Mechanism of action of sucralfate

 https://youtu.be/-uMkwAfSb-I

Loop diuretics increase calcium excretion and thiazides diuretics decrease calcium excretion

FUNCTION OF Na+ K+ 2Cl- channel

👉  Na K 2Cl channel at the thick ascending limb of loop of Henle is responsible for transport of  Na+, K+ and 2Cl- from intra-luminal to intra-cellular part of the loop of Henle.

👉K+ diffuses back into the lumen and Na+ is transported across the basolateral membrane to the ecf.

👉 Back diffusion of K+ into lumen creates a positive potential difference between the luminal (positive side) and basolateral (negativeside) membranes. 

👉 Positive potential difference drives reabsorption of Ca2+ and Mg2+  into the tubular capillaries.

MECHANISM OF INCREASED Ca+ EXCRETION BY LOOP DIURETICS

👉 Loop diuretics inhibit Na K 2Cl channel at the thick ascending limb of loop of henle.

👉  Reabsorption of Na K 2Cl does not occur

👉No development of positive potential difference.

👉No reabsorption of Ca2+

👉Increased excretion of Ca+

FUNCTION OF Na Cl SYMPORTER AT DISTAL TUBULE

👉 Reabsorption of only Na Cl. Therefore, unlike loop of Henle, there is no role of K+ back diffusion and therefore no question of positive potential difference.

👉 No potential difference driven Ca2+ reabsorption 

MECHANISM OF DECREASED Ca2+ EXCRETION BY THIAZIDE DIURETICS

👉  Inhibition of Na Cl symporter

👉 Decreased Na in tubular epithelial cells

👉 Compensatory increased functioning of Na+ Ca2+ exchanger at the basolateral membrane  to maintain  intracellular Na+.

👉 Decreased intracellular Ca in the epithelial cells.

👉 Increased reabsorption of Ca+ from luminal to intracellular side

👉Decreased Ca+ excretion in urine

Penicillinase resistant penicillin (methicillin), MRSA and Ceftaroline

 

Ø In gram positive bacteria, peptidoglycan residues cross link to form cell wall.

Ø Cross linking occurs by transpeptidation of glycine with D-alanine of two adjacent peptidoglycan residues.

Ø Beta lactam antibiotics inhibit the enzyme transpeptidase that cross links peptidoglycan residues.

Ø Penicillinase (beta lactamase) producing gram positive bacteria destroy beta lactam ring and become resistant to beta lactam antibiotics.

Ø Penicillinase resistant penicillin (methicillin) are not destroyed by penicillinase producing bacteria. So, such bacteria are sensitive to methicillin and known as Methicillin Sensitive Staph aureus (MSSA).

Ø Methicillin Resistant Staph aureus (MRSA) produce altered transpeptidase (PBP2a). PBP2a do not bind with beta lactam antibiotics and therefore MRSA is resistant to all beta lactam antibiotics.

Ø Therefore, non-beta lactam antibiotics like sulfonamides, tetracyclines, clindamycin, vancomycin, linezolid etc are used in the treatment of MRSA. Vancomycin and linezolid have proven efficacy in treatment of MRSA.

Ø Vancomycin was discovered in the 1950s but seldom used in therapeutics because of adverse effects.

Ø When MRSA were reported in 1960s, vancomycin rapidly became popular for treatment of MRSA. No beta lactam was effective against MRSA at that time.

Ø Only after many years of research, the first beta lactam antibiotic with clinically significant anti-MRSA activity was approved in 2010. The name of the beta lactam antibiotic effective against MRSA is ceftaroline.

Are we adequately treating amoebiasis: the forgotten role of diloxanide furoate

 

Coming soon

Reye’s syndrome with aspirin: one man's meat is another man's poison

Aspirin is a drug with multiple uses. At low dose, it is used as an anti platelet. It has analgesic, anti-pyretic and anti-inflammatory actions in a wide dose range. However, aspirin is not the drug choice for fever in any age group. Paracetamol is considered safer. In children, it is more true because aspirin has been found to be associated with Reye’s syndrome when used as antipyretic in children suffering from chickenpox, influenza and other viral illness. In such illness, aspirin may cause hepatic mitochondrial damage. There is inhibition of fatty acid metabolism and increase in serum ammonia levels. Hyperammonemia may induce diffuse cerebral edema and raised intracranial pressure. The child presents with profuse vomiting, stupor which may rapidly progress to coma, cardio respiratory failure and death.

Congenital adrenal hyperplasia- an example of gene error in enzyme expression: the defect in one enzyme, ‘backlashes’ in the other.

 The human body is like a test tube. Thousands of reactions, catalysed by enzymes go on simultaneously. The system of reactions are intricately interconnected, in as much, that the slowing or absence of enzyme activity in one pathway leads to a compensatory increase in the interconnected pathways. The system is analogous to a traffic blockade in a thoroughfare, that leads to spontaneous diversion of the traffic to the adjacent interconnected roads. The biochemical ‘conglomerate’ runs mechanisms that propels the human body to struggle and survive. Stressors are plenty and the body responds adequately and timely. The adrenal gland is the seat of the response to stress. Adrenaline from adrenal medulla fills the body with energy and ‘strength’ in the hour of acute stress. Simultaneously, at all times, be it the ‘acute stress’ or otherwise, the adrenal cortex continuously ‘infuses’ the  corticosteroids into the circulation to maintain the state of ‘vigil’ required for ‘existence’. The adrenal cortex synthesises three important hormones- the Glucocorticoids, mineralocorticoids and androgens. The parent ‘raw material’ of the three hormones is same, and is nothing but cholesterol. In Congenital Adrenal Hyperplasia (CAH), the enzymes synthesising aldosterone and cortisol are partially or completely repressed. Low serum cortisol exerts a feedback stimulation on the pituitary to produce large quantities of ACTH. The result of ACTH action on adrenal cortex is adrenal hyperplasia. However, the adrenal overgrowth is not able to produce aldosterone or cortisol. Instead, the enzymatic machinery is diverted towards production of large amounts of androgens. Depending upon the degree of enzyme repression, a female child may present with ambiguous genitalia at birth or virilization features with growth; a male child may develop precocious puberty; and both male and female child may present at birth with extreme salt wasting, vomiting, dehydration, hyponatremia and failure to thrive. While extreme salt wasting and dehydration is an emergency, necessitating fluid and electrolyte replacement, long term management of the condition involves replacements ment of  cortisol or aldosterone or both depending upon the deficiencies. Surgical management of ambiguous genitalia is not a life saving measure but options for corrective surgical procedures should be kept open for the proper psychological and social rehabilitation of the patient.

The ‘other side’ of paracetamol : overdosage

 One of the most commonly used antipyretic and analgesic is paracetamol. Considered to be very safe with the least nephrotoxic potential, it is widely prescribed in all age groups. Like most lipid soluble drugs, paracetamol is metabolised in the liver. The major metabolites are sulphate and glucoronide conjugates of the drug which are highly water soluble and rapidly eliminated from the body. A minor metabolite is N acetyl p aminobenzoquinone Imine (NAPQI) formed by CYP2E1. With increase in dose, the major pathways are saturated, and the formation of  the metabolite NAPQI increases. NAPQI has hepatotoxic potential. The endogenous scavengers ( read glutathione) detoxify the toxin but in overdosage of paracetamol, the scavengers are overwhelmed and hepatotoxicity occurs. The antidote recommended for treatment of paracetamol induced liver injury is N acetyl cysteine. N acetyl cysteine is an antioxidant and is a precursor of  glutathione and therefore replenishes tissue glutathione stores. Replenished glutathione detoxify NAPQI and prevent hepatic injury.