Ans. Methotrexate is used as immunosuppressant drug (in rheumatoid arthritis, psoriasis and other autoimmune disorders) in low doses.

 While in high doses methotrexate is used as anti-cancer drug.

It is one of the most commonly used anticancer drug. Methotrexate is useful in choriocarcinoma, non-Hodgkin lymphoma, Breast, bladder, head and neck cancers, childhood acute lymphoblastic leukaemia (ALL) etc.

Methotrexate is folic acid analogue (structurally resembles folic acid). It inhibits dihydrofolate reductase enzyme (DHFRase), due to which conversion of dihydro folic acid (DHFA) to tetrahydro folic acid (THFA) is prevented.

This Tetrahydro folic acid is essential coenzyme, required for purine and thymidylate synthesis which are necessary components for DNA and RNA synthesis and cell division.

When methotrexate is given in higher doses, it acts on rapidly dividing cells including cancer cells and host cells. The action on rapidly diving host cell (like bone marrow) are responsible for its side effects.

Major adverse effect of methotrexate are bone marrow suppression, thrombocytopenia, mucosytosis, diarrhoea, alopecia.

Folinic acid/leucovorin is a form of folate that can be readily utilized by the body and it prevents the normal cells form methotrexate adverse effect (they can perform their normal function in presence of methotrexate). While cancer cells having higher need of folate then normal cells, does not protected to same extent.

So adding Folinic acid/leucovorin is useful while cancer treatment because-

1. Rescue from Methotrexate Toxicity (reduced side effects)
2. Shortening of Recovery time from chemotherapy
3. It is possible to give higher doses of Methotrexate during cancer treatment as normal cells are less affected (increased therapeutic index)

A rare condition, in which patient passes up to 19 liters of urine a day (polyurea) and due to excessive fluid loss, feel thirsty all the time and drink lots of liquids (Polydipsia). This condition occurs due to decreased production of Anti diuretic hormone (ADH) or when ADH production is normal but ADH is not able to act on Kidneys (Collecting ducts specifically).  

ADH (vasopressin)

• Produced by Hypothalamus
• Posterior pituitary gland stores and releases it
• ADH makes the collecting ducts permeable by its action on V2  receptors and the water is reabsorbed in the body by the collecting ducts.
• Without presence of ADH, collecting ducts are impermeable to water and hence excess fluid loss.

Central diabetes insipidus

• Decreased production of ADH or vasopressin.
• Central diabetes insipidus is the most common type
• T/t –  Desmopressin  ( Longer acting, V2 receptor selective)
• Given orally or intranasally
• Also given orally in bed wetting in children (nocturnal enuresis)

Nephrogenic diabetes insipidus

• when pituitary gland releases enough antidiuretic hormone (ADH, or vasopressin) but
• kidneys don’t respond to ADH properly and can’t retain water.
• Thiazides diuretics are effective (shows antidiuretic effect paradoxically in DI)
• Reduces urine volume in both type of DI.

Points to remember –

Desmopressin – – Administered orally / intranasally (nasal spray)
                              – DOC for Central DI
                               – DOC for nocturnal enuresis (orally)

 Thiazide diuretics – used in renal DI
 Amiloride – DOC for lithium induced nephrogenic DI  (some drugs can also induce DI eg. lithium)
 Insulin – used in Diabetes mellitus

A female patient, 32 year old is admitted in emergency department, she was dehydrated, hyperventilating and have impaired consciousness. After investigations relevant findings are- known diabetic type-1 patient, using insulin subcutaneously and presently suffering from fever for 5 days, recently having episode of nausea, vomiting along with pain abdomen. blood investigations are suggestive of hyperglycemia, hyperketonemia and acidosis. Urine examination demonstrate ketones in urine.

Discussion-

It is a case of Diabetic Ketoacidosis. It can be life threatening and considered as medical emergency. More common in Type-I Diabetics, it is precipitated by Infection, stress, trauma, inadequate dose of insulin. Patient has severe hyperglycemia and excessive ketone bodies along with vomiting, abdominal pain, impaired consciousness, metabolic acidosis, dehydration etc.

Management-

As it is a life threatening condition, regular monitoring of vital signs, plasma glucose, blood pH, electrolytes, plasma acetone is needed. As management plan we have to take care of Dehydration, hyperglycemia ( 600-800 mg/dl) and acidosis along with infection (if present) .

(1) Fluid and electrolyte replacement – Normal saline is infused i.v., initially at the rate of 1 liter in first hour (If shock is present then rapid infusion of normal saline until blood pressure rises to normal), then Continue IV normal saline 500 ml/hour for next four hours

(2) Hyperglycaemia management– Intravenous Regular insulin (0.1 U/kg i.v. is followed by 0.1 U/kg/hour till blood glucose reaches 300 mg/dl, usually takes 4-6 hours). Then stepwise approach to shift from IV to SC insulin when patient has fully recovered.

(3) Acidosis Management- If severe acidosis is present (arterial blood pH <7.00) then sodium bicarbonate is used.

(4) KCl – As we know that there is loss of potassium in urine during ketoacidosis and IV insulin causes dose dependent decline in serum potassium and ultimately both conditions can lead to serious hypokalemia. So, after 2–3 hours, KCl 10–20 mEq/hr is added to the i.v. fluid.

(5) Antibiotics- If the precipitating cause is infection, then find and treat the infection with appropriate antibiotic simultaneously.

I hope that this case based study will help you to understand the basic principles in management of this medical emergency……..have a great day

Or BPH (Benign Prostatic Hyperplasia) and now a days clinicians only say it Benign Prostatic Enlargement (BPE), Hyperplasia or Hypertrophy commented after Biopsy report.

Let’s start our Learning adventure……….

Now what is BHP …….it’s the Benign Hyperplasia/Hypertrophy of Prostate, well thank God for the self explanatory name, so

Its Benign ……….and in fact it is the most common benign tumor in men, and it is not a precancerous condition.

BPH is a nonmalignant enlargement of the Prostate gland caused by cellular hyperplasia of both glandular and stromal elements that can leads to….

• Hesitancy (It’s the trouble starting to urinate or Delay in initiating urination)

• Intermittency (Urinary stream that is not continuous)

• Incomplete voiding (I think you know that one…)

• Weak urinary stream

• Prolonged micturition

• Increased frequency of urination

•Nocturia (It is the condition where patient have to wake up during night to urinate…more often, of course)

•Urgency (compelling need to void that can not be deferred)

Do you know that healthy human prostate is slightly larger than a walnut (4cm by 3cm)…….. It surrounds the urethra just below the urinary bladder and can be felt during a rectal exam.

Now the problem in urination in BPH is due to two components

(a) Static component: That problem in urination is due to increase in size of gland, and the enlargement depends on DHT (DiHydroTestosterone). DHT is an Androgen, a sex hormone. Testosterone is converted to DHT with help of an enzyme ( 5 α reductase )

(b) Dynamic component : the problem in urination is due to increase in tone of smooth muscles of the bladder neck, trigone and urethra. The increased tone of these smooth muscle is due to α-1 receptors, and to be specific we can say α-1 A receptors (Recall what you have studied during ANS section about adrenergic receptors α and β)

Now we know the problem……….and the next step is to solve it…..

So the Immediate relief (and by immediate i mean one to two weeks), can be gained by relaxing the smooth muscles of the bladder neck, trigone and urethra and this action is achieved by blocking the α-1 receptors by the drugs (i.e. Alpha 1 Blockers like Prazosin) but we prefer longer acting brothers of Prazosin like Alfuzosin, Doxazosin, Terazosin due to convenience of once daily dosing.

The problem with blocking α-1 receptors is that they are present on blood vessels also (remember α-1 Constricts and β-2 Dilates) and blocking α 1 receptors can cause the decreased blood pressure and postural hypotension and tachycardia also and don’t forget about another important side effect of the Alfa blockers i.e. Inhibition of ejaculation.

And that’s why in normotensive patients we prefer α-1 A selective blockers (as this subtype is more prominent in the prostate and urethral pathway) which are Tamsulosin and Silodosin.

And they does not cause the effect on the blood vessels and so no significant change in BP (which is mediated by the subtype α-1 B)

So we can conclude easily that ………

The drug of choice in BPH patient with Hypertension is Prazosin or Doxazosin (Alpha 1 Blockers).

The drug of choice in BPH patient without Hypertension is Tamsulosin or Silodosin (Alpha 1 A Blockers)

So, the α-1 blockers relaxes the urine pathway and facilitate the urine flow but the main problem of increased size of prostate (static component) is still unaddressed.

As i stated earlier the enlargement in size depends on DHT (DiHydroTestosterone).

This DHT (DiHydroTestosterone) is formed by the Testosterone with help of enzyme 5 α reductase

Testosterone ——-Enzyme 5 α reductase ——– DHT (DiHydroTestosterone)

And the formation of DHT is blocked by inhibiting the enzyme 5 α reductase

And that’s why 5 α reductase inhibitors like Finasteride and Dutasteride are used and they respond by Decreased prostate size and increased urinary flow in most patients.

Though this beneficial effect can take upto six month for maximum response.

The Combination of Tamsulosin (0.4 mg) + Finasteride (5 mg) is also available, the combination will act on both static and dynamic components and the cost of this combination is nearly 400 rs /15 capsules.

And if the problem is not resolved by the drugs then the surgery is the main option (Transurethral resection of the Prostate)

Hope, you enjoyed the presentation.

Happy learning……..

Dear students, today our topic of discussion is “Drugs used in Cough”.

We are discussing this topic to understand cough, its types and mechanism of action of drugs used in cough.

After reading this topic you will be able to understand how to judicially use anti cough drugs and what are their adverse effects.

So usually “cough” is a protective reflex in our body and it tries to expel the respiratory secretions or foreign particles from air passage.

It can be divided into (I) Productive and (II) Non productive cough (i.e. dry cough).

                (I)Productive cough – It means Production of excessive sputum. In this type of cough Antitussive drugs (Drugs which suppress cough reflex) should not be used. The approach should be to reduce the viscosity and increase production of secretions so it can be expelled easily, and that’s why “expectorants” are used which we will discuss later.

                (II) Non productive cough (i.e. dry cough). –

it serves no useful purpose. It should be suppressed and thus “antitussive” should be used.

Now we move forward towards classification:-

(1)Pharyngeal Demulcents:-      

They are the substances which soothe the throat by a protective covering on throat (Pharynx) and provide relief by reducing impulses from inflamed or irritated mucosa 

 Lozenges (you know strepsils, vicks tablet etc.)

Honey (remember your parents advising you to have honey and ginger in mouth for cough)

Glycerine etc.

(2)Expectorants :- 

These drugs act by increasing the volume or decrease the viscosity of bronchial secretions/mucus (or both) and make easy to expel the secretions and provide relief.

Expectorants can be divided into

(I)Mucokinetics –

As we can understand by the name “Mucokinetics” they stimulate the outflow of serrations ( by increasing the volume of secretions and/or by stimulation and outward mucociliary movements)

Eg- Guaiphenesin (plant product, FDA approved OTC drug for expectorant use, Increased secretions and ciliary action)

   -Tolu balsam  (plant product MOA, same as Guipenasin)

   -vasaka               (plant product MOA, same as Guipenasin)

  -sodium/potassium citrate (increase secretion by salt action)

   – Potassium iodide (act by irritating mucosa) (remember whenever iodine is involved anywhere thyroid functions may impair)

   – Ammonium chloride (nauseating property so reflexly increase respiratory secretions)

(II)Mucolytics –

They decrease the viscosity of mucous and facilitate its removal by cough reflex .

That’s why in Expectorants cough reflex should not be abolished.

Bromhexine – Depolymerised mucopolysaccharides in mucous and make it thin for expulsion

                Main S.E. are rhinorrhoea, lacrimation,hypersensitivity,  gastric irritation

Ambroxol– metabolite of bromhexine, same MOA and S.E.

Acetylcysteine– Act on disulfide bond of mucoprotein presents in sputum and make it less visid (thin). It can be used orally or by inhalation.

(Remember same drug is used in acute paracetamol poisoning where it can be used by I.V. route or orally )

 Carbocysteine etc.

(3)Antitussive-

Raise the CNS threshold of cough centre.

Can be used only in dry (unproductive) cough or when cough is harmful and need to be suppressed eg. After surgery. Blocking of productive cough with a powerful antitussive like opioids can cause accumulation of secretions further lead to airway obstruction and atelectasis.

(I)Opioids-

Codeine- more selective to cough centre, low abuse liability then morphine and main side effect is constipation and as like morphine at higher dose it cause drowsiness and respiratory depression and thus use cautiously in drivers and people need attention during work and due to respiratory depression it is contraindicated in asthmatics.

While Pholcodine has no addictive properties and efficacy similar to codeine and longer acting also

Noscapine is also opioid alkaloids with no addictive property but can release histamine and cause bronchoconstriction in asthmatics

(II)Non Opioid antitussive

Dextromethorphan– as effective as codeine, devoid of constipation and abuse liability (unlike codeine)

But can produce drowsiness, nausea and ataxia.

(4)Antihistaminics:-

No direct effect on cough but can be effective in allergic conditions and relief in other type of cough is due to their anticholinergic and sedative effects (and that’s why first generation antihistaminics are used ) eg. Chlorpheniramine, Diphenhydramine, Promethazine

(5)Bronchodilators-

In bronchial hyperreactivity (like asthma) leads to cough due to  bronchoconstriction and bronchodilators like Salbutamol or terbutaline etc. are used.

In nutshell

If a patient approaches you with a cough and if it is more than two weeks then sputum examination for Acid fast bacilli (AFB)smear and culture should be sent.

Always treat cough as a symptom.

Viral cough (usually non-productive) subside itself within a week or two and demulcents are useful and sufficient for relief.

If you want to suppress the non productive cough then use antitussives like Dextromethorphan/ noscapine/ pholcodine/codeine

If cough is productive then guaiphenesin/ ambroxol/bromhexine etc. Expectorants can be used although it is also seen that liquid sputum is hard to expel out by mucociliary action and thus only guaifenesin is only FDA approved OTC drug for expectorant use.

FDA also recommends that OTC cough and cold agents (eg, products containing antitussives, expectorants, decongestants, and antihistamines) not be used in infants and children younger than 2 year.

                                                                      Happy learning….. Have a great time

Have you ever heard your Pharmacology teacher or Physician saying that a drug, for example, lithium has a “narrow therapeutic window” or “Low therapeutic Index”…..

well, what is the meaning of this……

Lets Explore…..

In simple words Therapeutic Index is a measure of “safety of drug” .

Means if a drug has High Therapeutic index it is more safe ……..

So, we always want to give a drug with higher Therapeutic index because they are more safe.

and how do we calculate the “Therapeutic index” ….. well, it is calculated in Experimental animals (I know , animal cruelty )

First, we start with a low dose of drug in animals and start increasing the dose gradually, and then there comes a dose which produces the desired effect in 50% of the population of the animal (Termed as Median Effective Dose “ED50” ) and we kept increasing the dose and there comes a dose on which 50 % animals dies (Termed as Median Lethal dose “LD 50”)

And after this killing, we are now ready to calculate the Therapeutic index which is …..

Therapeutic index = LD50/ED50

and i always get confused in the formula (Yep, i am too forgetful)…….. so i remember it by TILE (TI=L/E)

So, now you have learned so much …. then imagine how do we calculate it in humans..(I hope, you are not thinking about killing your 50% of the patients by drug toxicity)

And the good news is, in humans we prefer Therapeutic range or Therapeutic window……

Therapeutic range / Therapeutic window

Therapeutic range or Therapeutic window is calculated in humans and by definition “it is the range of drug, which is bounded by the dose which produce minimum therapeutic effect and the dose which produces maximum acceptable adverse effect”.

If you are not understanding the above definition, then Don’t loose hope, keep reading, lets take an example…..

For example- Therapeutic window of Lithium is 0.5-1.3 mEq/L. (it means below 0.5 mEq/L lithium will not produce therapeutic effect and above 1.3 (nearly on 1.5 mEq/L) toxicity symptoms occur frequently.

So, a drug with a small therapeutic window must be given carefully, and sometimes measuring response or blood concentration of the drugs, is needed to avoid the serious Adverse effects.

Now, lets talk about the drugs which have low Therapeutic Index, now i think that you understand that low Therapeutic Index, means naturally small Therapeutic window.

Example- Lithium (it is used in Bipolar disorders), Carbamazepine, phenytoin (Antiepileptic drugs) theophylline (used in asthma) and warfarin (Anticoagulant) etc.

Hope this post will clear your concepts…….

Happy learning…..

Lets Explore this amazing concept of Plateau Principal of Drug Accumulation ………..

If the dose of a drug is repeated at short intervals before its complete elimination, the drug start accumulating in the body. ( Its normal, because we are giving the drug before its complete removal)

And nearly after five half lives, the drug in the body attains a state, where the rate of drug elimination equals to the rate of drug administration and this state is termed as Steady state .

Steady State Concentration where…

Rate of Drug Elimination = Rate of Drug Administration

or we can say that Plasma Concentration is at Plateau , and don’t confuse the plateau state with a constant plasma concentration, the plasma concentration is fluctuating , it is high when we administer drug and decreased gradually due to elimination, has a spike after delivering the drug again , but after the 5 plasma half life’s it will achieve a condition where it fluctuates about an average steady state level (Plateau)

And this is termed as Plateau Principal of Drug Accumulation.

So…………

Time required to achieve a steady state is ENTIERLY DEPENDS OF PLASMA HALF LIFE.

Now if you are with me…..Great, but most of the time, its the point where the students seem confused,

Let me clear this fog with an example…….

If we double the dose of drug (If previously we are giving 100 mg, we start giving 200 mg) then again after nearly five half lives the NEW STEADY STATE will achieved…..and obviously this time the plasma concentration Plateau will be higher…….(We are assuming here that drug follows first order kinetics)

And we are still experimentig……….so again after some time, we reduce plasma concentration to one fourth of previously (200/4=50 mg) , then we will see that again after Five half life the NEW STEADY STATE is achieved…..and obviously this time the plasma concentration Plateau will be much lower…….

So we are trying to make a point here, that after nearly five half lives there comes a condition where our body is adjusted to a condition where rate of drug elimination is equals to the rate of dug administration.

And what will happen if we reduce the intervals of administering the drug ?

Lets again take an Example…………Assuming the half life of a drug is four hour and we were repeating it at interval of four hours, after some time, we reduce the duration to one hour …… then now the amplitude of the fluctuation of plasma concentration will decrease (the ups and downs of the drug plasma levels or in pharmacology … Peaks and Troughs), because we are giving the drug more frequently.

In nutshell…..

If we increase the frequency of giving the drug or the dose is increased then Steady state concentration will be higher ………..BUT the TIME TO ATTAIN the steady state shall remain the same in both (Because it depends in plasma half life)

And what is the clinical importance of this…….did you remember lithium (Yes , the same drug we are using in the Bipolar disorders and having a narrow therapeutic index i.e. 0.5-1.3 mEq/L)

we know that we have to select the dose appropriately, so that the Steady state concentration will be the desired plasma concentration (i.e. 0.5 – 1.3 mEq/L).

and we have to decide the dosing interval properly because if the dosing interval will be more then ups and downs will be more, and during the ups it will produce toxicity and become ineffective during downs, so we can use this knowledge to decide the dose and dosing intervals so we can attain a desired range of plasma concentration.

Hope you will understand the concept………..

Happy learning…

In pharmacology it is one of the commonly asked questions….

Q. Explain why Indomethacin is used in children with Patent Ductus Arteriosus ?

Answer- you can get direct answer of this question from any book of Pharmacology you read….

But lets take this opportunity to develop our understanding about the disease and the drug. first we will understand what is Patent Ductus arteriosus……

Patent Ductus arteriosus-

First of all, we as Medical Students, knows very well that Pulmonary artery carries blood from right heart to the lungs.

And The Aorta carries blood from heart to the body…. … in foetus, ductus arteriosus is an extra blood vessel or you can say connection (Which is normal by the way in foetus) that connects The Pulmonary artery to the Aorta…….because before birth the lungs of the foetus are not activated and the foetus gets oxygen from the mother.

Do you know, that all newborns have this opening intact during birth and it closes on its own, as the baby starts breathing and lungs take charge of proving oxygenated blood.

But rarely, if it stays open, this condition is termed as Patent Ductus Arteriosus. (Comparatively more in premature infants)

We know that the right heart pumps blood to the lung and left heart to the body, here the blood from the left heart is pumped to the lungs also, which cause extra pressure on the lungs, this makes the heart and lung work harder and lungs can become congested.

Now How Indomethacin can be useful in Medical treatment of Patent Ductus Arteriosus?

Normally, the Patency of Ductus Arteriosus is due to the Prostaglandins (due to continuous secretions of PGE2 and PGI2)

And we know that Indomethacin is a NSAID (Non steroidal Anti-inflammatory Drugs) which exert their effects by Prostaglandin synthesis inhibition.

Indomethacin is a highly potent inhibitor of PG synthesis and when Indomethacin is given as IV injections 12 hourly three times at dose of 0.1 to 0.2 mg/kg, it achieves closure of PDA in majority of cases.

Hope you understand the concept and enjoyed the post…….

Happy learning……..

Well, in series of clearing our concepts…. lets take a look on a very favourite question of Examiners in Pharmacology…….

Q. Explain why Allopurinol is used in chronic Gout? or

Q. Explain why we don’t use Allopurinol in Acute Gout?

So, Acute gout is sudden, severe inflammation in joint where the joint become red, swollen and Extremely painful, i hope you remember that the Great Toe (specifically metatarso-phalangeal joint) is commonly involved.

and we also know, that gout is considered as metabolic disease, in which, there is HYPERURICAEMIA (Increased uric acid in blood, compared to normal values which is 2-6 mg/dl) . But in acute gout (let me remind you red, swollen, painful great toe) we need immediate treatment to make patient feel normal.

So, we give

1. NSAIDs (Non Steroidal Anti-inflammatory Drugs) – like Diclofenac, Indomethacin or Etoricoxib, in Relatively high and repeated doses (We have to control a painful situation)

2. Colchicine -though response is dramatic, but due to its higher toxicity NSAIDs are preferred now a days

3. Corticosteroids– Intraarticular injection of triamcinolone is preferred and as usual, we go to steroids when NSAIDs/Colchicine did not work or not tolerated. rarely we go for systemic steroids.

And now i can sense, someone hitting his head hard on the wall “you are supposed to tell us about why we use Allopurinol in chronic gout and not in the acute gout”?

Yes, you are right, but here i am trying to make a point that in acute gout the target is to control the painful inflammatory condition, not the level of uric acid.

And as you may know, Allopurinol is a drug which decreases the uric acid level as it is uric acid synthesis inhibitor (act by inhibiting “Xanthine Oxidase”, the famous enzyme responsible for synthesis of uric acid).

And Allopurinol is the first choice drug in Chronic Gout.

But the Allopurinol also should not be started during an acute attack, because as the uric acid level decreases, there are chances of shedding of urate crystals from articular cartilage into joint space and this can initiate or worsen an acute attack.

So, 1. Do Not starting allopurinol during Acute attack of gout

2. Start Allopurinol with NSAIDs initially, to prevent an acute attack, till uric acid level stabilizes.

Hope you enjoyed the concept…..

Happy learning………

Q. Name the drug of choice in acute Paracetamol Poisoning ?

Q. Role of N- Acetyl Cysteine in acute Paracetamol Poisoning ?

Now, to understand this better, we start with …………

Acute Paracetamol Poisoning – when anyone consumes a large dose (10 gm or more in adult) of paracetamol suddenly (within 24 hour time duration), it is a medical emergency and termed as acute paracetamol poisoning.

The patient usually comes to you with Liver tenderness, nausea, vomiting, abdominal pain and later on, sometime after day or two or three (depends on how massive the dose is) hepatic necrosis, renal necrosis and hypoglycemia occur and if untreated, then coma and death.

In short, we can say that, if more then 150 mg/kg as per body weight paracetamol is taken, then it produces serious toxicity and more then 250 mg/kg is usually fatal.

But the good news is that if N- Acetylcysteine is given to the patient within eight hours of acute Paracetamol poisoning then Hepatotoxicity is extremely rare (It is claimed to be 100 % effective if given within 8 hours, however if there is delay in starting treatment with N-Acetylcysteine, then as the time increases, the worst will be the outcome).

You can say, we use N- Acetylcysteine for Acetaminophen (Its another name for Paracetamol) Poisoning. remembering this by heart and it will help in your theory, viva and in real life emergency situation, as Paracetamol is one of the most common, over the counter drug available all over, hence overconsumption cases are not uncommon.

But why N- Acetylcysteine is used ? ………

well, lets dive deeper……when we take PCM then it metabolizes in Liver…..

During metabolism 1) it undergoes glucuronidation and sulfation mostly (do you remember that during metabolism there were Phase II reactions by which our body attach the water soluble substances like glucuronic acid etc. to the drug and make the drug water soluble, suitable to be execrated by urine)

2. Very small amount (nearly 5%) metabolized by P-450 dependent hydroxylation and after this an Highly reactive compound NAPQI (N-Acetyl-P-Benzoquine imine) is formed and it also further goes into glutathione conjugation and then execrated in urine.

One more point i want to add here that glutathione is a major antioxidant, protect our body from free radical injury.

When PCM is taken in excessive amount then there is excess NAPQI , Glutathione cannot meet with this sudden increased demand to neutralize NAPQI and there is Glutathione depletion in the liver.

Now in our body, there is NAPQI in excess and no glutathione to protect our liver from this highly reactive compound. At last, excess NAPQI binds to the cellular macromolecules and causes hepatic necrosis , renal necrosis etc.

And what changes, when we provide N- Acetylcysteine, well it act by….

1. It Replenish the Glutathione stores in the liver (N-Acetylcysteine is a glutathione precursor, and Glutathione is naturally occurring antioxidant produced in liver)
2. It binds with NAPQI (Yes, the reactive metabolite) and thus prevents it harmful effects.
3. It protect against extrahepatic injury due to its antioxidant and anti-inflammatory properties.

If you want to know the dose and the route…….

150 mg/kg by i.v. route (In 200 ml 5% glucose) over 20 minutes repeated again after 20 hours.

Here are some interesting facts, that Alcoholism, malnutrition , Cancers are some other conditions which are usually associated with glutathione deficiency and no wonder, in chronic alcoholics the fatal dose of PCM can be reduced to 5 grams.

And in children below six years you rarely see PCM toxicity because the PCM syrups/drops are provided in a limited dose and also the metabolism is dominated by the sulfation. (But taking very high doses eg. PCM tablets can lead to severe liver and renal damage)

Hope you enjoyed the concept…..

Happy learning……will back to you soon …..

As alcohol is now becoming a common social evil among our society, we as Doctors always have to take care that our patient will avoid the alcohol during treatment.

There are some drugs for which patient should be warned strictly to avoid alcohol during treatment and even 12 hours before and after starting treatment. List of some main drugs are given below (Drugs causing Disulfiram like reactions).

Because if the patient consume even small amount of alcohol during treatment with these drugs, then he will suffer with severe distressing problems like headache, nausea, vomiting, sweating, vertigo, blurred vision, hypotension, dizziness, burning sensation, tightness in chest, mental confusion and even circulatory collapse.

The duration depends on the amount of alcohol consumed, usually it takes one to four hours.

This is a typical story with the drug Disulfiram, and as usual, we use these side effects to help “motivated” alcoholics to quit alcohol and this is known as Aversion therapy.

So, Aversion therapy is given only to (1) a motivated person and (2) That person should not be physically dependent on alcohol.

And what we do in “Aversion Therapy” ?

Well, we give Disulfiram to our motivated patient who want to quit alcohol, at a dose of 500mg/ day for one week and then 250 mg/day (Tab. Deadict 250 mg.) continued later and if our motivated person losses its control, then after consuming alcohol…….this time, no High, but lots of distressing problems will be waiting for him to fell like doom, for hours.

So, we use Disulfiram in the Aversion therapy….. but there are other drugs also which are given in different conditions and cause Disulfiram like reaction

Drugs causing Disulfiram like Reaction (Alcohol should be avoided strictly while using these)

• Metronidazole (Extensively used in amoebiasis and anaerobic bacterial infections) along with Tinidazole, Secnidazole, Ornidazole.
• Griseofulvin (Antifungal)
• Cefotetan (Second Generation Cephalosporin)
• Cefamandole (Second Generation Cephalosporin)
• Cefoperazone (Third Generation Cephalosporin)
• Chlorpropamide (Oral Antidiabetic drug belongs to sulfonylurea group)

Q. Why Disulfiram used in Aversion therapy? or Why Disulfiram cause Distressing symptoms in Alcoholics?

As we know that when a person consumes alcohol (Ethyl alcohol) then the enzyme Alcohol dehydrogenase act on it and will turn it into Acetaldehyde.

This aldehyde if not metabolized quickly then create all the distressing problems mentioned above and don’t forget that it is also responsible for the Hangover, from now onwards, if you hear salman Khan singing “ Hangover teri Yaadon Ka” then recall its not the memories of the girl responsible for his hangover, its the acetaldehyde formed due to consumption of ethyl alcohol.

So, this acetaldehyde is quickly metabolized by the Enzyme Aldehyde Dehydrogenase and convert our notorious acetaldehyde into acetic acid which is non toxic and metabolized by our body easily.

And this is the location where the Disulfiram act, it inhibit the enzyme Aldehyde Dehydrogenase and as the concentration of acetaldehyde rises in the blood the mentioned distressing symptoms occurs (also known as aldehyde syndrome).

Hope this article will help you understand the concept in a better way…

Happy Learning…….

We all have seen news about deaths of people dying suddenly, after consumption of “Poisonous” alcohol or read about this in newspapers …….

Why does this happen? why we are not able to prevent these deaths/casualties? why these all casualties belong to mainly lower socioeconomic groups?

well, lets discuss………..

The the causative agent behind this is mostly the inadvertent use of Methyl Alcohol…………..even small amount (15 ml) of methanol can cause blindness …….and 30 ml can cause death.

India, where the taxation on the Ethyl alcohol is extremely high, people of lower socioeconomic group attracted to the cheap alternatives for getting high, one of the method is locally made alcohol, this type of alcohol is illegally made in the farms without any proper temperature control and distillation methods or quality control and their whole idea is to make cheap alcohol, but sometimes, the methyl alcohol formed during the process, and the mishappening occurs………

Sometime we intentionally mix methyl alcohol in small quantity with ethyl alcohol to prevent ethyl alcohol from misuse eg. in Hand Sanitizers .

If we see the metabolism of methyl alcohol, it is similar to ethyl alcohol, at first the alcohol dehydrogenase act on methyl alcohol and the resultant is also aldehyde (formaldehyde) and later Aldehyde Dehydrogenase act on formaldehyde and Formic acid is formed.

Just like Ethyl alcohol it also follows the Zero order kinetics.

I hope you remember my last blog about Disulfiram where we discussed about metabolism of Ethyl Alcohol (https://pharmacology.life/2021/08/04/disulfiram-like-reactions/)

All the toxic effects of methyl alcohol are due to Formic Acid……..The further metabolism of formic acid is slow, later it is converted into carbon di oxide, which is folate dependent process.

The Problem started few hours after consumption methyl alcohol. The patient has Headache, Nausea, Vomiting, Pain abdomen, disorientation, hypotension and visual symptoms (Loss of visual acuity, ocular damage, dilated pupils which are non reactive)

The formic acid is specifically toxic to the Retina (Cause retinal damage and ultimately blindness, even in small amount of 15 ml)

Formic acid also cause severe acidosis, circulatory collapse, bradycardia, coma, respiratory depression and cause of death is usually due to respiratory failure.

How can we manage Patients of Methyl Alcohol Poisoning ?

1. We keep the Patient in dark room to protect eyes from light.

2.Gastric lavage with Sodium Bicarbonate and

3. IV sodium bicarbonate is used to prevent damage from Acidosis. It is one of the most important measure, as it can also help in preventing retinal damage.

4. Ethyl alcohol (10% in water) given through Nasogastric tube (I repeat, through Nasogastric tube, No IV Formulation for alcohol is available till date). it acts by saturating the aldehyde dehydrogenase, so less aldehyde dehydrogenase is available for the methyl alcohol and hence less Formic acid. (Though, think about the awkward situation where a family brings a patient of Methyl alcohol poisoning, and you are asking for alcohol and giving it to the patient by nasogastric tube)

5. Specific antidote – Fomepizole, well previously we use this name only for answering the viva questions, because in reality it was not commercially available in India. But in 2019 a Gujarat based Pharmaceutical company Zydus Cadila has launched the fomepizole injection (Thankfully, and the rate is also nearly 900 rs for 1.5 gm injection and if you are thinking why 1.5 gm, then calculate the amount of fomepizole for 60 kg patient as mentioned below)

And Fomepizole is way much better and preferred than Ethyl alcohol, because of its specific action in inhibiting aldehyde dehydrogenases. Fomepizole is used IV with loading dose of 15 mg/kg over 30 mins, followed by 10 mg/ kg every 12 hours, One more point to be noted that Fomepizole is also drug of choice in Ethylene glycol poisoning.

5.Hemodialysis can be done

6. Folate therapy– Folinic acid (Calcium leucovorin) 50 mg injected six hourly reduce formic acid level by increasing its oxidation.

Hope this information will help you to understand the current scenario of Methyl alcohol poisoning in India…………

Happy learning………………….

As we all know that Morphine is an excellent analgesic, used in acute pain conditions like trauma, cancer pain, acute myocardial infarction pain etc.

But Morphine use is contraindicated in Patients with head injury ……..WHY?

• Morphine causes marked Respiratory depression in dose dependent manner.

Due to respiratory depression there is retention of carbon di oxide

• This leads to cerebral vasodilation, which cause Increased intracranial tension, which can lead further brain damage and may be fatal.

• Morphine interfere with assessment of Head injury patient prognosis (As in assessment of head injury patients pupillary signs are important).

Morphine itself produces Miosis, Altered mental state and can cause vomiting also, which interfere with head injury assessment.

So due to all above mentioned causes, its better to avoid morphine in a patient with head injury……….

Hope you enjoyed the explanation…….. Happy learning

Lets imagine, that during Medicine ward posting, attending Medicine OPD, you note that a patient comes to the Physician with his medical test reports which were previously prescribed by the Physician, while writing the prescription to the patient the physician tells you to observe the findings in that patient…

You notice that patient is a male, nearly 60 year old, overweight, having dyspnoea, you also notice peripheral edema, with basal crepitation’s (Congratulations, you know how to use your stethoscope) and tender hepatomegaly…..

You also observe that in his medical report he is carrying Chest X Ray, ECG, ABG and Echocardiography with routine blood tests (well good, you are attentive too).

you submit your findings and Physician tells you that it was a case of Acute Congestive Heart Failure and he also tells you that the patient has been admitted in hospital and prescribed with Inj. Furosemide 80 mg IV stat repeated after 3 hours with other medications.

Now watching you, straight into your eyes and with a smile on face, he asks you ” Why Furosemide is given to this patient”?

can you tell the answer…. if you are thinking about the “diuretic action of furosemide“, yes its partial correct answer but it cannot describe the dramatic quick response seen in congestive heart failure patients especially Left ventricular heart patients…..to know the answer ..lets dive deeper……

High ceiling diuretics (Furosemide,bumetenide) are used for mobilizing edema fluid (as this a condition of heart failure….heart is fail in doing its normal work and there is accumulation of fluid in the lungs and the peripheral organs leading to congestive symptoms)

As we know that IV furosemide is given in the congestive heart failure and it quickly relives the congestive symptoms even before its diuretic action, the reason is…….. furosemide increases the prostaglandin formation and cause systemic venodilation and the fluid present in the pulmonary circulation now shifts to the systemic circulation, this provide a quick relief from the dyspnoea and patient feels better, later on the diuretic action of furosemide starts (yes, you were right too) and the excessive fluid from the body is execrated providing further symptomatic relief.

So, for the early quick response, credit goes to the Prostaglandin releasing effect of furosemide which cause venodilation…….

Some Interesting facts related to this topic–

1. This type of symptomatic relief can be achieved by use of Morphine also https://pharmacology.life/2021/08/20/use-of-morphine-in-acute-left-ventricular-failure/
2. After prolonged use resistance may develop to the high ceiling diuretics and to overcome this resistance we add spironolactone.

Use of furosemide/ Morphine provide only symptomatic relief, ACE inhibitors or ARB,s are given concurrently to retard the progression of disease and to decrease mortality (along with other drugs as per the stage of CHF).

Q. In Acute left ventricular failure Morphine is used by intravenous route and it provides nearly dramatic relief why?

Explanation- As Morphine has vasodilatory action (Due to histamine release and depression of vasomotor center)…….it reduces preload of blood, and there is shifting of blood from pulmonary site to systemic circuits (due to greater vasodilation in the systemic blood vessels) which ultimately relives pulmonary congestion and edema

Morphine acts also by its calming effects and thus decreasing the sympathetic stimulation and finally it reduces the cardiac work.

Morphine is used specifically in acute left heart failure…..as it only helps to shift blood from lungs to systemic circuit

Hope you understand the concept…….Happy learning

It is a condition of Acute severe Asthma which is usually precipitated by upper respiratory tract infection, sometimes Drugs like NSAIDs , Acute emotional stress or Inhaled allergens can also lead to status asthmaticus.

It is considered as medical emergency and no wonder, that its management is asked commonly by the examiners.

It usually occurs to the asthmatic patients, having non allergic type of asthma (Intrinsic), and taking routine inhalational bronchodilators is mostly of no use because of dense mucous plug, which blocks the drug to reach its site of action and this attack may soon lead to hypoxemia and acidosis.

Usually patient appears with severe signs and symptoms…..

Initial symptoms are like asthma (wheezing, coughing, shortness of breath) and it does not respond to the regular inhalational bronchodilator therapy and soon lead to status asthmaticus where high pitched wheezing with absent breath sound, hypotension and bradycardia may present…

Patient usually seems agitated or confused, oxygen saturation lower then 90 %, PEFR (peak expiratory flow rate) is less then 30%, cyanosis (bluish tint to the lips) and exhaustion can be seen.

So here we are dealing with

(1) Immediate and severe bronchoconstriction and (2) respiratory tract infection (mostly)

and the treatment protocol is………….

• Highflow humidified oxygen inhalation, usually 4L/min , maintain SpO2 more then 90%

• Injection Hydrocortisone 100 mg i.v. stat, followed by 100 mg four hourly infusion

• Injection Salbutamol / terbutaline 0.4 mg i.m/s.c.

• Nebulized salbutamol + Ipratropium bromide intermittent inhalation

• Antibiotic therapy for chest infection (Precipitating factor)

• And also correct dehydration (Parenteral administration of 5% Glucose saline)
• Treat acidosis by sodium bicarbonate infusion
• Intubation and Mechanical ventilation, if needed.

Lets start SERM in brief…………

Tamoxifen, Raloxifene and Toremifene are the example of SERMs

Tamoxifen – Estrogen receptor antagonistic activity in Breast, used in the treatment and prevention of breast carcinoma.

Toremifene– Newer congener of tamoxifen

Raloxifene– Used in Prevention and treatment of osteoporosis in postmenopausal women.

Now after short briefing, lets dive deeper…………………

Well, as we know that female hormone Estrogen plays a variety of roles.

It decreases the bone resorption

It improves the lipid profile

But it increases the risk of Brest and endometrium carcinoma also

So, while giving the estrogen due to any cause (eg. in postmenopausal women as Hormone replacement therapy or to prevent osteoporosis in menopausal women) we are having some good and wanted effects and some unwanted/deleterious effects like increased incidences of breast and uterus carcinoma.

And after lots of experiments especially on the ovariectomized rats, SERMs were introduced which have agonistic action on estrogen receptors in some tissues and antagonistic action on other tissue in a selective manner. In another words they have estrogenic or antiestrogenic effects depending on tissues.

Tamoxifen-

Estrogen antagonistic activity  – In Breast

Estrogen agonistic activity – Bone and uterus

It is used in the treatment of breast carcinoma in postmenopausal women with more prominent effect on estrogen receptor positive tumors.

Also used in Prevention of breast carcinoma in high risk women

Increased bone density due to reduced bone resorption (estrogen agonistic activity)

Tamoxifen is a orally effective drug with long duration of action.

Due to its agonistic/ estrogenic activity on uterus, it increases the chances of endometrial carcinoma.

It increases the chances of thromboembolism due to increased blood coagulability (induction of synthesis of clotting factors II, VII, IX & X).

Nausea, vomiting , anorexia, hot flushes, vaginal dryness skin rashes can also occur.

Toremifene

It is a newer congener of Tamoxifen with similar effects and side effects, indicated in treatment of metastatic breast cancer in postmenopausal women.

Raloxifene

Estrogen receptor Agonist at bones

Used in Prevention and treatment of osteoporosis in postmenopausal women.

And it has antagonistic activity at endometrium and breast

Hence no increased chances of endometrial and breast carcinoma.

And it is also approved for prevention of breast cancer in high risk women

Side effect profile includes – hot flushes, vaginal bleeding

However increased chances of thromboembolism is also a serious concern which also increases the chances of deep vein thrombosis and pulmonary embolism.

So, this is SERM in a brief manner….

Hope this article helps you to understand the concept better………Happy learning

Now, I have taken this challenge to simplify Bisphosphonates,  let me try to complete this task in three sentences…..

1. Bisphosphonates are the drugs commonly used for treatment of Osteoporosis.
2. Example are Alendronate, Zoledronate (zoledronate is most potent, given by infusion in dose of 4 mg yearly, i repeat, once every 12 month, for t/t of osteoporosis)
3. Esophageal irritation, erosion and ulcers with oral drugs are common and renal toxicity, osteonecrosis of jaw are seen with use of zoledronate

Now if i get your attention………..lets dive deeper

Bisphosphonates are the drugs which act by decreasing the activity of osteoclasts,  they get entry in osteoclasts by endocytosis and they –

1. Increased apoptosis of osteoclasts
2. Inhibit differentiation of osteoclast precursors (this is method by which osteoclasts are formed) by suppressing IL-6

If we talk about pharmacokinetics, Bisphosphonates are poorly absorbed from GIT and produce esophageal irritation, erosion and ulcers as major side effects.

To prevent these side effects of oral bisphosphonates, it is advised to take these drugs empty stomach with full glass of water, and instruction is given to patient “not to lie down for at least thirty minutes after taking these drugs” , these measures prevent the contact of drug from esophageal mucosa.

These drugs are divided into three generations

First generation –  Etidronate

Least potent, rarely used now a days

Second generation – Alendronate, Pamidronate

Third Generation– Risedronate, Zoledronate

More potent, Higher efficacy

These drugs are widely used for-

1. Osteoporosis – Idiopathic osteoporosis, age related osteoporosis, steroid induced osteoporosis, postmenopausal osteoporosis etc.  
2. Hypercalcemia of malignancy– common complication in malignancy, this is a condition of medical emergency. oral bisphosphonates are not useful. Pamidronate or zoledronate are used.
3. Bone metastasis (Osteolytic)– Due to osteolytic suppression action, they are useful in stopping osteolytic lesions and reduce bone pain
4. Paget’s disease– this is a disease caused due to abnormal osteoclast activity, thus  bisphosphonates are useful

Now a days, Bisphosphonates are the First choice drugs for osteoporosis

Zoledronate has also antitumor effect (it additionally interfere with mevalonate pathway)

A male name Ramesh,42 years, bank clerk, was bought in Community Health Center emergency department at 9:00 pm with complaints of chest pain from evening, which was radiating to the left shoulder, vomiting, sweating, shortness of breath were also present.

On examination he seems pale and fearful, his BP was 110/70 mm hg, ECG shows typical ST elevation and cardiac marker (Troponin-T) is also increased.

Q. If you were in place of that doctor, how will you manage this patient before referring him to higher center?

So, in this hypothetical scenario, the patient is suffering from ST segment elevated MI (STEMI), we can save this patient by –

a) Reliving pain and apprehension

b) Preventing further damage produced by the infarct and also reduce the infarct size

c) Preventing complications and further attack

So we give…………….

1. Morphine 10 mg, Intravenous route – you can administer IM also, because time is the key here. it act by reliving pain, and by decreasing preload and afterload. Sometime, if morphine is not available then we use Diazepam IV to reduce anxiety, but morphine is preferred (as morphine control apprehension, has positive effect by decreasing preload and afterload, and also excellent pain control)
2. Glyceryltrinitrate (GTN) 0.5 mg sublingual is administered quickly and repeat after five minutes, upto three doses if needed (Monitor BP, as patient can go into hypotension as in this case, start the IV infusion of saline/dextrose to maintain blood volume, but take care of volume overload also)
3. Streptokinase 1.5 million units infusion given over 1 hour. As we know that it is thrombolytic agent which is antigenic in nature (because it is obtained from beta hemolytic streptococci), so it can produce allergic reactions, but still used at primary and secondary referral units (irrespective availability of better, non antigenic thrombolytic agents like Alteplase), because of its low cost (Streptokinase costs nearly 2,000 INR compared to alteplase which costs nearly 40,000 INR). Note- contraindications of the thrombolytic therapy are – recent history of surgery, stroke, bleeding disorders etc.
4. Aspirin 300 mg orally , to be given immediately. It is an antiplatelet drug and can reduce mortality and should be continued even after recovery.
5. Metoprolol (first IV then orally), if given at early stage can reduce the infarct size and possible consequences and has effect of reducing arrhythmias and mortality (if no contraindications eg. Asthma)
6. ACE inhibitor – Enalapril 5 mg two times a day orally, to be given as early as patient is stable hemodynamically (do not give in hypotensive patient), they afford survival benefit in long term by reducing progression of heart failure and preventing cardiac remodelling.

Now a days Primary Percutaneous coronary intervention (PCI) with stenting/ coronary angioplasty is preferred in place of fibrinolytic agents, but availability of Infrastructure and Clinician are major issues especially at primary and secondary level

Hope you enjoyed the topic…………. Happy learning

These are the adhesive patches which contains the drug and when applied to the skin surface, they deliver the drug at constant rate, into the systemic circulation

Glyceryl trinitrate, Fentanyl, Nicotine, Oestradiol, Isosorbide dinitrate , Hyoscine are example of drugs which can be administered through Transdermal patches

Diclofenac transdermal patch are also now available.

The Transdermal therapeutic system contains the drug in reservoir (a place where drug is stored) and the release of drug is controlled by another layer having micropores.

when the adhesive layer is applied on skin, the drug from the reservoir part is delivered to the skin in a controlled manner (yes, due to rate controlling micropore membrane)

Advantages of the TTS (Transdermal therapeutic system)

• Prolonged and sustained effect of drug is maintained (Duration of action is increased and at constant plasma level)
• Patient compliance is good (what an easy and convenient way to administer a drug…..)
• Little first pass metabolism

Disadvantages of the TTS

• Can cause local irritation, erythma. (usually mild, can be minimized by applying it to different site every time).
• Comparatively more expensive
• Large doses of drug cannot be given

lets have some example of the patches and their uses…….

1.Glyceryl trinitrate transdermal patch — used in angina pectoris — applied at chest

2.Nicotine transdermal patch –used to quit smoking—applied at arm

3.Testosterone transdermal patch— used in testosterone deficiency—applied at scrotum

4.Fentanyl transdermal patch— used to produce analgesia (eg. in cancer pain)— applied at arm/back

Hope you enjoyed the concept ……. have a great time ……

Starting with definition……..

Drugs which can be legally procured without the prescription of a registered medical practitioner.

So, in brief these drugs does not requires prescription or these drugs can be taken as self medication.

This concept is more popular in the USA where their drug regulatory authority US Food and Drug Administration (USFDA) classifies their drugs into –

• Drugs which are restricted to sale by prescription
• And nonprescription or over-the-counter medications

The USFDA reviews the OTC ingredients for both safety and efficacy and they can also switch the drugs from prescription drugs to non prescription category after proper reviews, when they think that these drugs are safe for use without medical supervision.

In USA directions for safe use of OTC agents are mentioned on leaflets in form of “Drug Facts” label which includes indications, contraindications (when to use and when not), status in pregnancy etc. They also provide their information regarding OTC drugs online.

you can visit the site of USFDA by clicking on the following link and see the switch list of drugs…..

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/prescription-over-counter-otc-switch-list

While in India we don’t have any Separate category of “OTC drugs” in Drugs and Cosmetic rules 1945 (D&C rules 1945).

“Oh”, then how we decide that which drug is OTC in India ?

As we don’t have any legal definition of OTC drugs in D&C rules 1945, we have list of prescription only drugs (Drugs which need prescription to procure, eg. drugs in schedule G,H,H1 and X), and drugs which are not mentioned in these lists are considered as OTC drugs in India.

Ayurvedic Medicines / Herbal ingredients does not need sale license and can be sold even by non chemist also.

So, hopefully this information will make you understant this topic more clearly……

Have a great time…….........

Case based Learning of Pharmacology –

Q.     A 30 years old female came to the OPD with complaints of weakness, feeling tired all the time, sudden weight gain, puffiness on the face and eyelids and headache.

On further examination she gives history of irregular scanty menses and intolerance to the cold, also dry skin and dry, brittle hair along with brittle nails, she has heart rate of 52/ min (bradycardia) with ECG showing long PR interval and flat T wave.

The diagnosis is confirmed by the blood reports which shows raised serum TSH and low serum free thyroxine (FT3 and FT4).

• What is the diagnosis and
• How will you manage this patient ?

Answer-

• It is a case of Hypothyroidism, which is one of the commonest endocrine disorders.
• To mange this patient we give Levothyroxine (synthetic salt of Thyroxine i.e. T4 )

Here now, the treatment strategy is to provide thyroxine (T4 ) by oral route and goal is to achieve normal TSH level.

Levothyroxine 50-100 mcg/day empty stomach is usually prescribed, and dose is adjusted by adding 12.5 or 25 mcg Levothyroxine gradually, if TSH is still high or decrease the dose by  12.5 or 25 mcg if TSH is suppressed.

If T4 and TSH both are low or both are high, then refer this case to the endocrinologist as it indicates the pathology at Hypothalamus or Pituitary level.

• Clinical Gems-
• Levothyroxine should always be given empty stomach to avoid interaction with food as it can impair the absorption of levothyroxine.
• Always explain to the patient that treatment is lifelong and the decision to modify dose or stop treatment should be done with proper consultation always.
• In pregnant hypothyroid patient, it is really important to take daily dose of Levothyroxine and maintain normal thyroid level, as it can affect the foetal brain development.
• Hypothyroidism can cause infertility in females due to frequent anovulatory cycles and it can be managed by restoring normal thyroid level.
• Myxoedema coma is a condition of medical emergency, arises as an end state untreated hypothyroidism, although rare, it has high mortality.
• Treatment of choice in Myxoedema coma is LevoThyroxine 500 mcg given as IV bolus and then 100 -300 mcg daily, along with warming the patient, iv corticosteroids, correction of metabolic disturbances and other symptomatic measures like mechanical ventilation for respiratory failure.

Hope this post will help you to understand concept more clearly……….Happy learning……..

Five Points you Must know (about ACE inhibitors) –

1. These are the First Line Antihypertensive drugs in all Grades of Hypertension. As the name suggest, they inhibit the Angiotensin converting Enzyme in Renin Angiotensin Aldosterone System (RAAS). This RAAS physiologically regulates the electrolyte balance and plasma volume of body.
2. Captopril, Enalapril, Lisinopril, Perindopril, Fosinopril, Ramipril, Benazepril are example of ACE inhibitors.
3. All ACE inhibitors are Prodrugs (Except Captopril and Lisinopril).
4. ACE inhibitors are used in – (a) Hypertension– first line drugs in all grades of Hypertension (b) Congestive cardiac failure -Standard therapy for all grades of CHF, as they provide symptomatic improvement, decreased mortality as well as Hospitalization (c) Myocardial infarction – When given within 24 hours of an attack and then continued, then they reduce early and long term mortality (d) Diabetic nephropathy – long term therapy is proven useful in preventing progression of renal disease as well as proteinuria in diabetic patients. (e) Chronic renal failure– delays the progression of failure. (f) scleroderma renal crisis– it is an medical emergency in rheumatology, presented as acute onset renal failure with marked hypertension and ACE inhibitors have life saving effect in this condition (as this crisis is mediated by Angiotensin II)
5. Major side effects are– (a) Cough -Due to increased level of bradykinin, often discontinuation of the drug is needed and Angiotensin -II receptor antagonist like Telmisartan can be used in place of ACE inhibitors (b) Hypotension (c) Hyperkaliemia – cautious use with other drugs which increase K+ like NSAIDs (d) Teratogenicity – ACE inhibitors are contraindicated in pregnancy. Fetal growth retardation and hypoplasia of organs and fetal death can occur especially if given during second or third trimester of pregnancy. (e) Renal artery stenosis patients– ACE inhibitors can precipitate acute renal failure ion patients with renal artery stenosis hence contraindicated in same.

So lets recall once again, ACE Inhibitors like enalapril are first line drugs in hypertension, they are contraindicated in pregnancy and dry cough is their common side effect.

Hope this will help you to remember the concept easily…………………… Have a great day

Hello students,

Hope you are doing great……………Today we are going to know about a very important drug in pharmacology, which is Furosemide.

Now let oversimplify the facts about Furosemide in four easy points……

(1) Furosemide belongs to Loop Diuretics group…….These loop diuretics (Furosemide, torsemide, ethacrynic acid, bumetanide act by inhibiting Na+/ K+/ 2cl– transporter in the Thick Ascending loop on the kidney (that’s why the name loop diuretic).

(2) Loop diuretics are very powerful diuretics and are also known as High ceiling diuretics, which means as the dose of these drugs increase their diuretic effect also increases even at higher levels.

(3) used in –

1. Acute pulmonary edema – it can be due to acute left ventricular failure, Quickly or dramatic response by IV furosemide (vasodilator effect cause immediate relief and then fluid reduction due to diuretic effect)
2. Edema – Highly effective in edema of all origins (Cardiac, hepatic or renal)
3. Congestive cardiac failure– help by reducing fluid overload.
4. Hypertension – though thiazide diuretics are preferred in hypertension, but we can use furosemide in hypertension with renal insufficiency, or in resistant cases in hypertensive emergencies.
5. Sometime it is used along with blood transfusion to prevent volume overload in severely anemic patients.
6. Acute hypercalcemia – like in condition of hypercalcemia of malignancy.
7. Hyperkalaemia – can be treated by furosemide, given along with Nacl and water.

(4) Side effects are-

1. Hypokalemia – dose dependent
2. Hypocalcemia
3. Magnesium depletion
4. Hyponatremia – diuresis and hyponatremia can further cause hypovolemia and hypotension, which is treated with saline infusion if needed
5. Ototoxicity – seen with higher doses especially when used IV and generally reversible. more common with other loop diuretic ethacrynic acid (in which ototoxicity is irreversible). SHOULD BE AVOIDED WITH OTHER OTOTOXIC DRUGS like aminoglycosides.
6. Hyperglycemia- Caution in Diabetes
7. Hyperuricemia
8. Allergic reactions like skin rashes are more common.

So, Lets recap- Furosemide is a High ceiling (loop) diuretic, act by inhibiting Na+/ K+/ 2cl– transporter in the Thick Ascending loop.

Useful in Left ventricular failure and edema of all origin, produce loss of K+, Ca+ Mg+ .

Hope you enjoyed the concept…………….

PPIs are one the most commonly used drugs now a days, lets learn some important and interesting facts about Proton Pump Inhibitors (PPIs)

(1) Proton Pump Inhibitors are the most effective drugs for inhibiting the gastric acid secretion. They act by inhibiting H+K+ ATPase (Proton Pump) present in Gastric Parietal cells and this inhibition of proton pump is irreversible.

(2) Drugs in this group are – Omeprazole, Pantoprazole, Esomeprazole, Rabeprazole, Lansoprazole, ilaprazole etc. These drugs are Prodrugs.

(3) These are drug of choice in –

a. Peptic Ulcer Disease (due to any etiology)

b. Gastroesophageal reflux disease (GERD)

c. Zollinger Ellison Syndrome

(4) The PPIs are given empty stomach (One hour before food) and the reason are-

• When drug reaches at its peak level then at the same time, it will get the highest active proton pumps to act.
• Bioavailability of all PPIs are reduced by food, so by taking before food, we can improve bioavailability .

(5) These are very safe drugs and are well tolerated with minimal side effects.

These drugs have shown no harmful effects during pregnancy in humans, but have shown to be harmful in rodents, and despite showing the advice to avoid PPIs in pregnancy by the manufacturers, they are often prescribed during pregnancy.

Loose stools, headache, abdominal and joint pain can be feel by few.

On long term use (in years), they can cause Vitamin B12 and calcium deficiency due to their reduced absorption.

Now some more interesting facts about PPIs-

HIT & RUN drugs – As all PPIs have plasma t1/2 of 1-2 hours, but they inhibit the proton pump irreversibly and hence achieve the inhibition of acid secretion which lasts for 2-3 days (long after the drug is execrated hence, Hit & Run drugs)

• All PPIs are available orally, while Pantoprazole and Esomeprazole can be given IV .
• Oral PPIs are available as Enteric coated or delayed release form to protect them from molecular transformation in the acid in the stomach.
• Though PPIs act on parietal cell of stomach, they are weak bases and absorbed from the intestine.

Hope this post will help you to understand the PPIs more clearly………all the best

Pharmacology

It is the science of drugs.

Clinical Pharmacology

Scientific study of drugs in humans is termed as clinical pharmacology.

Drug

As per WHO drug is “Any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient”.

Receptor

A receptor is a macromolecule, which recognize the drug (or signal molecule or agonist) and initiate a response.

Affinity is the capacity of a drug to bind a receptor.

when a drug is combined with receptor, the ability of drug to activate the receptor is termed as Intrinsic activity. (Intrinsic activity can vary from +1 to 0 to -1, where +1 indicates the maximum intrinsic activity, shown by agonist and 0 means no intrinsic activity and this is seen in antagonist)

Agonist-

Agonist is a substance, which binds to the receptor and produce response.

It has affinity (yes, it needs to bind from receptor to produce a response)

It has maximum intrinsic activity (i.e +1, means it has ability to activate receptor at its maximum capacity)

Antagonist-

Antagonist is a substance which binds to receptor (yes, it has affinity), But it produces no response….i repeat, it produces no response means its intrinsic activity is Zero.

In other words we can say that it prevent the agonist from acting on receptor (because antagonist attached from receptor), but itself antagonist produce nil response (How innocent….)

Pharmacokinetis

“What the body does to the drug”.

In pharmacokinetics we study how the drug is going into, through and out of the body and how does the body is affecting the drug during whole process. we divide pharmacokinetics into absorption, distribution, metabolism (biotransformation) and execration (ADME).

Pharmacodynamics

Is “What the drug does to the body”

It is the study of actions of drug on the body and their mechanism of action, so, we can say that in this branch of pharmacology, we study how the drug works in our body and we study about Mechanism of drug action, receptors, effect of the dose and how they interact with physiological systems.

Essential medicines

As per WHO ” Essential drugs are those drugs that satisfy the priority healthcare needs of the population.”

we select these drugs with the relevance of the population, they must be effective and safe, cost effective, and available all the time in adequate amount and appropriate dosage forms in healthcare facility.

Pharmacovigilance-

As defined by WHO ” science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems”

Pharmacogenetics

This branch deals with variability in drug response due to genetic basis.

Pharmacogenomics

Now this branch use the knowledge of genetics to guide the proper drug and its dose on an individual basis.

“Confused” …………..let me help you, when you just study a drug that how does it differ from person to person due to their genetic difference it is termed as Pharmacogenetics.

But when you study the genetic information and decide which drug and in what dose is best suited as per the individual genetic makeup then it is Pharmacogenomics.

Oswald Schmiedeberg- Father of Pharmacology

Hope this post will help you to remember these definitions……….Happy learning…

Five Must Know points about Statins-

(1) HMG- COA reductase inhibitors AKA Statins are Most commonly used hypolipidemic drugs.( As they are best tolerated and most efficacious among hypolipidemic drugs)

They act by Inhibiting enzyme HMG COA reductase, this enzyme is important in cholesterol synthesis, as it inhibit conversion of HMG-COA into mevalonate which is rate limiting step during cholesterol synthesis.

(2) Lovastatin, Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin, Pitavastatin are the examples of statins.

Statins are usually given at bedtime as HMG COA reductase activity (cholesterol synthesis) is maximum at midnight.

Atorvastatin and Rosuvastatin are longer acting statins (t1/2 nearly 16 and 20 hours respectively) they can be given anytime for treatment of hyperlipidemia.

(3) Cholesterol is needed by our body for bile acid and steroid hormones synthesis.

After taking statins, the cholesterol synthesis is decreased, and liver respond to this situation by increasing the uptake of LDL from plasma (LDL is low density lipoprotein contains only cholesteryl esters)

So, statins reduce the LDL and cholesterol levels significantly, they also reduce Triglyceride and VLDL slightly and there is slight increase in the HDL (good cholesterol).

(4) Mostly statins are taken orally, their main adverse effects are myopathy and hepatotoxicity.

That’s why concurrent use of any other drugs causes myopathy (like Fibrates, niacin, amiodarone and verapamil etc.) or hepatotoxic drugs/ Alcohol should be avoided.

Other side effects are GI disturbances, allergic reactions, rhabdomyolysis.

(5) So, if we talk about the uses of statins-

• The statins are the first choice drugs for the patients with raised LDL levels and total Cholesterol levels (First line drugs for the familial and secondary hyperlipidemias).

• They also produce multiple other beneficial effects (Pleotropic effects).

They reduce the platelet aggregation, reduce inflammation, decrease arterial smooth muscle proliferation etc. due to their antioxidant property.

As a result they are useful in lowering mortality and morbidity in patients of coronary heart disease (especially in all type of atherosclerotic cardiovascular diseases).

• They are commonly used in patients with Myocardial infarction (afford secondary prophylaxis), thrombotic stroke, peripheral arterial disease, new onset angina etc.

In brief –

Atorvastatin is commonly used hypolipidemic drug with additional antioxidant properties, can cause myopathy and hepatotoxicity.

Hope this post will make you understand the concept more easily…………………..Happy learning ……

Today we are going to discuss about prodrug.

Q. What is Prodrug?

The prodrug is a drug which is inactive initially and convert into active form by process of metabolism (one or more active metabolites are produced after metabolism in body ).

Q. But why this concept of prodrug is important?

The answer lies in process of metabolism. usually, when we take a drug our body deal with it by metabolism followed by execration, and three types of fates of this drug can be possible due to metabolism

1.Most of the drugs we consume are in active form and our body soon convert them into inactive form.

2. Many drugs we take are in active form and after consuming they are converted into another active form (one or more active metabolites).

for example Diazepam, it is an active drug used in the seizures, which is converted into oxazepam in body, which is also an active metabolite.

3.For few drugs there is Activation of inactive drug, as these drugs which are inactive initially, will convert into one or more active metabolites and these drugs are termed as Prodrugs.

Example of Prodrug-

Levodopa (Prodrug) – Dopamine (Active form)
Enalapril (Prodrug) – Enalaprilat (Active form)

Lets discuss about prodrug “Levodopa”

• Prodrug levodopa is used in Parkinsonism
• when taken orally, it crosses the blood brain barrier and converted into Dopamine (active form) by metabolism at site of action i.e. CNS.
• so, the active form of drug (Dopamine) is reached at the target organ (CNS) easily as dopamine itself can not cross the blood brain barrier.

Prodrugs can be used to

• Prolong duration of action

• Improve taste

• Increase availability at site of action (like levodopa) etc.

Hope you enjoyed the article…..

So, today we are discussing about factor Xa Inhibitors and why they are preferred over old , classic warfarin.

• As name suggest these drugs directly inhibit factor Xa (important factor of coagulation cascade in common pathway)
• Examples are- Rivaroxaban and Apixaben

They have several advantages over warfarin like

1. They act rapidly and have short lasting action (unlike warfarin which act through inhibiting synthesis of vitamin K dependent clotting factors, so having a lag time, as the preformed clotting factors have to cleared off the bloodstream first)
2. Lower risk of bleeding as compared to warfarin hence..
3. No laboratory monitoring is required (unlike oral warfarin where INR has to be measured daily (initially) and later weekly)
4. Equally effective as anticoagulant compared to warfarin .
5. Very few drug interactions (we know that warfarin is metabolized by CYP2C9 and CYP3A4, and are 99% plasma protein bound, hence warfarin is liable to more drug interactions)
6. Clear guidelines regarding dosage as per indications (where warfarin is required frequent laboratory monitoring and dose adjustments)

So, no surprise that these drugs have gained popularity.

They are used for :-

A. Prophylaxis of Deep vein thrombosis/Pulmonary embolism after knee/hip replacement, high risk bed ridden patients.

B. Treatment of Deep vein thrombosis/Pulmonary embolism

C. For prophylaxis of stroke /systemic embolism in patients of nonvalvular Atrial Fibrillation

Hope you enjoyed the concept ……..

Today we are going to discuss about aminoglycosides (and i try to keep it simple, promise)

Aminoglycosides are the antibiotics derived from the soil actinomycetes (a strain of soil bacteria).

Streptomycin was the first member which was discovered in 1944 by Waksman and his colleagues.

It was the first antibiotic which can be used for the treatment of tuberculosis and later Waksman was awarded by Nobel prize for this breakthrough discovery.

Structurally they are the amino sugars joined by glycoside linkage (i am just saying that they are polar compounds).

Now we know that they are polar compounds, highly water soluble (now if you recall your pharmacokinetics you can easily conclude that they have difficulty in crossing the cell membrane). Aminoglycosides are neither absorbed nor destroyed in the GIT.

Aminoglycosides are not absorbed orally – ALL AMINOGLYCOSIDES ARE GIVEN PARENTRALLY (by i.v or i.m route)

They have very less penetration in Blood brain barrier.

They act by inhibiting protein synthesis (bactericidal drugs).

They bind to 30 s ribosome and

1) Freeze initiation of protein synthesis,

2) Misreading of the code (by entering one or more amino acid in peptide chain)

3) Interfere with polysome formation.

Aminoglycosides are not metabolize in the body hence excecated by kidney in unchanged form.

They all produce nephrotoxicity, ototoxicity and neuromuscular blockade as adverse effects.

Nephrotoxicity is almost reversible, during ototoxicity, cochlear damage causes deafness and it is permanent while vestibular damage started as headache, later causes nystagmus, vertigo and ataxia which can take months in recovery (often incomplete).

Examples and uses of aminoglycosides are-

Aminoglycosides should be avoided during pregnancy as they can cause ototoxicity in fetus.

These drugs exhibit concentration dependent killing and have prolong time dependent killing hence can be administration as single daily dosage.

They show synergistic effects when combined with Beta lactam antibiotics or vancomycin against gram positive bacteria.

So, if you with me till now, i think we have understand some very basic concepts about aminoglycosides.

Have a nice day, happy learning.

Neomycin is an aminoglycoside antibiotic.

Due to its extreme nephrotoxicity, we cannot use it by intravenous or intramuscular route.

By giving orally it is not absorbed nor metabolized. If you want to read more about aminoglycosides you can clink on the link (Must Know Interesting Points About Aminoglycosides)

Use of Neomycin in hepatic coma-

In normal circumstances the NH3 produced by colonic bacteria is detoxified by the liver. Liver convert NH3 into urea, which is excreted by kidneys.

But in hepatic coma patient, the NH3 produced by colonic bacteria is not detoxified by the liver and NH3 level increases which further causes encephalopathy.

When we give neomycin orally. it kills the gut bacterial flora and due to less NH3 formation, the condition improves, usually it takes 48 hours to act.

Note- Now a days we prefer less toxic agent in hepatic coma like lactulose. (to know more click on the link- Lactulose use in hepatic coma )

Other uses of Neomycin

1. Orally we can use neomycin to reduce aerobic gut flora before surgery (preparation of bowel before surgery).

To cover the anaerobic infections we combined it with metronidazole, which help in reducing postoperative infections.

2) It is most extensively used topically for wounds – burn cases, ear infections, eye infections (here it is commonly combined with polymyxin, bacitracin etc. for better coverage)

Q. Why lactulose is used in hepatic coma patients?

Well, as we are aware that in hepatic coma patient there is failure of liver.

Normally, colonic bacteria produces NH3 which is converted into urea by the liver. This urea is execrated by the kidneys.

During hepatic failure the detoxification of the NH3 does not occur. This NH3 is easily absorbed in the blood and can cause hepatic encephalopathy.

When we give lactulose to this patient (given orally 20 gm or more, three times a day), lactulose is further converted into lactic acid and acetic acid in gut.

This acid medium decreases the PH of the gut and and the NH3 produced by the colonic bacterial flora is converted into NH4+ (polar ammonium ion) which is not absorbed.

In short we can say that lactulose if given in hepatic coma patients, prevent the encephalopathy caused due to NH3 by converting it into its non absorbable form NH4+ .

As now we can understand that lactulose dose not cure the problem, but can be helpful in improving the mental status.

Some other interesting points about Lactulose–

It is a semisynthetic disaccharide made up of fructose and lactose.

It is neither digested nor absorbed in the small intestine.

It is commonly used in the constipation. when taken 10 gm or more with plenty of water, it produces soft stools (it retains water and when broken by bacteria, it become osmotically more active ).

Hope this post is helpful to you in understanding the concept.

Q. Why does pyridoxine is used with isoniazid in Tuberculosis treatment ?

Answer- As we know that isoniazid is an anti-tubercular drug. It acts by inhibition of synthesis of mycolic acid (which is an important component of mycobacterial cell wall).

Though isoniazid is well tolerated by the patients, but in some, it can cause neurotoxicity such as peripheral neuritis and other neurological manifestations like paresthesia, numbness, mental disturbance etc.

So, we use pyridoxine to prevent and also to treat the neurotoxicity.

The prophylactic dose of pyridoxine is 10 mg/day whereas isoniazid induced neurotoxicity is treated by pyridoxine 100 mg/ day.

Hepatotoxicity is also a major adverse effect of isoniazid, which is dose related and is reversible when the drug is stopped.

Some extra interesting points about Isoniazid-

• Its is an excellent antitubercular drug which acts on TB bacilli extracellularly and intracellularly.
• It is also one of the cheapest antitubercular drug.
• Specifically fast multiplying organisms are killed rapidly.
• It is an essential component of all antitubercular regimens (unless it is intolerable or resistant).
• It is also used in prophylaxis of tuberculosis (given for six months, daily)

Hope, this post is helpful to you in understanding this basic concept.

Have a nice day, happy learning………..