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👉 Retinoic acid receptor alpha (RAR-α) is a nuclear hormone receptor that binds to a DNA sequence, normally as a heterodimer with retinoid X receptor (RXR).

👉 Its ligands? All-trans retinoic acid or ATRA and 9-cis retinoic acid

👉 Without ligands -> RAR-RXR heterodimer INHIBITS transcription by recruiting transcription corepressors

👉 In the presence of ligand -> the co-repressor complexes dissociate from RAR-RXR, and transcriptional activation is induced.

👉 As its name suggests, a corepressor is a molecule (a large protein) that down-regulates the expression of certain genes, while a coactivator can enhance gene expression.

👉 Acute promyelocytic leukemia (APL) is an aggressive type of acute myeloid leukemia in which there are too many immature blood-forming cells (promyelocytes) in the blood and bone marrow.

👉 APL is mostly caused by a chromosomal translocation t(15;17) between the retinoic acid receptor alpha gene (RARα) and promyelocytic leukemia gene (PML).

👉 This way, a new, hybrid protein is formed: PML-RARα.

👉 PML-RARα ENHANCES the binding of transcriptional corepressors and prevents cellular differentiation from occurring, under PHYSIOLOGIC levels of ATRA

👉 PHARMACOLOGICAL concentrations of ATRA can dissociate the corepressors from RARα and allow DNA transcription and DIFFERENTIATION of the promyelocytes into mature GRANULOCYTES.

👉 Unlike other chemotherapies, ATRA does not directly kill the malignant cells.

👉 ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own.

There are 2 main types of oral anticoagulants:
⭐ direct oral anticoagulants (DOACs) - which directly inhibit THROMBIN and FACTOR X: DABIGATRAN, APIXABAN, RIVAROXABAN
*They do NOT require INR monitoring
⭐ anti-vitamin K anticoagulants (AVKs) - which inhibit vitamin K-dependent coagulation factors (II, VII, IX, X) and vitamin K-dependent anticoagulation proteins C and S: WARFARIN, ACENOCUMAROL

👉 Vitamin K works as a cofactor for GAMMA-GLUTAMYL CARBOXYLASE which activates vitamin K-dependent coagulation factors and anticoagulation factors (proteins S and C) through gamma-carboxylation of a glutamate residue in their structure. During the reaction, vitamin K is consumed and transformed into vitamin K epoxyde.

👉 Vitamin K is recycled by the enzyme VITAMIN K EPOXYDE REDUCTASE (VKOR). VKOR is the target of AVKs.

👉 Activated proteins S and C have a much lower half-life than activated vitamin K-dependent coagulation factors (8h vs 50h) meaning that once you stop their production, they will be the first to disappear from the serum. This leads to an initial hypercoagulable state which may even cause PERIPHERAL NECROSIS.

👉 After about 36h, plasma levels of the coagulation factors finally start decreasing. Full efficiency, however, is attained after about 5 days since the onset of AVKs administration.

👉 Normally, the therapeutic INR in AVKs administration should be between 2.0 and 3.0.







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Treatment of Hyperkalemia has to include 4 important steps:

🔵 antagonize the effects of hyperkalemia at the cellular level (membrane stabilization)

🔵 stop K+ intake (diet and parenteral administration)

🔵 decrease serum K+ levels by promoting the influx of K+ into the body cells

🔵 remove K+ from the body

1. As mentioned in the previous post, in the setting of hyperkalemia, the resting membrane potential is shifted to a less negative value (from −90 mV to −80 mV).

This means that the resting membrane potential is closer to the normal threshold potential of −75 mV. In this way, myocyte excitability increases and this leads to a high risk of arrhythmias.

When Ca2+ is given, the threshold potential shifts to a less negative value (from −75 mV to −65 mV). As you can see, the initial difference of 15 mV between the resting and threshold potentials is restored.

️2. Insulin stimulates the Na/K-ATPase pump, which moves K+ inside the cells in exchange for sodium in a 2:3 ratio. Glucose is co-administered with insulin in normoglycemic patients to prevent hypoglycemia.

3. Catecholamines activate Na/K-ATPase pumps through β2 receptor stimulation in a manner that is additive to the effect of insulin.

4. Sodium bicarbonate (NaHCO3) infusion can shift K+ from the extracellular to intracellular space by increasing blood pH. A higher pH draws the protons (H+) out of the cells (to re-balance the extracellular pH) in exchange for K+ which enters the cells.

5. Cation exchange resin exchange gut cations, most importantly K+, for Na+ ions which are released from the resin.

6. Loop diuretics facilitate renal K+ elimination. I.v. saline solution is given to prevent dehydration.

7. Hemodialysis is used only if the hyperkalemia is life-threatening.

In order to understand ECG changes in Hyperkalemia, we have to understand some basic principles.

👉 Na+ and K+ intracellular and extracellular concentrations are under the control of the Na+/K+-ATPase pump. These concentration gradients establish an electrical potential across the cell membrane called resting membrane potential: −90mV.

👉 As K+ levels increase in the extracellular space the concentration gradient for K+ diminishes, decreasing this way the resting membrane potential to around −80mV.

👉 This is important because the membrane potential at the ONSET of depolarization determines the number of Na+ channels activated DURING depolarization. As the resting membrane potential becomes less negative, the percentage of available Na+ channels DECREASES. This happens because, due to lower resting membrane potential, fewer Na+ channels manage to reactivate between action potentials.

👉 This leads to a SLOW impulse conduction through the myocardium. On ECG this is seen as a decreased P wave and a prolonged, wide QRS complex.

👉 The K+ efflux seen during repolarization is mostly due to Ikr CURRENTS, which are sensitive to extracellular K+ levels. Extracellular K+ has an ALLOSTERIC effect on the K+ channel and as K+ concentration INCREASES in the extracellular space, K+ conductance through the K+ channel (paradoxically) INCREASES.

👉 On ECG this occurs as tall, peaked T waves.










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