Metformin belongs to the Biguanide class of medications used to treat Type 2 Diabetes. Metformin works by decreasing the amount of glucose produced by the liver, improving insulin sensitivity, and by increasing cellular uptake of glucose.

In patients who develop acute or chronic renal failure, the clearance of metformin is decreased resulting in an increased risk of lactic acidosis, which may have a mortality rate up to 50%. Patients who receive IV contrast fluid are at risk for contrast-induced nephropathy and if they are concurrently on metformin, they may experience potentially fatal lactic acidosis. To avoid this issue, most patients scheduled to receive IV contrast have their metformin medication stopped at the time of contrast administration for at least 48 hours after the procedure.

In some patients who have preserved renal function and are receiving small amounts of contrast (< 100 mL), stopping the metformin may not be necessary because the risk of contrast-induced nephropathy is very low in these patients.

1. Baerlocher, M. O., Asch, M., & Myers, A. (2012). Metformin and intravenous contrast. Canadian Medical Association Journal, 185(1). doi:10.1503/cmaj.090550
2. Benko AFraser-Hill MMagner Pet al.Canadian Association of Radiologists.Canadian Association of Radiologists: consensus guidelines for the prevention of contrast-induced nephropathyCan Assoc Radiol J 2007;58:7987.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic that acts in the distal convoluted tubule of the kidney on the Na/Cl- symporter to reduce blood pressure/ volume. However, like any medication it comes with side effects. A common mnemonic used to remember these effects is HyperGLUC

HYPERglycemia (It occurs at higher doses of HCTZ (> 50 mg/d); Thiazides have a weak, dose-dependent, effect to stimulate ATP-sensitive K+ channels and cause hyperpolarization of beta cells, thereby inhibiting insulin release)

HYPERlipidemia (cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs))

HYPERuricemia (may precipitate acute gouty arthritis)

HYPERcalcemia (increased renal calcium resorption and decrease calcium in urine)

NOTE: It can have HYPO effects in serum: including HYPOkalemia, HYPOnatremia and HYPOtension (decreases blood volume and peripheral vascular resistance)


  1. CHAPTER 15: Diuretic Agents. Ramin Sam; David Pearce; Harlan E. Ives. Basic & Clinical Pharmacology, 13e

Avascular necrosis of the femoral head (ANFH) occurs when the blood supply to the femoral head is interrupted resulting in ischemia, death of the bone cells, and bone collapse.

Non-traumatic ANFH is a serious and common problem that can occur when patients are on glucocorticoid (GC) therapy; between 5-40% of patients treated with long-term glucocorticoid therapy will develop ANFH.

Although, the exact and complete mechanism of ANFH due to GC therapy is still under determination, a few mechanisms have been proposed.

1. Hypercoagulable Conditions 

It is thought that GCs can alter endothelial function by modulation of the Alpha-2-

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Macroglobulin (A2M)* gene and also by exerting effects on thrombosis formation. It is believed that through A2M and thromobosis formation alterations, GCs cause ischemia which ultimately results in ANFH.

A2M: a protein that plays a role in thrombosis by influencing inflammation, cell shedding, inhibiting fibrinolysis, and hemostatic plug formation.


2. Angiogenesis Suppression

It is hypothesized that angiogenesis is interrupted in patients with ANFH, however, the complete mechanism is not well understood.

Studies have shown that there is a relationship between ANFH and expression of VEGF. VEGF plays a key role in stimulating angiogenesis, but is also important in bone formation and repair. It has also been shown that when bone tissue undergoes VEGF gene transfection, the processes of angiogenesis and bone repair in necrotic bone are stimulated. These studies suggest that there is a correlation between use of GCs and angiogenesis suppression, however it remains to be more completely elucidated.


3. Increased Adipogenesis 

Although, the link between increased adipogenesis and long-term use of GCs is not completely understood, studies have shown the presence of an association.

Kim et al. (2008) looked at the association between sterol regulatory element binding factor (SREBP-2) gene polymorphisms and the risk of ANFH in the Korean population. SREBPs play a role lipogenesis, cholesterol homeostasis, and adipocyte development. In 2009, a study by Lee et al. showed that a polymorphism in intron 7 of the SREBP-1 gene was associated with increased likelihood of ANFH. Although, the relationship is still unclear, these studies do suggest the possibility of alterations in adipogenesis by GC therapy.


4. Bone Remodelling Shifting to Bone Resorption 

Bone morphogenetic proteins (BMPs) are proteins that are important in maintaining bone density through remodelling and repair processes. BMPs act as signals, or differentiating factors, which help convert mesenchymal cells into cells involved in forming bone and cartilage. Studies have shown that transfecting bone marrow stem cells with the human BMP-2 gene can repair early-stage ANFH. The results of these studies suggest that in ANFH, bone remodelling and repair may be altered by the use of GCs.

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  1. Pouya, Farzaneh, and Mohammed Amin Kerachian. “Avascular Necrosis of the Femoral Head: Are Any Genes Involved?” The Archives of Bone and Joint Surgery 3.3 (2015): 149-55.
  2. Chim SM, Tickner J, Chow ST, Kuek V, Guo B, Zhang G, et al. Angiogenic factors in bone local environment. Cytokine Growth Factor Rev. 2013;24(3):297–310.
  3. Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest. 2002;110(6):751–9.
  4. Samara S, Dailiana Z, Varitimidis S, Chassanidis C, Koromila T, Malizos KN, et al. Bone morphogenetic proteins (BMPs) expression in the femoral heads of patients with avascular necrosis. Mol Biol Rep. 2013;40(7):4465–72.
  5. Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine. 2012;41(2):183–90.
  6. Kim TH, Baek JI, Hong JM, Choi SJ, Lee HJ, Cho HJ, et al. Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population. BMC Med Genet. 2008;9:94.
  7. Lee HJ, Choi SJ, Hong JM, Lee WK, Baek JI, Kim SY, et al. Association of a polymorphism in the intron 7 of the SREBF1 gene with osteonecrosis of the femoral head in Koreans. Ann Hum Genet. 2009;73(1):34–41.
  8. Cao K, Huang W, An H, Jiang DM, Shu Y, Han ZM. Deproteinized bone with VEGF gene transfer to facilitate the repair of early avascular necrosis of femoral head of rabbit. Chin J Traumatol. 2009;12(5):269–74.

Iron poisoning is often listed in the classic metabolic acidosis mnemonic MUDPILES, but how does it cause an anion gap metabolic acidosis?

HOW? The mechanism appears to be multi-factorial.

  1. Acute excessive ingestion of iron causes direct corrosive damage to the GI tract.
  2. Free iron penetrates numerous organs such as the liver. It enters hepatocytes, damaging the mitochondria (disrupts oxidative phosphorylation) and increases lipid peroxidation. It also damages microsomes, and other cellular organelles.
  3. Excessive iron can affect the heart: resulting in fatty necrosis of the myocardium, increased capillary permeability, and a reduction in cardiac output.
  4. Free iron also stimulates the release of pro-dilatory agents such as serotonin and histamine resulting in hypo perfusion, anaerobic metabolism and lactic acidosis.
  5. In addition ferrous iron is converted to ferric iron; hydrogen ions are released, adding to the metabolic acidosis.

The profound damage to the liver results in: hypoglycemia, hyperammonemia, coagulation defects,

and hepatic encephalopathy occurs in the context of fulminant liver failure.
  1. Goyer RA. Toxic effects of metals. Klaassen CD, ed. Casarett & Doull’s toxicology:the basic science of poisons. 5th ed. New YorkCity, NY: McGraw-Hill, 1996;715-716.
  2. Williams RJ. Biomineralization: iron and the origins of life. Nature 1990;343:213-214.4.
  3. Osweiler GD, Carson TL, Buck WB, et al. Iron. Clinical and diagnostic veterinary toxicology. 3rd ed. Dubuque, Iowa: Kendall/Hunt Publishing Co, 1985;104-106.5.
  4. Hillman RS. Hematopoietic agents: growth factors, minerals, and vitamins. Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th ed. New York City, NY: McGraw-Hill,1995;1311-1340
  5. Proudfoot AT, Simpson D, Dyson EH. Management of acute iron poisoning. Med Toxicol. 1986 Mar-Apr;1(2):83-100.
  6. Greentree WF, Hall JO. Iron toxicosis. Bonagura JD, ed. Kirk’s current therapy XII small animal practice. Philadelphia, Pa: WB Saunders Co, 1995;240-242.3.

Neuroleptic medications can produce hyperprolactinemia even at very low doses and are the most common cause of galactorrhea in dopamine-receptors-blockedpsychiatric patients.


Hyperprolactinemia with neuroleptic use is secondary to the blockade of dopamine receptors with these drugs. (Dopamine normally inhibits prolactin, and with dopamine’s blockade, hyperprolactinemia can result.) Amenorrhea and galactorrhea are the main symptoms of hyperprolactinemia in women, and impotence is the main symptom in men, although men can also develop gynecomastia and galactorrhea.

NOTE: Other causes of hyperprolactinemia include severe systemic illness such as cirrhosis or renal failure, pituitary tumors, idiopathic sources, and pregnancy.


  1. Kleinberg DL, Davis JM, de Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61
  2. Wudarsky M, Nicolson R, Hamburger SD, Spechler L, Gochman P, Bedwell J, Lenane MC, Rapoport JL. Elevated prolactin in pediatric patients on typical and atypical antipsychotics. J Child Adolesc Psychopharmacol 1999;9:239-45

Digoxin [Antiarrhythmic (Class III)] competes with Potassium for binding to cellular Na+/K+ ATPase pumps. Hypokalemia predisposes the patient to Digoxin toxicity. Most common arrhythmia associated with Digoxin toxicity is paroxysmal atrial tachycardia with 2:1 block. However, Bradycardia can occur and presence of a bidirectional ventricular tachycardia is practically pathognomonic for Digoxin toxicity!

HOW?? When potassium levels are low, it allows increased Digoxin binding to ATPase pumps to exert its inhibitory effects.

NOTE: Digoxin toxicity can cause Hyperkalemia (Digoxin inhibits Na+/K+ ATPase, so K+ remains in the plasma). In theory, if you give IV Calcium it can cause an influx of Calcium into the cardiac myocytes resulting in a non-contractile state (the so called “Stone Heart“).


  1. Levine M et al. The Effects of Intravenous Calcium in Patients wit h Digoxin Toxicity. J Emerg Med. 2011;40(1):41–46.
  2. CHAPTER 124: Toxicology in Adults. Patrick McCafferty Lank; Thomas Corbridge; Patrick T. Murray. Principles of Critical Care, 4e
  3. Chapter 95. Adverse Cardiovascular Drug Interactions and Complications. Ileana L. Piña; Gerard Oghlakian. Hurst’s The Heart, 13e

Exogenous Dopamine is unable to cross the tight junctions of the endothelial cells in the blood-brain barrier (BBB). Dopamine has no clinically significant endogenous transporter on the blood-brain barrier and is otherwise too polar of a molecule to move through the lipid membrane. Levodopa, however, utilizes a receptor on the BBB known as Large amino acid transporter (LAT)  which allows it to be transported across the blood-brain barrier and decarboxylated into Dopamine.



  1. Tsuji A. Small Molecular Drug Transfer across the Blood-Brain Barrier via Carrier-Mediated Transport Systems. NeuroRx. 2005;2(1):54-62.
  2. Laterra J, Keep R, Betz LA, et al. Blood—Brain Barrier. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
  3. Kageyama T, Nakamura M, Matsuo A, Yamasaki Y, Takakura Y, Hashida M, Kanai Y, Naito M, Tsuruo T, Minato N, Shimohama S. The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier. Brain Res. 2000 Oct 6;879(1-2):115-21.

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in the elderly (accounting for 15-20% on autopsy- => alpha-synuclein deposition). 

It is characterized as clinically:

  1. fluctuating cognitive impairment
  2. visual hallucinations
  3. extrapyramidal motor symptoms (parkinsonism)

WHY AVOID HALDOL? Individuals suffering from DLB have a reduction in post-synaptic dopaminergic (D2) receptor activity. Hence when given D2-receptor antagonists, particularly traditional neuroleptic agents (i.e haldol), it can provoke severe neuroleptic sensitivity reactions (catatonia, decreased LoC, muscle rigidity)  in up to 50% of DLB patients.

NOTE: consider new generation anti-psychotics (Quetiapine is preferred by some LBD experts).


  1. McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, et al. Dementia with Lewy bodies. Lancet Neurol. 2004;3:19–28.
  2. Mosimann UP, McKeith IG. Dementia with Lewy bodies—diagnosis and treatment. Swiss Med Wkly. 2003;133:131–42.

Patients on Monoamine oxidase inhibitors (MAO) inhibitors (especially MAO-A inhibitors or non-selective MAO inhibitors) are advised to avoid Tyramine rich foods.mao-cheese-effect

  • Tyramine rich foods: sauerkraut, chicken liver, chocolate, and cheeses (Cheddar, Gruyère, and Stilton are especially high), alcohol/ wine, pickled fish (herring), broad beans, yeast extracts, tofu and soy sauce.

MECHANISM: Tyramine is a byproduct of Tyrosine metabolism by MAO in the liver. Typically it will have low bioavailability due to extensive first-pass effect in the liver. 

If the patient is taking a MOA inhibitor, Tyramine accumulates in the bloodstream; it has indirect sympathomimetic action causing the release of stored catecholamines. This is known as the “Cheese effect”!!!

Onset is typically rapid (15 mins- 1hr); the hallmark presentation of the Tyramine “Cheese” reaction are HYPERTENSION + SEVERE HEADACHE (occipital or temporal), palpitations, nausea and vomiting. Typically resolving within 4-6 hours, however can be fatal!

NOTE: Selegiline (MAO-B selective) and rasagiline do not functionally inhibit MAO-A and are not associated with the “Cheese effect” with doses typically used in clinical practice!


  1.  CHAPTER 9: Adrenoceptor Agonists & Sympathomimetic Drugs. Basic & Clinical Pharmacology, 13e. Italo Biaggioni; David Robertson
  2.  Chapter 179: Monoamine Oxidase Inhibitors. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e. Frank LoVecchio


  • Both medications are often used to treat neuropathic pain and epilepsy
  • Mechanism: Both work via inhibition of Ca+ influx and block release of excitatory neurotransmitters. However, exact mechanism not known!
  • Both drugs can be taken without food
  • Neither drug binds to plasma proteins
  • Both drugs are renally excreted and not metabolized by the liver (CYP Enzymes)
  • Half-life of both is ~6 hours


Pregablin (Lyrica)

Gabapentin (Neurontin)

  • Also indicated for fibromyalgia, and generalized anxiety disorder.(Better for seizure reduction),
  • rapid absorption (peak concentration in 1-2hrs)
  • Absorption is linear (first order), therefore Pregablin plasma concentration increases proportionately with increasing dose.
  • slower absorption (peak concentration in 3-4hrs)
  • Oral gabapentin exhibits saturable absorption; pharmacokinetics less predictable (zero-order)
  • Gabapentin plasma concentration does not increase proportionally with increasing dose

**pregabalin may have some pharmacokinetic advantages over gabapentin; This may be the reason for improved pharmacodynamic effect.


  1. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010 Oct;49(10):661-9. doi: 10.2165/11536200-000000000-00000.