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)

Note- The Methotrexate toxicity cannot be overcome by directly giving folic acid- as it is not able to convert into its active form due to methotrexate. (while folinic acid can be directly utilized).

Hope this information is useful to you…….  

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.

In our body pyridoxine acts after activation (it is converted into coenzyme pyridoxal phosphate). This activation is interfered by isoniazid and there is increased excretion of pyridoxine also.  

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………..

Answer-

Advantages of LMW heparin over heparin are

1. 1. LMW heparin is longer acting (longer t1/2)– it can be given S.C. once daily.
   2.  Better bioavailability and has consistent action with predictable response- variability in response is minimised
   3. aPTT/ clotting times are not prolonged – laboratory monitoring is not needed
   4. Low risk of HIT syndrome
   5. Lower risk of osteoporosis compared with heparin – safer for long term use.

Answer-

Addition of vasoconstrictor in local anaesthetics (LA) leads to vasoconstriction of that local area (obviously....), due to which

1. Duration of action of LA is prolonged (by decreasing their rate of removal from the local site into the circulation)
2. Systemic toxicity is also reduced (more LA is available at site for more duration and less systemic distribution)
3. Provide more bloodless field for surgery (less blood loss due to vasoconstriction)

Q. Explain why Amoxicillin is used in combination with clavulanic acid

                               or

Q. Explain why Ampicillin combined with sulbactam

                               or

Q. Why Piperacillin is combined with Tazobactam

Answer-

Many gram positive and gram negative bacteria produces enzyme β lactamase.

And this β lactamase enzyme inactivates the beta lactam antibiotic (like Amoxicillin, Ampicillin, Piperacillin).

As the name suggests β lactam antibiotics have β lactam ring in their structure and this ring is targeted by β lactamase enzyme to make these antibiotics ineffective.

These β lactamase inhibitors (like Clavulanic acid, Sulbactam, Tazobactam) are combined with β lactam antibiotics (like Amoxicillin, Ampicillin, Piperacillin) and inhibit bacterial enzymes (β lactamase).

So we use

The β lactamase inhibitors are also known as suicide inhibitors as they also get inactivated after binding with bacterial enzymes.

These β lactamase inhibitors does not posses any antibacterial activity but they protect the β lactam antibiotics from the bacterial enzymes (β lactamase).

Q. Explain why pyridoxine is given 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 paraesthesia, 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.

Q. Why lactulose is used in hepatic coma patients?

Answer -  as we are aware that in hepatic coma patient there is failure of liver.

Normally, colonic bacteria produce 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 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.

Q. Why Neomycin is used in hepatic coma patients?

Answer - 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

Q. Why Carbidopa is combined with Levodopa in treatment of Parkinsonism ?

Answer-

• In parkinsonism there is deficiency of Dopamine, in the nigrostriatal tract, due to loss of Dopamine secreting neurons
• To treat this condition we give Levodopa which is the precursor of the Dopamine
• Levodopa is decarboxylated by the enzyme Dopa Decarboxylase and provide Dopamine in the brain and peripheral tissues.
• But, peripheral tissues like liver and intestine also contain the enzyme Dopa Decarboxylase and when taken orally they decarboxylase more then 95% of the Levodopa and as result most of the dopamine is acting peripherally and producing side effects (remember the target was to increase dopamine in the brain)
• So we use Peripheral Decarboxylase inhibitors (Like carbidopa and benserazide) and as the name suggest they inhibit only peripheral Dopa Decarboxylase, as carbidopa cannot cross Blood brain barrier.
• That’s why, when levodopa is given with carbidopa, carbidopa prevent the peripheral conversion of levodopa into dopamine.

Benefits of combining Levodopa with Carbidopa/Peripheral Decarboxylase Inhibitor

1. The dose of levodopa is reduced by 75% , as now no conversion of levodopa into dopamine peripherally.
2. Due to reduced systemic concentration of Dopamine, systemic side effects like Nausea, Vomiting (due to CTZ stimulation, and if you recall its the area which is not covered by BBB) and Cardiac complications are also reduced (Dopamine produce tachycardia due to cardiac stimulation).
3. Due to sustained effect of cerebral dopamine level On – Off effect is also minimized (after continuous therapy of Levodopa, after two to five years, when we take levodopa there is rapid improvement of the symptoms (eg. in hypokinesia and rigidity) and after some time (few hours) there is loss of therapeutic effects (On and off), after taking levodopa again improvement in symptom and again quick loss (aka On-Off effect).

so its beneficial to add levodopa with carbidopa, we have to use less dose, with lesser side effects and sustained level of dopamine in brain.

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

Answer - 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.

Q. Explain why furosemide is used in acute left ventricular failure?

Answer-  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 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 vasodilation…….

Q. Morphine use is contraindicated in Patients with head injury?

Answer-

1. Morphine causes marked Respiratory depression in dose dependent manner.
2. 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.
3. 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.