Lidocaine and phenytoin- both are sodium channel blockers. Lidocaine is a local anaesthetic and an anti-arrhythmic. Phenytoin is an anticonvulsant. What explains their differential action? Is it because of their difference in pharmacokinetics.

 Drugs, more than often, have multiple actions. The ability of drugs to interact with different targets and sometimes same target in different tissues impart this promiscuous property to drugs. For example Na+ channels are ubiquitous in the body. There are two types of Na+ channels- voltage gated  and epithelial. Voltage gated Na+ channels are present mainly in the brain, heart and muscles. Epithelial Na+ channels are present in kidney and skin. Drugs which interact with the Na+ channels, therefore, have widespread actions in the body. Phenytoin which is used as an anticonvulsant acts by inhibiting the Na+ channels in the brain, but is also arrhythmogenic due to its action on the cardiac Na+ channels. Similarly, lignocaine which is a local anaesthetic (blocks epithelial Na+ channel) when infiltrated subcutaneously, and is also used as an anti-arrhythmic drug (blocks cardiac Na+ channels). However, the rapid elimination of lignocaine does not allow the attainment of a sufficient level in the brain to act as an anticonvulsant. We understand that the pharmacodynamics is important for the action of a drug, but a drug that does not reaches the target fail to exert any influence, making pharmacokinetics equally important for drug action. 

Soldiers fight a battle to win a war (pharmacodynamics) and the warships that take the soldiers to the battlefield (pharmacokinetics) are the war-makers.

CNS depression after an acute generalised tonic clinic seizure - “The ghostly calm after the plundering cyclone.”

 An all pervasive, flooding of electrical activity occurs during an episode of generalised tonic clinic seizure. The abnormal electrical disturbances get manifested in the form of sustained, severe, generalised and vigorous contractions of all or most of the group of the muscles of the body. The condition is a medical emergency and unless  intervened promptly with the right medical therapy, is often fatal. In the aftermath of the serious event, the patient goes into an obtunded state. This phase which occurs after the episode of convulsion is known as the post-ictal state. Mostly, the patients sleep for prolonged periods, sometimes with audible snoring. The underlying mechanism of the post-ictal state is not clearly known, but the ‘storm’ that has passed during the episode of GTCS must have ‘inflicted’ a state of ‘refractoriness’ to the neurons. Likely, in such a state, the ‘routine’ transmission of impulses suffer a major ‘setback’ throwing the patient into a state of CNS depression. We can also speculate that there has been depletion of neurotransmitters from the presynaptic neurons during the ‘agitated’ phase of seizure. Collectively, the post-ictal phase is an inactive state of the brain where the higher cognitive functions, the autonomic system and the peripheral nervous system are highly subdued and suppressed.

Cocaine and it’s effect on the cardiovascular physiology

 The direct effect of cocaine on the vagal centre in the brain can cause bradycardia, but the bradycardia is seldom seen clinically. At the usual doses taken by people who abuse cocaine, the peripheral adrenergic actions of the drug dominates over its central vagal response. The phenomenon is explained by the pharmacokinetics of the drug. Cocaine is a low molecular weight tropane alkaloid (Pka=8.6), which is easily transported across the nasal, gut and alveolar membranes. However, it transport into the brain depends upon a proton driven antiporter. The stimulatory action of cocaine is rapid and provides the abuser with the sought for “kick”. At any time point after the intake of the drug, the peripheral cardiovascular effects of the drug dominates over the central vagal action. The peripheral adrenergic action is due to over accumulation of catecholamines in the synaptic cleft of the adrenergic neurones leading to vasoconstriction (blood vessels) and tachycardia (heart). Any reflex bradycardia mediated by central mechanism is overwhelmed by the peripheral adrenergic action. No doubt, subjects abusing cocaine present with accelerated hypertension, tachycardia and agitation in the emergency department. The severe vasoconstriction effect of cocaine may also precipitate coronary vasospasm and myocardial infarction in some drug abusers.

Acetazolamide in acute mountain sickness- the probable mechanism

 Acute mountain sickness is triggered by low oxygen at high altitudes. The ensuing hypoxia leads to adaptive changes by the human body.

In the brain, the adaptive response is vasodilatation. The objective is to improve perfusion. Overtime, this leads to carbon dioxide retention, increase in intracranial tension and oedema. The condition is known as high altitude cerebral oedema.

In the lungs, the adaptive response is vasoconstriction because of ventilation perfusion mismatch. Overtime, this leads to tissue damage and oedema. The condition is known as high altitude pulmonary oedema. 

The respiratory centre senses the hypoxia and in response hyperventilation occurs. Hyperventilation washes away carbon dioxide from blood leading to alkalosis.

So, in the pathophysiology of acute mountain sickness, hypoxia, oedema and alkalosis co-exist.

The treatment aims to alleviate hypoxia, oedema and alkalosis.

Hypoxia is corrected by giving supplemental oxygen.

Oedema is corrected by giving diuretics and steroids.

Alkalosis is corrected by giving acetazolamide.

The only diuretic which is able to cause acidosis is acetazolamide.

So, acetazolamide becomes the diuretic of choice in acute mountain sickness because it corrects alkalosis.

The steroid of choice is dexamethasone.

Multi drug therapy- the new weapon against cancer

 We all know that multi-drug therapy is a key way to prevent the emergence of resistance in infectious diseases. It not only provides rapid cure but also stamps out those strains of the infective organism which would have easily survived the onslaught of a single drug. Like the infectious organisms, cancer cells are also rapidly dividing cells, the growth and spread of which can be stopped using chemotherapy. There is astonishing similarity between drug resistance seen in infectious diseases and cancer. Infectious organisms have learnt to evade killing by antimicrobials by developing multiple mechanisms. In recent times, the problem of resistance in infectious organisms has become rampant and we find ourselves in very difficult situation to combat the infectious organisms. Similarly, in cancers which were sensitive to single drug of chemotherapy has over a period of time become more and more resistant. To overcome this problem multiple drug therapy with multiple anti-cancer drugs acting at multiple levels have been developed which not only kills the cancer cells in a shorter period of time but also prevents the development of resistance. Use of multiple drugs also decreases the chances of adverse effects associated with use of high dose of a single drug in cancer chemotherapy The doses of the respective drugs can be reduced such that the toxicity profile is much better. Nowadays we have an armamentarium of drugs against cancer-cytotoxics, biologicals, monoclonal antibodies, hormonal therapy. These drugs acts by different mechanisms and are effective in remission of cancer which otherwise would not have been possible with a single drug. In a classical example of drug resistance associated  with PGP (P glycoprotein) or MDR (multi-drug resistance protein), the cancer chemotherapeutic agent is extruded out of the cancer cells by the PGP resulting in decreased efficacy of the agent. In such conditions multiple drugs enables the remission of cancer even when one of the drugs is extruded out from the site of its action.

Seizure, epilepsy and convulsion-Are they same.

 People use “seizure” and “epilepsy” interchangeably, but they are not some. To understand better, I will put it like this, “ All epilepsy patients have seizures but all seizure patients are not epileptic” which means that there are non-epileptic causes of seizures also like hypoglycaemia, brain tumours, hypoxia, metabolic derangements, brain infections, cerebrovascular accidents etc. In other words, epilepsy is seizure without any organic cause or lesion. Sometimes, another terminology ‘convulsion’ is also used. It refers to the involuntary contraction/relaxation that occurs in seizure patients. ‘Convulsion’ is rather a layman’s term and you will find them referred to frequently in news and general discussion. It is to be remembered that some seizure disorder like absence seizure may not be manifested as ‘convulsions’

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Differential action of cortisol on tissues- the cellular checkpoints at the tissue level

 

·       Cortisol (and some amount of cortisone) is produced by the adrenal cortex in response to stress

·       Like all hormones, cortisol is secreted directly into the circulation and distributed uniformly throughout the body.

·       Most tissues of the body (mainly the liver and the adipose tissues) are rich in glucocorticoid receptors and poor in mineralocorticoid receptors. They have the enzyme HSD-11β Type 1 which converts cortisone into cortisol and promotes glucocorticoid action.

·       Some tissues of the body (kidneys, liver, lungs, colon, salivary glands) are rich in mineralocorticoid receptors and poor in glucocorticoid receptors. They are very sensitive to mineralocorticoid action of cortisol. They have the enzyme HSD-11β Type 2 which converts active cortisol into inactive cortisone and prevent excessive mineralocorticoid action of cortisol.

Oxygen delivery devices

 

Mode of O2 delivery	Maximum flow rate (litres/min	FiO2	Other notable features
Nasal cannula / prongs	5	·       1 litre/min flow rate-24%, ·       increases by 4% with every litre increase in flow rate ·       6 litres/min flow rate-44%,	·       Narrow-bored flexible tubes. ·       One end of the tube is attached to a graduated oxygen flow meter, the other end is split into two nozzles that loosely fits into the nostrils. ·       Beyond flow rates of 5 litres/min, the flow becomes turbulent leading to dissipation of delivered oxygen at the entry portal.
Face mask (simple)	5-10	35-55%	·       It is an expanded semi-rigid hollow enclosure that fits over the nose and oral orifice. ·       Flow rates less than 5 litres/min are not recommended because there is rebreathing of trapped expired air
Venturi mask	(blue-2, white-4, orange-6, yellow-8, red-10 and green-15)	24, 28, 31, 35, 40 and 60 % respectively	·       Oxygen inlet to the face mask is fitted with oxygen content regulators of varying capacity. ·       The FiO2 can therefore be tightly controlled as per need of the patient
NRBM	10-15	Up to 100%	·       The oxygen inlet to the mask is side-fitted with an inflatable oxygen reservoir bag. ·       During inspiration, oxygen is sourced from the inflowing oxygen as well as from the reservoir.
(HFNC)	Maximum rate- 70 litres/min	Up to 100%	·       electromechanical device that generates an admixture of warm humidified air containing oxygen of desired concentration

The electrophysiology of cardiac action potential in non-pacemaker cells: watch the video

 The “heart” of the functioning of the heart is the fast cell to cell communication between the cardiac myocytes. Upon generation of the pacemaker potential, the impulse is transmitted electrically to the adjacent cells. An action potential begins with rapid firing of fast Na+ channels resulting in rapid depolarisation (phase 0), following which there is an early repolarisation (phase 1). In the phase 2, Ca++ moves into the cells triggering massive release of calcium from the endoplasmic reticulum. And the cell contracts...

Delve into the depths of the molecular mechanism of the cardiac action potential. Click the 

https://youtu.be/tHttyFRjddM

Ranolizine in ischemic heart disease

 https://youtu.be/-ZoM9dIfqSE

The mid life crisis in the life of a women. What can we do to help her?

A 45 year old lady presents with the chief complaint of irregular menses. She had amenorrohoea for the last three months but 10 days back the periods started with heavy menstrual bleeding and was still continuing. She had one living child aged 20 years. An abdominal ultrasound revealed no obvious abnormality that could explain the heavy menstrual bleeding. Her thyroid status was euthyroid. She has no history of any comorbid condition. What is the most likely diagnosis?    What treatment would you suggest for the patient?

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.

Steroids: the ‘manna dew’ or the ‘devil’s bait’

 Steroids are hormones which are indispensable for physiological functions. In naturally occurring conditions of deficiency of these hormones, the treatment of choice is replacement in required doses. 

Steroids have also anti-inflammatory actions at supra-physiological doses. The bulk of indications of steroids are attributed to their anti-inflammatory action. Steroids do not alter the causative factor but provides symptomatic relief by suppressing inflammation.

So, while the hormone replacement therapy is used for adreno-cortical insufficiency and congenital adrenal hyperplasia, the list of indications of the anti-inflammatory use of steroids is ‘endless’.

Adverse effects with replacement therapy are rare because they are simply the replacement of the physiological requirements with the right dose. Side effects which are dose dependent may occur during dose adjustment or lack of proper monitoring.

On the other hand, anti-inflammatory doses which are supra physiological are very commonly associated with adverse effects. The incidence of adverse effects increases with the dose and duration of therapy. While hyperglycaemia, fluid retention, delayed wound healing, secondary infections can occur immediately after steroid initiation, fat redistribution, osteoporosis, myopathy, peptic ulcer and cataract can occur in the long run.

An inevitable consequence of long term steroid therapy is suppression of the hypothalamus-pituitary adrenal axis. It is generally innocuous during ongoing steroid therapy, but if abruptly stopped, will land the patient in acute adrenal crisis. The condition is life threatening. So any steroid therapy which is continued for more than two weeks is gradually tapered with decrease in the daily dose every week allowing time for the HPA axis to regain its normal functioning.

In the end, we can say that steroids are life saving drugs  (Manna’s dew) providing relief and solace to the suffering millions but if used improperly can turn the Manna’s dew into the ‘devil’s bait’.

Corticosteroids: the ‘floating switches’ that ‘ignites’ the physiological ‘engine’

 Nature has quaint ways of  doing its job. The nervous system of an organism takes cues from the environment and initiates a well crafted, precisely timed sequence of events (See someone nudging the ball and set it rolling down the hill) to adjust to the surroundings. The environment is a bountiful of stressors. In addition to the promptly generated neuronal response, a slow and sustained adaptive mechanism drives the forces of ‘struggle and survival’ in the living organism. The Hypothalamus-Pituitary takes the ‘lead and first role’ in ‘pushing the ball down the hill’ and a relay run begins. The corticotropin releasing hormone from the hypothalamus ‘runs’ to the pituitary; the pituitary in turn continues the relay run by releasing corticotropin (also commonly known as ACTH); ACTH ‘runs’ to the adrenal cortex which releases the adrenal corticosteroids. Adrenal corticosteroids are of two types- the glucocorticoids and the mineralocorticoid. The most well known endogenous glucocorticoid and mineralocorticoid are cortisol and aldosterone respectively. The ‘run’ ‘stops’ at the adrenal cortex from where the adrenal cortisol hormones are disseminated to every nook and corner of the body. The actions of corticosteroids are widespread but tissue dependent. The corticosteroids act as ‘floating switches’ ready to ‘ignite’ the ‘flames’ of cellular processes in the cells which have the ‘matching switches’ in the respective cells. The ‘matching switches’ are the glucocorticoid receptors (GR) and the mineralocorticoid receptors (MR). Both the GRs and MRs are intracellular cytoplasmic receptors. The GRs are ubiquitous and are responsible for translation of most of the actions of the glucocorticoids through the glucocorticoid response elements (GRE). The MRs are present in kidneys, hippocampus and colon. The glucocorticoids can also bind with MRs, in fact, with much greater affinity than the mineralocorticoid and can result in manyfold higher activation of mineralocorticoid response elements (MRE). Fortunately, nature has bestowed a mechanism to prevent the excessive action of glucocorticoids in such cells. The glucocorticoids are selectively inactivated by the enzyme 11 hydroxysteroid dehydrogenase and only the mineralocorticoid are available for action.