver shows centrilobular necrosis. Treatment is guided by time since ingestion. Within 1 hour of ingestion, activated charcoal can be used. Blood levels of acetaminophen are measured. Definitive treatment is with N-acetyl cysteine which provides sulfhydryl groups that attach to NAPQI, hence preventing hepatic necrosis. It also reduces NAPQI to acetaminophen, acts as a precursor to glutathione, has antioxidant and anti-inflammatory properties, increases sulphate conjugation, increases local nitric oxide and oxygen delivery. Severe cases may also need hemodialysis and liver transplantation.

Effect of ageing on drugs

• Decreased hepatic and renal clearance
• Increase in Vd of lipid soluble drugs*
• Decrease in Vd of water soluble drugs**
• Increased elimination half life
• Decrease in first pass metabolism
• Effects of drugs like verapamil, warfarin,morphine, diazepam are increased
• Effects of drugs like furosemide, propranolol are decreased
• Increased adverse effects of neuroleptics like delirium, arrhythmias, extrapyramidal symptoms and postural hypotension

* Includes digoxin, ethanol, theophylline, cimetidine, gentamicin. Reduce loading dose.

** Includes diazepam, lidocaine, thiopental. Increase in half life.

Types of chemotherapy

Vinca alkaloids cause microtubule depolymerization by binding to beta tubulin resulting in apoptosis Paclitaxel binds to beta tubulin and enhances microtubule assembly, polymerization and bundling Vinca destabilizes while paclitaxel stabilizes the microtubule

Tachyphylaxis

Some drugs become less efficacious or lose their effects as they are continued over a period of time. It is a type of tolerance or desensitization. Mechanisms include depletion of chemicals needed for pharmacological action like neurotransmitters, changes in receptor state like phosphorylation or in receptor numbers like downregulation. Sometimes counterregulatory physiological changes may offset the action of the drug. It is seen with nitroglycerin, topical corticosteroids, local anesthetics, nicotine etc. Temporary withholding the drug or giving drug free hours can restore sensitivity.

####Metronidazole It is commonly used to treat anaerobic and protozoal infections. Metronidazole is metabolized to nitro free radicals which cause DNA damage and inhibition of protein synthesis. It is effective against E.histolytica, Trichomonas, Giardia lamblia, Bacteroides sp, Clostridium sp, Fusobacterium sp, Gardnerella vaginalis, H.pylori etc. Adverse effects include nausea, metallic taste, headache, diarrhea, pruritus, peripheral neuropathy, seizures and probable carcinogenicity. It has an antabuse like reaction if alcohol is consumed concurrently

Warfarin induced skin necrosis

It typically occurs 2-5 days after the initiation of warfarin therapy. It occurs due to depletion of vit K dependent anticoagulants proteins C and S. It is seen due to thrombosis in blood vessels of the skin especially in areas of fat abundance and presents with pain, purplish rash, blistering , blue toe syndrome and skin necrosis in the breast, thighs, buttocks and abdomen. Management is by stopping warfarin, vit K, heparin and protein C concentrates.

Heparin induced thrombocytopenia

• Can be immune or non-immune
• Thrombocytopenia plus increased thrombosis in a patient on heparin therapy, more severe in immune type
• More common with UFH, but also seen with LMWH
• Due to antibodies to complex of heparin and platelet factor 4, which leads to platelet lysis
• Platelet lysis causes clotting leading to DVT, PE, AMI, stroke, black toes, bruising, etc.
• Typically occurs 1-2 weeks after initiation of heparin therapy
• Laboratory findings are decreased platelet count and increased platelet factor 4 antibody
• Treat by stopping heparin, anticoagulation with alternate agents like direct thrombin inhibitors, fondaparinux and/or warfarin
• Platelet transfusion is contraindicated due to increased risk of thrombosis!

Cephalosporin generations

Types of beta lactamases

• Class A: Penicillinases, susceptible to clavulanic acid, sulbactam and tazobactam. TEM1, SHV1 in Enterobacteria; ESBL or extended spectrum beta lactamases confer resistance to penicillins, third generation cephalosporins, aztreonam but are sensitive to carbapenems and cephamycins like cefoxitin and cefotetan
• Class B: Metallo-beta-lactamases, need metal ions like zinc for activity, not inhibited by clavulanic acid, sulbactam; resistant to carbapenems and aztreonam. They may be sensitive to colistin
• Class C: Cephalosporinases, Amp C, resistant to clavulanic acid and all beta lactams except carbapenems
• Class D: Oxacillin hydrolyzing enzymes, resistant to oxacillin, penicillin, cloxacillin, methicillin, weakly inhibited by clavulanic acid

Penicillin types

Colchicine

It binds to tubulin and blocks the assembly and polymerisation of microtubules. Colchicine also inhibits neutrophil chemotaxis and the release of a crystal-derived chemotactic factor (CCF) from neutrophil lysosomes, superoxide formation and phagocytosis.** **It is used in the treatment of acute gout, familial meditteranean fever, Behcet’s disease and inflammatory disorders. Adverse effects include diarrhea, nausea, vomiting, neutropenia, neuropathy and organ failure. Doses should be decreased in renal and/or hepatic failure. Colchicine has a narrow therapeutic index. Rhabdomyolysis can occur when given along with statins. Dose should be reduced when cyt P450 inhibitors are co-prescribed.

Ultra fast acting insulin or Fiasp

It is a recently FDA approved form of insulin aspart that is designed to speed up the absorption of subcutaneous insulin by adding vitamin B3 or niacin and L-arginine. It is used in type 1 and 2 DM and can be injected up to 20 minutes after starting a meal. Onset of action is within 15-20 minutes and duration of action is 7 hours.

Commonly used antidotes

Comparison between proton pump inhibitors and H2 blockers

PPIs (omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole)

• Bind to and inhibit H+/K+ ATPase or proton pump located in the parietal cells
• Used to treat GERD, peptic ulcers, H.pylori gastritis, prevention of stress ulcers and NSAID induced gastritis
• Adverse effects include nausea, headache, diarrhea, vomiting, hypergastrinemia, pneumonia, fractures, hypomagnesemia, Vit B12 deficiency, Cl.difficile colitis, acute interstitial nephritis, SLE
• Interfere with the absorption of ketoconazole, itraconazole, isoniazid, oral iron supplements, protease inhibitors
• Inhibit CYP2C19 and may decrease the hepatic activation of clopidogrel and reduce it’s antiplatelet activity
• Bind to and inhibit histamine H2 receptors on the basolateral surface of gastric parietal cells thereby decreasing acid production and secretion
• Used to treat GERD, duodenal and peptic ulcers and prevention of stress ulcers
• Less potent than PPIs
• Adverse effects include diarrhea, constipation, fatigue, drowsiness, headache, muscle aches, prolongation of QTc in renal failure (famotidine), rarely liver failure and CNS effects
• Cimetidine is a potent inhibitor of cyt P450 and should be avoided with warfarin, theophylline and SSRIs
• Cimetidine may cause galactorrhea, gynecomastia, impotence and reduced sperm count

Treatment options for resistant bacteria