Pharmacology Sem-VI Solved Question Bank PDF

PHARMACOLOGY-III QUESTIONS FROM PREVIOUS YEAR QUESTION PAPERS UNIT-1: 1. PHARMACOLOGY OF DRUGS ACTING ON RESPIRATORY SYSTEM SHORT ESSAYS (05 MARKS) 1. What is bronchial asthma? Classify drugs used in its treatment. (DEC -2020)...

PHARMACOLOGY-III QUESTIONS FROM PREVIOUS YEAR QUESTION PAPERS UNIT-1: 1. PHARMACOLOGY OF DRUGS ACTING ON RESPIRATORY SYSTEM SHORT ESSAYS (05 MARKS) 1. What is bronchial asthma? Classify drugs used in its treatment. (DEC -2020) Bronchial asthma is characterised by hyperresponsiveness of tracheobronchial smooth muscle to a variety of stimuli, resulting in narrowing of air tubes, often accompanied by increased secretion, mucosal edema and mucus plugging. Symptoms include dyspnoea, wheezing, cough and may be limitation of activity. 2. Mention xanthine derivatives and write their mechanism of antiasthmatic action. (MAR- 2021). Methylxanthines: Theophylline (anhydrous), Aminophylline, Choline theophyllinate, Hydroxyethyl theophylline, Theophylline ethanolate of piperazine, Doxophylline. Mechanism of Action: Methylxanthines act by the following mechanisms: i. Phosphodiesterase (PDE) is the enzyme that degrades cyclic-AMP. Methylxanthines inhibit PDE (PDE3, PDE5) and thereby enhance cAMP levels. cAMP brings about bronchodilation, and also inhibits the release of mediators of inflammation like cytokines and chemokines. ii. Methylxanthines are antagonists at adenosine receptors. It is now known that adenosine induces contraction of smooth muscle cells in the airways and stimulates histamine release from airway mast cells. Hence antagonists of the adenosine receptors cause bronchodilation. iii. Acetylation of histones is involved in the activation of inflammation. Methylxanthines enhance deacetylation of histones and have been also shown to enhance or restore the responsiveness to glucocorticoids in asthmatics and COPD patients. 3. What are respiratory stimulants? Explain pharmacology of anyone.(NOV-2021), (NOV-2022). ANALEPTICS (Respiratory stimulants): Doxapram, Prethcamide, Nikethamide, Almitrine, Caffine, etc. These are drugs which stimulate respiration and can have resuscitative value in coma or fainting. They do stimulate respiration in subconvulsive doses, but margin of safety is narrow; the patient may get convulsions while still in coma. Mechanical support to respiration and other measures to improve circulation are more effective and safe. The role of analeptics in therapeutics is very limited. Situations in which they may be employed are: (a) As an expedient measure in hypnotic drug poisoning until mechanical ventilation is instituted. (b) Suffocation on drowning, acute respiratory insufficiency. (c) Apnoea in premature infant. (d) Failure to ventilate spontaneously after general anaesthesia. Doxapram Short acting analeptic. Acts by promoting excitation of central neurons. At low doses it is more selective for the respiratory centre than other analeptics. The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate, A pressor response may result following doxuprum administration. Provided there is no impairment of cardiac function, the pressor of is more marked in hypovolernic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of ca-techolamines has been noted. MOA: Doxapram produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. It is thought to stimulate the carotid body by inhibiting certain potassium channels. Route of administration: I. V.  Excreted rapidly. Continuous IV. infusion of Doxapram has been found to abolish episodes of apnoea in the premature infant not responding to Theophylline. Adverse effects are nausea, cough, restlessness, muscle twitching, hypertension, tachycardia, arrhythmias and convulsions. Uses: Acute respiratory failure, Acute hypercapnia, COPD 4. What are mucolytics? Give examples. Write mechanism of action of Bromohexine. (JUN- 2022), (JUN-2024) Mucolytics: Bromhexine, Ambroxol, Acetyl cysteine, Carbocisteine These agents break the thick tenacious sputum and lower the viscosity of sputum, so that sputum comes out easily with less effort. Bromhexine A derivative of the alkaloid vasicine obtained from Adhatoda vasica (Vasaka), is a potent mucolytic and mucokinetic, capable of inducing thin copious bronchial secretion. It depolymerises mucopolysaccharides directly as well as by liberating lysosomal enzymes— network of fibres in tenacious sputum is broken. It is particularly useful if mucus plugs are present. Side effects are rhinorrhoea and lacrimation, nausea, gastric irritation, hypersensitivity. 5. Explain pharmacology of Salbutamol. (JUN- 2023) Salbutamol and terbutaline are short-acting and selective ß2 agonists. Given by inhalation, they are fastest- acting bronchodilators with peak effect in 10 minutes. The action after inhalation lasts for 3–4 hours. Mechanism of Action Adrenergic agonists stimulate ß2 receptors in the bronchial smooth muscles which in turn cause activation of adenylyl cyclase resulting in increased cAMP levels. This increased cAMP leads to bronchodilatation. The increased cAMP in mast cells inhibit the release of inflammatory mediators. They also reduce bronchial secretions and congestion (by acting on α receptors).  Pharmacokinetics: Inhaled salbutamol delivered mostly from pressurized metered dose inhaler (pMDI) produces bronchodilatation within 5 min and the action lasts for 2–4 hours. Salbutamol undergoes presystemic metabolism in the gut wall, oral bioavailability is 50%. Oral salbutamol acts for 4–6 hours, is longer acting and safer than isoprenaline, but not superior in bronchodilator efficacy. Dose: 2–4 mg oral, 0.25–0.5 mg i.m./s.c., 100–200 μg by inhalation. Adverse Effects: Muscle tremors are the dose related side effect. Palpitation, restlessness, nervousness, throat irritation and ankle edema can also occur. Hypokalaemia is a possible complication. Uses: i. Bronchial asthma—they can be given by inhalation. ii. COPD. iii. As uterine relaxants to delay premature labour. 6. Explain pharmacology of selective β2 agonists. (NOV-2023) SAME AS QUESTION NO.6 SHORT ANSWERS (02 MARKS) 7. Write uses of E xpectorants end Antitussives. (DEC-2020) Expectorants (Mucokinetics) are drugs believed to increase bronchial secretion or reduce its viscosity, facilitating its removal by coughing. Antitussives: These are drugs that act in the CNS to raise the threshold of cough centre or act peripherally in the respiratory tract to reduce tussal impulses, or both these actions. Because they aim to control rather than eliminate cough, antitussives should be used only for dry nonproductive cough or if cough is unduly tiring, disturbs sleep or is hazardous (hernia, piles, cardiac disease, ocular surgery). 8. What are nasal decongestants? Give examples. (DEC-2020), (JUN-2022), ( JUN- 2023) A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory. Nasal decongestants are α1 agonists. Nasal decongestants act by stimulating the α1 receptors present in the blood vessels of the nasal mucosa. They may be used 1. Orally Ephedrine, pseudoephedrine, phenylephrine 2. Topically (as nasal drops) Oxymetazoline, xylometazoline naphazoline, phenylephrine, mephentermine, metaraminol 9. List respiratory stimulants. (MAR-2021) Doxapram, Prethcamide, Nikethamide, Almitrine, Caffine, Aminophylline, etc. 10. Mention four antitussive agents. (MAR-2021) (a) Opioids: Codeine, Ethylmorphine, Pholcodeine. (b) Nonopioids: Noscapine, Dextromethorphan, Chlophedianol. (c) Antihistamines: Chlorpheniramine, Diphenhydramine, Promethazine. (d) Peripherally acting: Prenoxdiazine. 11. What are the differences between expectorants and Antitussives? (NOV-2021), (JUN-2024) 12. Mention mast cell stabilizers. (NOV-2021) Sodium cromoglycate, Ketotifen. 13. What are the Differences between bronchial asthma and COPD? (JUN-2022), (JUN-2024) 14. Give examples for mast cell stabilizers. (NOV-2022) Sodium cromoglycate, Ketotifen. 15. Discuss the adverse drug reactions of bromhexine. (NOV-2023) Rhinorrhoea and lacrimation, nausea, gastric irritation, hypersensitivity. 16. Define Mucolytics with examples. (NOV-2022), ( JUN-2023) Mucolytics: Bromhexine, Ambroxol, Acetyl cysteine, Carbocisteine These agents break the thick tenacious sputum and lower the viscosity of sputum, so that sputum comes out easily with less effort.  17. What are the causes of COPD? (NOV-2023) 2. PHARMACOLOGY OF DRUGS ACTING ON GASTRO INTESTINAL SYSTEM LONG ESSAYS (10 MARKS) 18. Classify anti-ulcer agents with examples. Write mechanism of action, adverse effects and therapeutic uses of PPIs. (DEC-2020), ( JUN- 2023 ) Mechanism of action: Adverse Effects: Omeprazole and other PPIs are well-tolerated and are largely safe drugs. 1. Prolonged acid suppression may allowbacterial over growth in the stomach resulting in increased risk of gastrointestinal infections. 2. Dizziness, headache, diarrhoea, abdominal pain, nausea, arthralgia and rashes are rare. 3. Long-term administration may result in: Vitamin B12 deficiency & decreased absorption of magnesium, calcium and iron. ↑ Gastrin levels due to reduced gastricacidity. Atrophic changes in the stomach have been noticed after 3–4 years of use. Uses: 1. Peptic ulcer 2. GERD 3. Dyspepsia 4. Drug-induced ulcers 5. H. pylori regimen 6. Zollinger-Ellison syndrome 7. Gastrinoma 19. Classify antiemetics with examples. Explain mechanism of action and uses of domperidone. (MAR-2021), (NOV-2021) Mechanism of action Domperidone is a D2 dopamine receptor blocker like metoclopramide. It blocks the dopamine receptors in the CTZ and thereby acts as an antiemetic. Advantages over metoclopramide are—domperidone does not cross the blood–brain barrier and hence extrapyramidal and neuropsychiatric side effects are rare. Because CTZ is outside the BBB, domperidone can produce its antiemetic effects. Uses: Domperidone can be used in place of metoclopramide and is preferred over it by many clinicians. 1. Gastro-oesophageal reflux disease (GERD) 2. As Antiemitic. 3. As preanaesthetic medication 4. In endoscopy to assist passage of tubes into the duodenum.  5. Delayed gastric emptying 20. What are laxatives and purgatives? Classify them with examples. Write the mechanism of action and uses of saline cathartics. (JUN-2022) These are drugs that promote evacuation of bowels. A distinction is sometimes made according to the intensity of action. a) Laxative or aperient: milder action, elimination of soft but formed stools. b) Purgative or cathartic: stronger action resulting in more fluid evacuation. Mechanism of Osmotic Purgatives or Saline Cathartics. Uses: 1. Acute functional constipation (atonic or spastic) – bulk laxatives. 2. To prevent straining during defaecation in patients with cardiovascular disease, eye surgery, hernia, etc. – docusates or bulk laxatives. 3. In patients with hepatic coma to reduce the blood ammonia level – lactulose. 4. Preoperatively in bowel surgery, colonoscopy and abdominal X-ray – osmotic laxatives or bisacodyl. 5. Following anthelmintics (e.g. for Taenia solium) – saline laxatives are used to expel the worm segments. 6. In drug poisoning to wash out the poisonous material from the gut – saline laxatives. 7. To treat constipation in children and pregnant women – lactulose 21. Classify antiulcer drugs with examples. Write the mechanism of action, adverse effects and uses of Omeprazole. (NOV-2022) SAME AS QUESTION NO.18 22. Classify laxatives and purgatives with examples. Write mechanism of action and uses of irritant purgatives. (NOV-2023) Laxatives and Purgatives Classification: Reffer Question no. 20 Irritant/Stimulant purgative Mechanisms: 1. Powerful Laxatives: These drugs are potent laxatives that produce griping. 2. Increase Gut Motility: They directly increase gut motility by acting on myenteric plexus neurons. 3. Water and Electrolyte Accumulation: These drugs cause the accumulation of water and electrolytes in the gut lumen by altering the absorptive and secretory properties of mucosal cells. 4. Inhibition of Na⁺/K⁺ ATPase: At the basolateral membrane of villous cells, they inhibit Na⁺/K⁺ ATPase, reducing the transport of Na⁺ and water into the interstitium. 5. Increased Secretion: They increase secretion by activating cAMP in crypt cells, with involvement of prostaglandins. Notes: Large doses of stimulant purgatives can cause excessive purgation. Side Effects: 1. Fluid and Electrolyte Imbalance: This can lead to disturbances in the body’s balance of fluids and electrolytes. 2. Hypokalemia: Decreased potassium levels after regular use. 3. Colonic Atony: Long-term use can produce colonic atony, leading to decreased bowel motility. Important Caution: These drugs should not be used in pregnancy. Uses of Stimulant Purgatives: 1. Relief of Constipation: Stimulant purgatives are primarily used to relieve constipation, especially when other types of laxatives (bulk-forming, osmotic) are ineffective. 2. Bowel Evacuation Before Procedures: They are commonly used before medical procedures like: o Colonoscopies or other diagnostic tests to clear the bowel. o Surgery on the bowel or abdominal area where a clean colon is required. 3. Treatment of Drug-Induced Constipation: In cases where medications such as opioids cause constipation, stimulant purgatives can be helpful. 4. Short-Term Treatment of Constipation: They are typically recommended for short-term use when rapid bowel evacuation is needed. 5. Management of Constipation in Bedridden Patients: Long-term bedridden or immobilized patients may benefit from stimulant purgatives to ensure regular bowel movements. 23. Classify antiemetic drugs with examples. Write the mechanism of action, adverse effects and therapeutic uses of Ondansetron. (JUN-2024) Classification of Antiemetic drugs: Refer Question no. 19. Ondansetron: 5-Hydroxytryptamine released in the gut is an important inducer of emesis and the nerve endings including vagal affarents in the gut are rich in 5-HT3 receptors. It is believed that anticancer drugs, radiation therapy and infection of the gastrointestinal mucosa induce the release of 5-HT in the gut which initiates emetic reflex through 5-HT3 receptors present in the gut, nucleus tractus solitarius (NTS) and area postrema in the brain. Ondansetron blocks 5-HT3 receptors in the GI tract, CTZ and nucleus tractus  solitarius and prevents vomiting. It is a powerful antiemetic and can be given orally or intravenously (4– 8 mg). Pharmacokinetics: Oral bioavailability of ondansetron is 60–70% due to first pass metabolism. It is hydroxylated by CYP1A2, 2D6 and 3A, followed by glucuronide and sulfate conjugation. It is eliminated in urine and faeces, mostly as metabolites; t½ is 3–5 hrs, and duration of action is 8–12 hrs (longer at higher doses). Adverse Effects: All 5-HT3 antagonists are well tolerated with minor adverse effects like headache, constipation, abdominal discomfort and rashes. Dolasetron may prolong QT interval and should be avoided in patients with prolonged QT interval. Uses: 1. 5-HT3 antagonists are the most effective agents for prevention and treatment of chemotherapy- induced nausea and vomiting (CINV). 2. They are also effective in hyperemesis of pregnancy, postoperative, postradiation and drug-induced vomiting but they are ineffective against motion sickness. 3. Ramosetron can be used in irritable bowel syndrome. SHORT ANSWERS (02 MARKS) 24. Enlist non systemic antacids. (DEC-2020) Magnesium hydroxide, Mag. trisilicate, Aluminium hydroxide gel, Magaldrate, Calcium carbonate 25. Mention four Antidiarrheals. (MAR-2021) 1. Loperamide (Imodium): 2. Bismuth subsalicylate (Pepto-Bismol): 3. Diphenoxylate and atropine (Lomotil): 4. Probiotics: such as Lactobacillus or Saccharomyces boulardii 26. What are antacids? Write their uses. (NOV-2021) Antacids are medications that neutralize stomach acid, typically composed of alkaline ions that counteract the acidity in the gastrointestinal (GI) tract. They help to relieve discomfort caused by excess stomach acid and are available in various forms, such as tablets, liquids, or chewable capsules. Uses of Antacids: 1. Relief of Heartburn (Acid Reflux/GERD) 2. Treatment of Peptic Ulcer Disease 3. Relief of Indigestion (Dyspepsia) 4. Reduction of Hyperacidity in Gastritis 27. What are appetizers? Give examples. (JUN-2022) Appetizers are substances or medications that stimulate appetite and promote the desire to eat. They are commonly used in cases where individuals experience a lack of appetite, such as during illness, convalescence, or due to specific conditions like anorexia or certain digestive disorders. Examples of Appetizers: 1. Bitters (e.g., Gentian, Quassia): 2. Cyproheptadine: 3. B Complex Vitamins (e.g., Thiamine): 4. Domperidone: 28. What are carminatives? Give examples. (NOV-2022) Carminatives are substances or medications that help relieve gas (flatulence) from the gastrointestinal tract. They work by reducing the formation of gas, aiding its expulsion, or soothing the digestive tract, which helps reduce bloating, abdominal discomfort, and colic. Carminatives are often derived from natural herbs and are commonly used in cases of indigestion or irritable bowel syndrome (IBS). Examples of Carminatives: 1. Peppermint (Mentha piperita): 2. Ginger (Zingiber officinale): 3. Fennel (Foeniculum vulgare): 4. Cardamom (Elettaria cardamomum): 29. What are antidiarrheal? Give examples. ( JUN-2023) Antidiarrheals are medications or agents used to treat or manage diarrhea, which is characterized by frequent, loose, or watery bowel movements. These drugs work by either slowing down intestinal motility, reducing fluid secretion, or treating the underlying cause of diarrhea, such as infection or inflammation. Examples for Antidiarrheal Agents.: Loperamide, Diphenoxylate, Bismuth Subsalicylate, Racecadotril (Acetorphan). 30. What are antacids? Give examples. (NOV-2023) Antacids are medications that neutralize stomach acid, typically composed of alkaline ions that counteract the acidity in the gastrointestinal (GI) tract. They help to relieve discomfort caused by excess stomach acid and are available in various forms, such as tablets, liquids, or chewable capsules. Common Ingredients in Antacids: Aluminum hydroxide Magnesium hydroxide Calcium carbonate Sodium bicarbonate 31. Write the mechanism of action of pantoprazole. (JUN-2024) Mechanism of Action of Pantoprazole: 1. Inhibition of the H⁺/K⁺-ATPase (Proton Pump): o Pantoprazole selectively inhibits the enzyme H⁺/K⁺-ATPase, also known as the proton pump, located in the parietal cells of the stomach lining. o The proton pump is responsible for the final step of acid secretion, where hydrogen ions (H⁺) are exchanged for potassium ions (K⁺) into the gastric lumen, leading to the production of hydrochloric acid (HCl). 2. Irreversible Binding: o Pantoprazole forms a covalent bond with the proton pump, leading to irreversible inhibition of the enzyme. This means the proton pump is completely shut down, significantly reducing the secretion of gastric acid. o Acid secretion is inhibited both basally (under resting conditions) and stimulated (by food,  gastrin, or other stimuli). 3. Reduction in Gastric Acid Production: o By inhibiting the proton pump, pantoprazole reduces the production of gastric acid, which in turn: ▪ Relieves symptoms of acid-related disorders (e.g., heartburn, acid reflux). ▪ Allows the healing of ulcers and erosions in the stomach and esophagus. ▪ Lowers the risk of further acid damage in conditions like GERD and Zollinger- Ellison syndrome.  UNIT-2: CHEMOTHERAPY LONG ESSAYS (10 MARKS) 32. Classify Penicillins. Write mechanism of action, adverse effects and uses of Penicillin - G. (DEC-2020) Mechanism of Action: The rigid cell wall of the bacterium maintains the integrity, shape and protects it from lysis due to osmotic pressure. Peptidoglycan—a complex polymer, is an important component of the cell wall. It consists of glycan chains which are cross-linked by peptide chains. The glycan chain is made up of alternating sugars N- acetylglucosamine and N-acetylmuramic acid. The glycan chain is cross-linked to peptide chain and the cross- linking provides strength to the cell wall. In gram-positive bacteria; the thick peptidoglycan layer provides mechanical strength to the cell wall. Penicillins inhibit the synthesis of the peptidoglycan layer. PBP—penicillin-binding protein The synthesis of the peptidoglycan requires enzymes called transpeptidases. The last step in the synthesis of peptidoglycan chain is the process of cross-linking with the help of the enzymes transpeptidases—the penicillin binding proteins (PBPs). PBPs are enzymes present in the cell membrane which take part in crosslinking of the peptidoglycan. β-lactam antibiotics covalently bind to PBPs and inhibit the synthesis of peptidoglycans, resulting in the formation of cell wall deficient bacteria. These undergo lysis. Thus, penicillins are bactericidal and act on actively multiplying bacteria. Gram-positive bacteria are more susceptible to penicillins because they have a thick cel lwall which is vital for their living and is easily accessible to penicillins while gram-negative bacteria have a thin cell wall. Pencillins are highly safe because the peptidoglycan layer is unique to bacteria and is absent in higher animals. Adverse Effects: Penicillins are highly safe drugs with a high therapeutic index; most adverse effects are not serious in therapeutic doses except hypersensitivity reactions. Local: Pain at the site of IM injection (due to irritation), thrombophlebitis on IV injection particularly large doses due to irritation. CNS: Large doses of PnG >20 mega units injected IV may produce confusion, muscle twitchings, convulsions and coma particularly in the presence of renal dysfunction. Superinfections are rare because of narrow spectrum of activity of penicillins. Jarisch-Herxheimer reaction: When penicillin is injected to a patient with syphilis, there is sudden destruction of spirochetes and release of their lytic products. This triggers a reaction with fever, myalgia, shivering, exacerbation of syphilitic lesions and vascular collapse. Uses: Penicillin G is the antibiotic of choice for several infections unless the patient is allergic to it. 1. Pneumococcal infections 2. Streptococcal infections 3. Meningococcal infections 4. Staphylococcal infections 5. Syphilis 6. Diphtheria 7. Anaerobic infections 8. Actinomycosis 9. Tetanus and gas gangrene 10. Other infections 11. Leptospirosis 12. Prophylactic uses: a. Rheumatic fever b. Gonorrhoea and syphilis c. Valvular heart diseases Disadvantages of Natural Penicillins Natural penicillins have the following disadvantages: Narrow spectrum of activity Not effective orally—acid labile Susceptible to penicillinase Risk of hypersensitivity Hence, semisynthetic penicillins were obtained in an effort to overcome these disadvantages.  33. Write sources, mechanism of action, adverse effects and therapeutic uses of tetracyclines. (MAR-2021) These are a class of antibiotics having a nucleus of four cyclic rings. The first member of the family was chlortetracycline derived from the soil organism Streptomyces aureofaciens. It was introduced by Benjamin M. Duggar in 1948. This was followed by oxytetracycline produced from Streptomyces rimosus. In 1952 by removing the chlorine atom from chlortetracycline, tetracycline was produced. Investigations on the mutant strains of Streptomyces aureofaciens in 1957 led to discovery of demethyltetracycline like, first member demeclocycline. It contrasted markedly from penicillin and streptomycin (the other two antibiotics available at that time) in being active orally and in affecting a wide range of microorganisms—hence called ‘broad- spectrum antibiotic’. Oxytetracycline soon followed; others were produced later, either from mutant strains or semi synthetically. A new synthetic subclass ‘glycylcyclines’ represented by Tigecycline has been added recently. Mechanism of action i) Tetracyclines enter Gram-negative bacteria by passive diffusion through porin proteins in the outer membrane, followed by active (energy-dependent) transport across the inner cytoplasmic membrane. Uptake into Gram-positive bacteria, such as Bacillus anthracis (the causative agent of anthrax), occurs similarly via an energy-dependent transport system. In contrast, mammalian cells lack the active transport system found in susceptible bacteria. ii) Tetracyclines bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA-ribosome complex. This action prevents the addition of further amino acids to the nascent peptide. Antibacterial spectrum: i) Tetracyclines have broad spectrum of activity covers both gram positive and gram-negative bacteria, Rickettsia, Treponema pallidum, mycoplasmas, and Chlamydiae, etc. They are primarily bacteriostatic. ii) Gram positive bacilli e.g. Clostridia, Listeria, Corynebacteria, B. anthracis are inhibited. iii) Gram negative bacterias like H.ducreyi, Calmmato bacterium granulomatis V.cholerae. are sensitive to tetracyclines. Antibacterial resistance: i) Resistance develops in graded manner. ii) Bacteria acquire capacity to pump out the tetracycline out of the cell iii) Acquire a plasmid mediated synthesis of a protection protein which protects the ribosomal binding site from tetracycline. iv) Nearly complete cross resistance is seen among different members of tetracycline. Pharmacokinetics: i) Absorption: They are usually given orally, old tetracyclines have incomplete absorption due to low solubility and binding to Ca++,Al++Fe++and Mg++ in foods or drugs. Newer agents like Doxycycline and Minocycline are completely absorbed irrespective of food. ii) Distribution: They widely distributed in the body (volume of distribution (>1L/Kg).Concentrated in liver, kidney, spleen, connective tissues in bone. Protein binding is variable. The CSF concentration is about 1/4th of plasma concentration. iii) Metabolism: They are partly metabolized with some degree of enterohepatic circulation. iv) Excretion: They are primarily excreted by glomerular filtration so, has to be reduced in glomerular failure. Adverse effects: i) Irritative effects: they can cause epigastric pain, nausea, vomiting and diarrhoea by irritant property. Intramuscular injection is very painful. ii) Liver damage: Fatty infiltration of liver and jaundice occurs occasionally. iii) Kidney damage: Prominent only in presence of existing kidney disease Fanconi syndrome produced by outdated tetracycline due to degraded products like epitetracycline, anhydrotetracycline and epianhydrotetracycline iv) Phototoxicity: Higher incidence are seen with demeclocycline and doxycycline. v) Teeth and bones: Calcium tetracycline chelate gets deposited in developing teeth and bone. If given in mid-pregnancy to 5 months of extra-uterine life leads to brown discoloration, ill-formed teeth more susceptible to caries. Given in late pregnancy lead or childhood can cause temporary suppression of bone growth. vi) Antianabolic effect: Reduced protein synthesis so have catabolic effects They induce negative nitrogen balance and can increase blood urea. vii) Diabetes insipidus: Demeclocycline antagonizes ADH action and reduce urine concentration. viii) Vestibular toxicity: Minocycline has produced ataxia, vertigo and nystagmus. ix) Hypersensitivity This is infrequent with tetracyclines. Skin rashes, urticaria, glossitis, pruritus ani and vulvae, even exfoliative dermatitis have been reported. Angioedema and anaphylaxis are extremely rare. Complete cross sensitization is exhibited by different tetracyclines. x) Superinfection Tetracyclines are frequently responsible for superinfections, because they cause more marked suppression of the resident flora. Uses: i) Empirical therapy ii) First choice drugs in: Venereal diseases, atypical pneumonia, Cholera, Brucellosis, Plague, Relapsing fever etc. iii) Second choice drugs in: Tetanus, anthrax, listeria, patients allergic to penicillin etc. iv) Urinary tract infections, Amoebiasis , acne vulgaris, prophylactic use in COPD  34. Classify semi synthetic penicillins with examples? Discuss antimicrobial spectrum, mechanism of action and uses of ampicillin. (NOV-2021) SEMISYNTHETIC PENICILLINS Semisynthetic penicillins are produced by chemically combining specific side chains (in place of benzyl side chain of PnG) or by incorporating specific precursors in the mould cultures. Thus, procaine penicillin and benzathine penicillin are salts of PnG and not semisynthetic penicillins. The aim of producing semisynthetic penicillins have been to overcome the shortcomings of PnG, which are: 1. Poor oral efficacy. 2. Susceptibility to penicillinase. 3. Narrow spectrum of activity. 4. Hypersensitivity reactions (this has not been overcome in any preparation). In addition, some β-lactamase inhibitors have been developed which themselves are not antibacterial, but augment the activity of penicillins against β-lactamase producing organisms. Classification: 1. Acid-resistant alternative to penicillin G: Phenoxymethyl penicillin (Penicillin V). 2. Penicillinase-resistant penicillins: Methicillin, Cloxacillin, Dicloxacillin. 3. Extended spectrum penicillins: (a) Aminopenicillins: Ampicillin, Bacampicillin, Amoxicillin. (b) Carboxypenicillins: Carbenicillin. (c) Ureidopenicillins: Piperacillin, Mezlocillin. 4. ß-lactamase inhibitors: Clavulanic acid, Sulbactam, Tazobactam. EXTENDED SPECTRUM PENICILLINS These semisynthetic penicillins are active against a variety of gram- negative bacilli as well. Aminopenicillins This group, led by ampicillin, has an amino substitution in the side chain. Some are prodrugs and all have quite similar antibacterial spectra. None is resistant to penicillinase or to other ß-lactamases. Ampicillin It is active against all organisms sensitive to PnG. In addition, many gram-negative bacilli, e.g. H. influenzae, E. coli, Proteus, Salmonella Shigella and Helicobacter pylori are inhibited. However, due to wide-spread use, many of these have developed resistance; usefulness of this antibiotic has decreased considerably. Ampicillin is more active than PNG for Strep. viridans, enterococci and Listeria; equally active for pneumococci, gonococci and meningococci (penicillin- resistant strains are resistant to ampicillin as well) less active against other gram-positive cocci. Penicillinase producing Staph. are not affected, as are other gram-negative bacilli, such as Pseudomonas, Klebsiella, indole positive Proteus and anaerobes like Bacteroides fragilis. Mechanism of Action: PHARMACOKINETICS Ampicillin is not degraded by gastric acid; oral absorption is incomplete but adequate. Food interferes with absorption. It is partly excreted in bile and reabsorbed- enterohepatic circulation Occurs. However, primary channel of excretion is kidney, but tubular secretion is slower than for PNG. Plasma t1⁄2 is 1 hr. Uses: 1. Urinary tract infections. 2. Respiratory tract infections 3. Meningitis. 4. Gonorrhoea. 5. Typhoid fever. 6. Bacillary dysentery. 7. Cholecystitis. 8. Subacute bacterial endocarditis. 9. H. pylori. 10. Septicaemias and mixed infections. ADVERSE EFFECTS: Diarrhoea is frequent after oral administration. Ampicillin is incompletely absorbed the unabsorbed drug irritates the lower intestines as well as causes marked alteration of bacterial flora. It produces a high incidence (up to 10%) of rashes, especially in patients with AIDS, EB virus infections or lymphatic leukaemia. Concurrent administration of allopurinol also increases the incidence of rashes. Sometimes the rashes may not be allergic, but toxic in nature. Patients with a history of immediate type of hypersensitivity to PnG should not be given ampicillin as well. 35. What are aminoglycoside antibiotics? Write the antimicrobial spectrum, mechanism of action, adverse reactions and therapeutic uses of streptomycin. (JUN-2022), (JUN-2024) Aminoglycosides (AGs) are antibiotics with amino sugars joined by glycosidic linkages. These are a group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more aminosugar (streptidine, 2-deoxy streptamine, garosamine) residues. They are derived from the soil actinomycetes of the genus Streptomyces (streptomycin, kanamycin, tobramycin, neomycin) and the genus Micromonospora (gentamicin and sisomicin)—hence the difference in spelling. Streptomycin was the first member discovered in 1944 by Waksman and his colleagues. Amikacin and netilmicin are semisynthetic products. Aminoglycosides include: Streptomycin, gentamicin, tobramycin, kanamycin, paromomycin. Newer ones—amikacin, sisomicin, netilmicin. Topical—neomycin, framycetin. Streptomycin obtained from Streptomyces griseus is mainly effective against aerobic gramnegative bacilli. When used alone, bacteria, especially the tubercle bacillus rapidly develops resistance to it. Streptomycin is the least nephrotoxic among aminoglycosides. Antibacterial Spectrum Aminoglycosides have a narrow spectrum and are effective mainly against aerobic gramnegative bacilli like E. coli, Proteus, Y. pestis, Nocardia, V. cholerae, Pseudomonas, Brucella, Salmonella, Shigella and Klebsiella. Mechanism of Action Aminoglycosides, being water-soluble, penetrate the bacterial cell membrane through aqueous pores and reach the periplasmic spaces. They are taken up and transported across the cell membrane into the cytoplasm by an oxygen-dependent active transport process. It is observed that aminoglycosides disrupt the bacterial cell membrane and this also allows penetration of the drug into the bacterium from the periplasmic space. Inside the cell , aminoglycosides bind to 30S ribosomes and inhibit bacterial protein synthesis—block initiation of protein synthesis, cause termination of protein synthesis and cause addition of incorrect amino acids resulting in the synthesis of abnormal proteins. Aminoglycosides are bactericidal. Higher the concentration, greater is the bactericidal effect (dose-dependent killing). A residual bactericidal effect—postantibiotic effect—remains even after the plasma levels of aminoglycosides fall. Hence, even though they have a short t½, they can be given once a day. Mechanisms of Bacterial Resistance. Bacterial resistance to aminoglycosides is due to 1. Aminoglycoside inactivating enzymes: On binding to aminoglycosides, the enzyme inactivates aminoglycosides which fail to bind to the target ribosomes. 2. Low affinity of ribosomes—acquired by mutation. 3. Decrease in permeability to the antibiotic. There is partial cross-resistance among various aminoglycosides. Aminoglycosides Exhibit 1. A concentration-dependent killing effect – higher the plasma concentration, more of the bacteria killed rapidly. 2. A postantibiotic effect – bactericidal effect is present even when serum concentration falls below MIC. Therefore, once-daily dosing regimen is effective. Pharmacokinetics Aminoglycosides are not absorbed from the gut but when instilled into body cavities or applied over large wounds, they may get rapidly absorbed. Following IM injection, peak levels are seen in 60 minutes. They are not bound to plasma proteins and do not enter the cells or cross barriers—mostly remain in the vasculature. Aminoglycosides are excreted almost completely through the kidneys. Half-life is 2–3 hr but gets prolonged to 24–48 hr in renal impairment—dose should be reduced. Adverse Effects 1. Ototoxicity: 2. Nephrotoxicity: 3. Neuromuscular blocking effect: Apnoea and muscular paralysis have been reported. It may be reversed by administration of calcium salt. Aminoglycosides inhibit release of acetylcholine from motor nerve. Myasthenic patients are more susceptible to neuromuscular blocking effect of these drugs; hence, they should be avoided. 4. Hypersensitivity reactions are rare; occasionally skin rashes, drug fever and eosinophilia can occur. Cross-sensitivity between aminoglycosides may occur. 5. Use of aminoglycosides during pregnancy may cause ototoxicity in fetus. THERAPEUTIC USES OF AMINOGLYCOSIDES Among aminoglycosides, gentamicin is the most commonly used because it is cheap and effective against most of the aerobic gram-negative bacilli. 1. Severe aerobic gram-negative bacillary infections Urinary tract infection with pyelonephritis Pneumonia Meningitis Osteomyelitis Septicaemia Peritonitis Infected burns Gentamicin, tobramycin, amikacin and netilmicin are effective against P. aeruginosa. Amikacin and netilmicin are used for treatment of serious nosocomial infections due to gram- negative bacilli Aminoglycosides are often used in combination with penicillins/third generation cephalosporins in these conditions. 2. Bacterial endocarditis due to S. viridans and Enterococcus: 3. TB: Streptomycin, kanamycin and amikacin are used in the treatment of TB. 4. Other gram-negative infections Plague: Streptomycin/gentamicin is used intramuscularly. Brucellosis: Streptomycin/gentamicin is used in combination with doxycycline. Tularaemia: Streptomycin or gentamicin is the drug of choice. FQs and tetracyclines are also effective. 5. Gentamicin, tobramycin, neomycin, sisomicin, framycetin, etc., are used topically for gram-negative skin, eye and ear infections.  36. Define broad spectrum antibiotics with examples. Explain the mechanism of action, adverse effects and uses of tetracyclines. (NOV-2022) Broad-spectrum antibiotics are antibiotics that are effective against a wide range of bacteria, including both Gram-positive and Gram-negative organisms. Unlike narrow-spectrum antibiotics, which target a specific type or group of bacteria, broad-spectrum antibiotics can inhibit or kill a diverse group of bacterial species, making them useful in situations where the specific causative bacteria are unknown. Characteristics of Broad-Spectrum Antibiotics: Effective against multiple bacterial types (Gram-positive and Gram-negative). Useful for treating mixed bacterial infections. Commonly prescribed when the exact cause of an infection is not known, such as in cases of severe or life-threatening infections. Often used as empiric therapy before culture results are available. Examples of Broad-Spectrum Antibiotics: 1. Amoxicillin-clavulanate (Augmentin) 2. Tetracyclines (e.g., Doxycycline) 3. Chloramphenicol 4. Carbapenems (e.g., Meropenem) 5. Fluoroquinolones (e.g., Ciprofloxacin, Levofloxacin) Considerations: Broad-spectrum antibiotics can lead to antibiotic resistance if used excessively or inappropriately. They may also disrupt the normal bacterial flora, increasing the risk of superinfections, such as Clostridium difficile infection. Narrow-spectrum antibiotics are preferred when the specific bacteria causing the infection are identified. For Tetracyclines Refer Question No. 33 37. Classify cephalosporins with examples. Describe their mechanism of action and uses. (JUN- 2023) CEPHALOSPORINS These are a group of semisynthetic antibiotics derived from 'cephalosporin-C' obtained from a fungus Cephalosporium. Side chains at position 7 of ß-lactam ring (altering spectrum of activity) and at position 3 of dihydrothiazine ring (affecting pharmacokinetics). These have been conventionally divided into 4 generations. This division has a chronological sequence of development. Acquired resistance: Alteration in target proteins (PBPs) reducing affinity for the antibiotic. Impermeability to the antibiotic or its efflux so that it does not reach its site of action. Elaboration of B-lactamases which destroy specific cephalosporins (cephalosporinases); common mechanism. the most Individual cephalosporins differ in their: a) Antibacterial spectrum and relative potency against specific organisms. b) Susceptibility to B-lactamases elaborated by different organisms. c) Pharmacokinetic properties many have to be injected, some are oral; majority are not metabolized. Mechanism of action: Classification: Pnemonics to indentify cephalosporin class: Drugs with "a" followed by cef- first gen Drugs with " rol" in its name - fifth gen Drugs with " pi" in its name - fourth gen Drugs with "me/met/one/ten" - third gen Remaining drugs - second gen Therapeutic uses: Commonly used antibiotics wide range of negative and positive bacteria and anaerobes (except fragilis, MRSA, enterococci, mycobacteria, chlamydia) 1. Alternative to penicillin for ENT/ Upper respiratory tract/ cutaneous infections 2. Respiratory, urinary, soft tissue infections 3. Staphylococcal infections 4. Septicemias 5. Surgical prophylaxis 6. Meningitis 7. Gonorrhea 8. Typhoid 9. Mixed aerobic and anaerobic infections 10. Hospital acquired infections. 11. Prophylaxis and treatment of infections in neutropenia patients 38. Classify semi synthetic penicillins with examples. Describe their mechanism of action and uses. (NOV-2023) Refer Question No. 34 SHORT ESSAYS (05 MARKS) 39. Classify antibiotics on the basis of mechanism of action along with examples. (DEC-2020), (NOV-2022) 40. Write mechanism of action and uses of streptomycin. (DEC-2020) Refer Question No. 35 41. Write a note on causes and prevention of antimicrobial resistance. (MAR-2021) Drug resistance It refers to unresponsiveness of a microorganism to an AMA, and is akin to the phenomenon of tolerance seen in higher organisms. Development of Resistance to Antimicrobial Agents. There are several mechanisms by which an organism can develop resistance to an AMA. The important mechanisms are as follows: 1. Production of inactivating enzymes: For example, staphylococci, gonococci and E. coli produce !- lactamases that can destroy some of the penicillins and cephalosporins. 2. An efflux pump mechanism: It is a mechanism that prevents the accumulation of the drug in the microorganism, e.g. resistance of gram-positive and gramnegative bacteria to tetracyclines, chloramphenicol, macrolides, etc. 3. Decreased entry of AMA into the organism due to alteration in the channel/transporter required for its entry into the organism. 4. Alteration of the binding site: For example, change in penicillin-binding proteins (PBPs) in case of certain pneumococci with decreased affinity for penicillins. 5. Absence of metabolic pathway: For example, sulphonamide-resistant bacteria can utilize preformed folic acid without the need for usual metabolic steps. Prevention of drug resistance It is of utmost clinical importance to curb development of drug resistance. Measures are: a) No indiscriminate and inadequate or unduly prolonged use of AMAs should be made. This would minimize the selection pressure and resistant strains will get less chance to preferentially propagate. For acute localized infections in otherwise healthy patients, symptom-determined shorter courses of AMAs are advocated. b) Prefer rapidly acting and selective (narrowspectrum) AMAs whenever possible; broad-spectrum drugs  should be used only when a specific one cannot be determined or is not suitable. c) Use combination of AMAs whenever prolonged therapy is undertaken, e.g. tuberculosis, SABE, HIV- AIDS. d) Infection by organisms notorious for developing resistance, e.g. Staph. aureus, E. coli, M. tuberculosis, Proteus, etc. must be treated intensively. e) Antibiotics should be used only when necessary. f) Selection of the appropriate antibiotic is absolutely important. g) Correct dose and duration of treatment should be followed. h) Combination of drugs should be used as in tuberculosis to delay the development of resistance. 42. Write mechanism of action and merits of cotrimoxazole. (MAR-2021) COTRIMOXAZOLE The fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole. Trimethoprim is a diaminopyrimidine related to the antimalarial drug pyrimethamine which selectively inhibits bacterial dihydrofolate reductase (DHFRase). Cotrimoxazole introduced in 1969 causes sequential block of folate metabolism. Trimethoprim is >50,000 times more active against bacterial DHFRase than against the mammalian enzyme. Thus, human folate metabolism is not interfered at antibacterial concentrations of trimethoprim. Antibacterial spectrum: Antibacterial spectra of trimethoprim and sulphonamides overlap considerably. Additional organisms covered by the combination are—Salmonella typhi, Serratia, Klebsiella, Enterobacter, Yersinia enterocolitica, Pneumocystis jiroveci and many sulphonamide-resistant strains of Staph. aureus, Strep. pyogenes, Shigella, enteropathogenic E.coli, H.influenzae, gonococci and meningococci. Mechanism of action: Sulfonamides inhibit the conversion of PABA to dihydrofolic (DHF)acid and trimethoprim inhibits dihydrofolate reductase (DHFR) and thus prevents the reduction of DHF to tetrahydrofolic(THF) acid. The two drugs thus blocks equential steps in folic acid synthesis and the combination is synergistic. Given alone, both trimethoprim and sulfonamides are bacteriostatic but the combination is bactericidal. Trimethoprim has a high degree of selective affinity for bacterial DHFR compared to the human enzyme. The ratio of ‘trimethoprim: sulfamethoxazole ‘used is 1:5 to attain the right plasma concentration. The optimal peak plasma concentration of the combination is in the ratio1:20 (trimethoprim: sulfamethoxazole). Among sulfonamides, sulfamethoxazole is chosen since its pharmacokinetic properties closely match with that of trimethoprim. Resistance: Development of resistance to the combination is slower when compared to either drug given alone. Bacteria may acquire resistance by mutation or by acquisition of a plasmid coding for an altered DHFR. But widespread use of the combination over a long period has resulted in reduced responsiveness of over 30% originally sensitive strains. Pharmacokinetics: Both trimethoprim and sulfamethoxazole have similar t½ (10 hr). They are given orally but may also be given IV. Both are well absorbed from the gut and widely distributed in the body. Trimethoprim has good distribution into the tissues including prostatic and vaginal fluids. Because of its basic nature, trimethoprim concentrates in the acidic fluids. Trimethoprim adequately crosses blood-brain barrier and placenta, while sulfamethoxazole has a poorer entry. Moreover, trimethoprim is more rapidly absorbed than sulfamethoxazole—concentration ratios may vary with time. Trimethoprim is 40%plasma protein bound, while sulfamethoxazole is 65% bound. Trimethoprim is partly metabolized in liver and excreted in urine. Both the drugs are excreted by the kidneys to an extent that in renal failure the dose has to be reduced. Adverse Effects: Nausea, vomiting, headache, glossitis, stomatitis and allergic skin rashes are relatively common. In patients with folate deficiency, cotrimoxazole may precipitate megaloblastic anaemia. Haematological reactions like anaemia and granulocytopenia are rare. AIDS patients are more prone to adverse effects of cotrimoxazole. Patients with renal disease may develop uraemia. Cotrimoxazole should not be given in pregnancy as it is an antifolate drug and could be teratogenic. Uses: 1. Urinary tract infection 2. Respiratory tract infections 3. Bacterial gastroenteritis 4. Typhoid 5. Pneumocystis jiroveci infection 6. Chancroid 7. Melioidosis 8. Toxoplasmosis 43. Explain rationale behind combined therapy of antimicrobial agents with examples. (NOV- 2021), (JUN- 2024) COMBINATION OF ANTIMICROBIALS: Use of a combination of antimicrobials may have synergistic, antagonistic or indifferent (no change) effects. Hence, appropriate drugs should be used for combination. Two bactericidal drugs given together (e.g. penicillin + aminoglycosides) are generally synergistic. Combination of a bacteriostatic with a bactericidal drug is not useful because bacteriostatic drugs inhibit the multiplication of bacteria and thereby antagonize the effects of bactericidal drugs (as bactericidal drugs act on actively multiplying bacteria). Hence, such combinations should be avoided. A combination of antimicrobial agents is indicated in certain specific situations. The combination serves one of the following purposes: 1. To obtain synergism: Combination of antibiotics to attain synergism is recommended in: Bacterial endocarditis: Penicillin + streptomycin/gentamicin is synergistic. Pseudomonas infections: Carbenicillin + gentamicin Pneumocystis jiroveci pneumonia: Trimethoprim + sulfamethoxazole ß-lactamase producing organisms like H. influenzae: Amoxicillin + clavulanic acid  Tuberculosis: INH + rifampicin. 2. Treatment of mixed infections: Intraabdominal infections, brain abscesses, genitourinary infections are often mixed infections. Aerobic and anaerobic organisms may be involved. Two or more antimicrobials can be used depending on the culture and sensitivity report. 3. Initial treatment of severe infections: Drugs covering both gram-positive and gramnegative pathogens may be used initially till the culture report is available, e.g. penicillin + aminoglycoside; cephalosporin + aminoglycoside. If anaerobes are likely to be present, metronidazole may be added. Samples for culture should, however, be taken before starting the antibiotics. 4. To prevent the emergence of resistance: In the treatment of tuberculosis and leprosy, combination of drugs is used to prevent the development of resistance. 5. To reduce the adverse effects: The doses needed may be lower when a combination is used. This may reduce the incidence and severity of adverse effects, e.g. amphotericin B + flucytosine in cryptococcal meningitis. Disadvantages of Antimicrobial Combinations 1. Risk of toxicity from each agent—especially if toxicity is overlapping—may get added up, e.g. many antitubercular drugs are hepatotoxic. Toxicity of one drug may be enhanced by another, e.g.Vancomycin + aminoglycosides → more severe renal toxicity 2. Selection of resistant strains: The few resistant mutants that remain may multiply unchecked. 3. Emergence of organisms resistant to multiple drugs. 4. Increased cost of therapy. 44. Classify tetracyclines with examples. Explain why tetracyclines causes discoloration of teeth. (NOV- 2021) Classification: Tetracyclines cause discoloration of teeth due to their ability to bind to calcium ions in the developing teeth. This discoloration is permanent and typically occurs in children whose teeth are still developing, but it can also affect the teeth of fetuses if the mother takes tetracyclines during pregnancy. Mechanism of Tetracycline-Induced Tooth Discoloration: 1. Calcium Binding: o Tetracyclines have a high affinity for calcium ions. When administered during periods of tooth development (generally from the second half of pregnancy up to about 8 years of age), tetracyclines can bind to calcium in the hydroxyapatite of bones and teeth. 2. Deposition in Dentin and Enamel: o Once bound to calcium, tetracyclines are deposited in the dentin and enamel of developing teeth. This occurs particularly in the teeth’s calcifying tissues, leading to incorporation of the drug into the teeth matrix.  3. Photodegradation: o Tetracyclines are sensitive to light. After deposition in the teeth, exposure to light causes the drug to undergo photodegradation, resulting in a change in color. The teeth often develop a yellow, brown, or gray hue over time, depending on the extent of exposure and duration of tetracycline use. 4. Timing of Exposure: o Discoloration is more likely to occur if tetracyclines are taken during specific phases of tooth development: ▪ In utero (if taken by the mother during pregnancy). ▪ In infancy (when deciduous teeth are forming). ▪ In early childhood (when permanent teeth are developing). Appearance of Tooth Discoloration: Yellow-gray or brown discoloration, which may affect all or part of the teeth, depending on the duration and timing of exposure. The degree of discoloration can vary from mild to severe, depending on the dose and duration of tetracycline exposure. Prevention: Tetracyclines are contraindicated during pregnancy, breastfeeding, and in children under the age of 8 (when teeth are still developing) to prevent tooth discoloration. Alternative antibiotics are usually recommended for these populations. Note: By binding to calcium in developing teeth, tetracyclines interfere with normal tooth coloration, leading to permanent discoloration in affected individuals. 45. What are sulfonamides? Classify them with examples. (JUN-2022) SULFONAMIDES Sulfonamides were the first effective antibacterial agents to be used systemically in man. They were introduced by Domagk in 1935 and in the next few years several of them were synthesized and widely used. A large number of sulfonamides were produced and used extensively in the subsequent years, but because of rapid emergence of bacterial resistance and the availability of many safer and more effective antibiotics, their current utility is limited, except in combination with trimethoprim (as cotrimoxazole) or pyrimethamine (for malaria). Classification: 46. Define chemotherapy. Write classification of antibacterial agents. (JUN- 2023) Chemotherapy can be defined as the use of a chemical substance in infectious diseases to destroy microorganisms without damaging the host tissues. CLASSIFICATION Antimicrobial drugs can be classified in many ways: A. Chemical structure 1. Sulfonamides and related drugs: Sulfadiazine and others, Sulfones—Dapsone (DDS), Paraaminosalicylic acid (PAS). 2. Diaminopyrimidines: Trimethoprim, Pyrimethamine. 3. Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin, Prulifloxacin, etc. 4. β-Lactam antibiotics: Penicillins, Cephalosporins, Monobactams, Carbapenems. 5. Tetracyclines: Oxytetracycline, Doxycycline, etc. 6. Nitrobenzene derivative: Chloramphenicol. 7. Aminoglycosides: Streptomycin, Gentamicin, Amikacin, Neomycin, etc. 8. Macrolide antibiotics: Erythromycin, Clarithromycin, Azithromycin, etc. 9. Lincosamide antibiotics: Lincomycin, Clindamycin. 10. Glycopeptide antibiotics: Vancomycin, Teicoplanin. 11. Oxazolidinone: Linezolid. 12. Polypeptide antibiotics: Polymyxin-B, Colistin, Bacitracin, Tyrothricin. 13. Nitrofuran derivatives: Nitrofurantoin, Furazolidone. 14. Nitroimidazoles: Metronidazole, Tinidazole, etc. 15. Nicotinic acid derivatives: Isoniazid, Pyrazinamide, Ethionamide. 16. Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin. 17. Azole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole. 18. Others: Rifampin, Spectinomycin, Sod. fusidate, Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin. B. Mechanism of action 1. Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin. 2. Cause leakage from cell membranes: Polypeptides—Polymyxins, Colistin, Bacitracin. Polyenes— Amphotericin B, Nystatin, Hamycin. 3. Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid. 4. Cause misreading of m-RNA code and affect permeability: Aminoglycosides— Streptomycin, Gentamicin, etc. 5. Inhibit DNA gyrase: Fluoroquinolones— Ciprofloxacin and others. 6. Interfere with DNA function: Rifampin. 7. Interfere with DNA synthesis: Acyclovir, Zidovudine. 8. Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Metronidazole. C. Type of organisms against which primarily active 1. Antibacterial: Penicillins, Aminoglycosides, Erythromycin, Fluoroquinolones, etc. 2. Antifungal: Griseofulvin, Amphotericin B, Ketoconazole, etc. 3. Antiviral: Acyclovir, Amantadine, Zidovudine, etc. 4. Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, Diloxanide, etc. 5. Anthelmintic: Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine, etc.  47. Define chemoprophylaxis. Write briefly on its types along with examples. (NOV- 2023) Chemoprophylaxis: Chemoprophylaxis refers to the use of chemical agents or medications to prevent the development of an infection or disease. It is a preventive approach employed when there is a risk of infection, especially in cases where exposure to pathogens is likely, such as in endemic areas or during travel to high-risk regions. Types of Chemoprophylaxis: 1. Primary Chemoprophylaxis: o Definition: This type of chemoprophylaxis is administered to prevent the initial occurrence of an infection or disease in individuals who are at high risk of exposure but are currently not infected. o Examples: ▪ Malaria prevention: Drugs like chloroquine or atovaquone-proguanil are given to travelers going to malaria-endemic areas. ▪ Tuberculosis (TB): Isoniazid can be administered to individuals who have been exposed to TB but are not yet infected (e.g., healthcare workers in contact with TB patients). 2. Secondary Chemoprophylaxis: o Definition: This refers to the use of medications to prevent the recurrence of an infection or disease in individuals who have already been infected once and are at risk of relapse or reactivation. o Examples: ▪ Herpes Simplex Virus (HSV): Acyclovir or valacyclovir can be given to individuals with frequent herpes outbreaks to prevent recurrences. ▪ Pneumocystis pneumonia (PCP) in immunocompromised patients (e.g., HIV-positive patients): Trimethoprim-sulfamethoxazole (TMP-SMX) is given as prophylaxis to prevent recurrence. 3. Tertiary Chemoprophylaxis: o Definition: This involves the use of medications to reduce or prevent complications of an ongoing infection in individuals with chronic or incurable diseases. o Examples: ▪ HIV infection: Use of antiretroviral therapy (ART) to prevent the progression of the disease and reduce the risk of opportunistic infections. 4. Mass Chemoprophylaxis: o Definition: This involves administering medications to a large population or community to prevent the spread of a disease, especially in the case of outbreaks or endemic diseases. o Examples: ▪ Mass drug administration (MDA) in areas with endemic lymphatic filariasis, where drugs like ivermectin and albendazole are given to entire communities to prevent infection. ▪ Meningococcal meningitis outbreaks: Prophylactic use of rifampin or ciprofloxacin in exposed populations during an outbreak. Indications for Chemoprophylaxis 1. To prevent endocarditis in patients with valvular lesion before undergoing surgical procedures: Surgical procedure n mucosal damage n bacteraemia n affects damaged valve n endocarditis. 2. To protect healthy persons: Chloroquine/mefloquine is used for chemoprophylaxis of malaria for those travelling to malaria endemic area. 3. To prevent infection in patients undergoing organ transplantation: Oral FQs can be used. 4. To prevent opportunistic infections in immunocompromised patients, e.g. cotrimoxazole is used to prevent Pneumocystis jiroveci pneumonia in AIDS patients. 5. Prior to surgical procedures: AMAs are administered to all patients prior to major surgical procedures or implantation of prosthetic devices and in diabetic patients or patients on prolonged corticosteroids to prevent wound infection after surgery. 6. To prevent infection in patients with burns: Topical silver sulphadiazine and systemic antibiotics are used.  7. To prevent infection in patients with urinary catheter: FQs are used in patients who are at high risk of infection. Suggested Chemoprophylactic Regimens. The effectiveness of chemoprophylaxis depends on the selection of a specific AMA, its dosage, time of initiation and duration of antimicrobial therapy. Empirical therapy: It is the use of AMAs before identification of causative organism or availability of susceptibility test results, e.g. combination of cefotaxime, vancomycin and ampicillin is used as empirical therapy for suspected bacterial meningitis (before test results are available) to cover possible organisms likely to cause meningitis. Definitive therapy: It involves the use of AMA after identification/susceptibility tests of the causative organism responsible for the disease. 48. Classify Tetracyclines with examples and write their mechanism of action. (NOV- 2023) Classification: Mechanism of action i) Tetracyclines enter Gram-negative bacteria by passive diffusion through porin proteins in the outer membrane, followed by active (energy-dependent) transport across the inner cytoplasmic membrane. Uptake into Gram-positive bacteria, such as Bacillus anthracis (the causative agent of anthrax), occurs similarly via an energy-dependent transport system. In contrast, mammalian cells lack the active transport system found in susceptible bacteria. ii) Tetracyclines bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA-ribosome complex. This action prevents the addition of further amino acids to the nascent peptide. 49. Write the mechanism of action, toxicity and uses of Cotrimoxazole. (JUN- 2024) REFER QUESTION NO. 42 SHORT ANSWERS (02 MARKS) 50. Mention four classes of antibiotics acting by inhibiting cell wall synthesis. (DEC-2020) Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin. 51. Mention four classes of antibiotics acting by inhibiting protein synthesis. (MAR-2021) (NOV- 2022) Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid. 52. What is Superinfection? Give examples. (NOV-2021), (JUN-2024) Superinfection: A superinfection is an infection that occurs during or after treatment for a primary infection. It typically arises because the use of broad-spectrum antibiotics or other antimicrobial treatments disrupts the normal microbial flora, creating an environment in which resistant or opportunistic pathogens can thrive. Superinfections are often caused by antibiotic-resistant organisms or fungi that are not affected by the antibiotics used to treat the initial infection. Examples of Superinfection: 1. Clostridioides difficile (C. diff) Infection 2. Oral or Vaginal Candidiasis (Yeast Infection) 3. Methicillin-resistant Staphylococcus aureus (MRSA) 4. Pseudomonas aeruginosa Infection 53. Give four reasons for combined use of antibiotics. (JUN-2022) A combination of antimicrobial agents is indicated in certain specific situations. The combination serves one of the following purposes: 1. To obtain synergism 2. Treatment of mixed infections 3. Initial treatment of severe infections 4. To prevent the emergence of resistance 5. To reduce the adverse effects 54. What i s Gray Baby syndrome? (NOV-2022) Gray baby syndrome: Newborn babies given high doses of chloramphenicol may show ‘Gray baby syndrome' manifested as vomiting, refusal of feeds, hypotonia, hypothermia, abdominal distension, metabolic acidosis and ashen gray cyanosis. It may be fatal. As the newborn cannot metabolize (due to inadequate hepatic glucuronidation) and excrete chloramphenicol adequately, toxicity results. However, it is seen with higher doses only and can largely be avoided. 55. Mention two modes of antibiotic resistance. (JUN-2023) Development of Resistance to Antimicrobial Agents. There are several mechanisms by which an organism can develop resistance to an AMA. The important mechanisms are as follows: 1. Production of inactivating enzymes: For example, staphylococci, gonococci and E. coli produce !- lactamases that can destroy some of the penicillins and cephalosporins. 2. An efflux pump mechanism: It is a mechanism that prevents the accumulation of the drug in the microorganism, e.g. resistance of gram-positive and gramnegative bacteria to tetracyclines, chloramphenicol, macrolides, etc. 3. Decreased entry of AMA into the organism due to alteration in the channel/transporter required for its entry into the organism. 4. Alteration of the binding site: For example, change in penicillin-binding proteins (PBPs) in case of certain pneumococci with decreased affinity for penicillins. 5. Absence of metabolic pathway: For example, sulphonamide-resistant bacteria can utilize preformed folic acid without the need for usual metabolic steps.  UNIT-3: CHEMOTHERAPY LONG ESSAYS (10 MARKS) 56. Classify antitubercular agents. Explain mechanism of action of INH and Rifampicin. (DEC- 2020) Mechanism of Action of ISONIAZID: INH inhibits the synthesis of mycolic acids which are important components of the mycobacterial cell wall. The cell wall of mycobacteria differs from other bacteria in having large amounts of mycolic acids which form essential components of mycobacterial cell wall. INH, a prodrug, freely enters the mycobacteria and is converted to an active form by an enzyme catalase- peroxidase (Kat G) present in the mycobacteria. This active form covalently binds certain enzymes and thereby inhibits mycolic acid synthesis. Mechanism of Action Rifampicin: Rifampicin binds to the ß subunit of the DNA dependent RNA polymerase and inhibits RNA synthesis in the bacteria. It is bactericidal. In therapeutic concentrations, rifampicin cannot bind human RNA polymerase and it, therefore, selectively destroys the bacteria. Moreover, it reaches the cavities, caseous material and penetrates macrophages.  Resistance due to genetic mutation in DNA and RNA polymerase results in reduced binding of rifampicin to RNA polymerase. 57. Classify antifungal agents with examples. Write mechanism of action, adverse effects and therapeutic uses of Triazoles. (MAR-2021) Triazoles: Fluconazole, itraconazole, terconazole, voriconazole, posaconazole, ravuconazole. The older antifungals need to be given intravenously and are quite toxic. Azoles are newer synthetic antifungals that are effective orally and are less toxic. Azoles include imidazoles and triazoles. The triazoles have more selective effect on fungal sterol synthesis than imidazoles. Triazoles are also longer-acting. Ketoconazole, miconazole and clotrimazole are the commonly used imidazoles—of them clotrimazole and miconazole are used only topically. Antifungal spectrum has a broad-spectrum antifungal activity. They inhibit dermatophytes, Blastomyces dermatitidis, Candida, Cryptococcus neoformans, H. capsulatum, Coccidioides, some Paracoccidioides and other deep mycoses. Mechanism of Action: Azoles inhibit the synthesis of ergosterol, an important component of the fungal cell membrane.  Azoles inhibit the fungal cytochrome P450 enzyme lanosine 14 -demethylase which catalyses the conversion of lanosterol to ergosterol. Thus, it results in ergosterol deficiency which results in weak fungal cell membrane and fungal replication. They also interfere with the function of some fungal enzymes and inhibit the growth of the fungi. Since azoles have higher affinity to fungal than human CYP 450 enzymes, some selective activity is attained. Resistant strains are now common in AIDS patients and is due to genetic mutations resulting in altered enzyme 14α- demethylase. Miconazole and Clotrimazole. They are used topically for dermatophytic and Candida infections. They are available as cream, gel, lotion, solution, spray, vaginal pessary, etc. Clotrimazole troche is also available. KETOCONAZOLE: KTZ is a prototype drug among azoles. It is effective orally as well as topically for various fungal infections, such as candidiasis, dermatophytosis and deep mycosis. It is the most toxic among azoles, hence used commonly by topical route for Candida and dermatophytic infections. For most of the systemic mycosis, it has been replaced by triazoles. Pharmacokinetics. It is orally effective. Acidic environment favours the absorption of KTZ; hence, its bioavailability is reduced by drugs like H2-blockers, proton pump inhibitors or antacids. It is highly bound to plasma proteins, metabolized in liver extensively and excreted mainly in faeces. Adverse Effects. KTZ is the most toxic among azoles, but it is less toxic than AMB. Anorexia, nausea and vomiting are the most common side effects. KTZ reduces adrenal cortical steroids, testosterone and oestrogen synthesis – thus causes gynaecomastia, oligospermia, loss of libido and impotence in males, and menstrual irregularities and amenorrhoea in females. The other side effects are hepatotoxicity, hypersensitivity reactions like skin rashes and rarely itching. Uses 1. Dermatophytic infections: Both are useful topically for tinea pedis, tinea cruris, tinea corporis and tinea versicolor. 2. Candida infections: They are used topically for the treatment of oral, pharyngeal, vulvovaginal and cutaneous candidiasis. 3. Miconazole is also useful in otomycosis. 58. Classify antifungal agents with examples. Discuss anti-fungal spectrum, mechanism of action and uses of systemic Triazoles. (NOV-2021) REFER QUESTION NO. 57 59. Classify antifungal agents with examples. Write the mechanism of action, adverse reactions and therapeutic uses of amphotericin B. (JUN-2022) Amphotericin B: Amphotericin B obtained from Streptomyces nodosus is a polyene antibiotic containing many double bonds. Antifungal spectrum: Amphotericin B has a wide antifungal spectrum. AMB is active against — Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Torulopsis, Rhodotorula, Aspergillus, Sporothrix, etc. Dermatophytes are inhibited in vitro, but concentrations of AMB attained in infected skin are low and ineffective. It is fungicidal at high and static at low concentrations Resistance to AMB during therapy has been rarely noted among Candida in a selected group of leucopenic cancer patients, but it is not a problem in the clinical use of the drug. AMB is also active on various species of Leishmania, a protozoa. Mechanism of action: Amphotericin B binds to ergosterol present in fungal cell membrane and forms pores in the cell membrane. Through these pores, cell contents leak out resulting in cell death. Since amphotericin has greater affinity for the fungal membrane sterol, i.e., ergosterol and also because cholesterol is the main sterol in human cells, the action of amphotericin is selective for the fungi. Pharmacokinetics: Amphotericin is not absorbed orally. Given IV, it is >90% bound to plasma proteins, widely distributed in the body has a long t½ of 15 days. It is not soluble in water and hence it is dispensed as a colloidal suspension for IV use. does not cross BBB. It is metabolized in liver and excreted slowly in urine and bile. Adverse Effects. AMB is the most toxic of all antifungal agents. The acute reactions are fever, chills, headache, dyspnoea, GI disturbances, phlebitis at the site of injection, etc. The drug should be continued. Coadministration of steroid can minimize the reaction. Anaemia and electrolyte disturbances are commonly seen. Anaemia is less with lipid-based formulations. Nephrotoxicity with azotaemia is seen in most of the patients on AMB therapy. Hepatotoxicity can occur occasionally. Headache and convulsions may occur on intrathecal administration. Interactions Flucytosine has supra-additive action with AMB in the case of fungi sensitive to both (AMB increases the penetration of 5- FC into the fungus). Aminoglycosides, vancomycin, cyclosporine and other nephrotoxic drugs enhance the renal impairment caused by AMB. Uses: Amphotericin B is the drug of choice for all life-threatening mycotic infections because it is fungicidal and has a broad antifungal spectrum. Amphotericin B is given intravenously in the treatment of mucormycosis, invasive aspergillosis, cryptococcosis, sporotrichosis, trichosporanosis, blastomycosis, histoplasmosis, coccidioidomycosis and Para coccidioidomycosis. In cystitis due to Candida, amphotericin B is used to irrigate the bladder. Amphotericin B is also used to prevent relapse of cryptococcosis and histoplasmosis in patients with AIDS. Amphotericin B can be given orally in fungal infections of the gut. It is used topically in candidiasis (3% lotion, cream, ointment). Leishmaniasis: In kala-azar and mucocutaneous leishmaniasis, amphotericin is used as an alternative. 60. Define classify antimalarial drugs with examples. Write the mechanism of action, adverse  effectsand uses of Artemisinin. (NOV-2022) (JUN-2023) Antimalarial agents are a class of medications used to prevent or treat malaria, a disease caused by Plasmodium parasites, which are transmitted to humans through the bites of infected Anopheles mosquitoes. These agents work at different stages of the parasite's life cycle in the human host, targeting various species of Plasmodium including P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Artemisinin: Artemisinin, a highly bitter compound, is a sesquiterpene lactone obtained from the plant Artemisia annua which has been used in the Chinese traditional medicine ‘Quinghaosu’ for almost 2000 years. Several semisynthetic analogs have been obtained with better efficacy and improved pharmacokinetic profile including—artesunate, dihydroartemisinin, artemether and arteether. Artemisinin derivatives are now the first line drugs in the treatment of falciparum malaria. Mechanism of action: Artemisinin interacts with haem resulting in the generation of free radicals that bind to the macromolecules as well as membrane proteins and damage the macromolecules and the parasite membrane. It could also inhibit calcium ATPase in the parasite. Though resistance does not develop readily, strains of P. falciparum which are less susceptible to artemether and treatment failures have been reported. Hence monotherapy with these drugs should be avoided. Actions: Artemisinin is a potent, rapidly acting, erythrocytic schizonticide effective against all the 5 plasmodial species, including MDR P. falciparum. It is also effective against gametocytes (but not the liver stages). It is useful in cerebral malaria. No resistant strains are known so far. Recrudescence is common due to its short t½. Combining with mefloquine avoids this. Though artemisinin is thought to be safe in pregnancy, it has been shown to be teratogenic in  animals. Artemisinin has activity against other organisms like T. gondii, Leishmania major and schistosomes. Pharmacokinetics: Artemisinin is poorly soluble in water and oil. The derivatives are suitable for administration by different routes. Artesunate—water soluble—oral, IM, IV, rectal. Artemether—lipid soluble—oral, IM and rectal. Dihydroartemisinin—water soluble—oral. Arteether—longer—IM. Oral bioavailability of artemisinin compounds is poor ( 6 skin lesions, as well as all smear positive cases. 82. Outline mechanism of action of metronidazole. (JUN-2022) Metronidazole is a prodrug. Susceptible microorganisms including anaerobic bacteria and certain protozoa reduce the nitro group of metronidazole by a nitroreductase and convert it to a cytotoxic derivative. This derivative binds to DNA and inhibits protein synthesis. Aerobic bacteria lack this nitroreductase and are, therefore, not susceptible to metronidazole. 83. What are blood schizonticides? Give one example. (JUN- 2023) Blood schizonticides are drugs that specifically target and eliminate the erythrocytic (red blood cell) stage of malaria parasites (Plasmodium species). These drugs are crucial for treating malaria because they kill the multiplying forms of the parasite within red blood cells, thereby preventing the progression of the disease. Examples: Chloroquine, quinine, artemisinin and derivatives destroy parasites in the RBCs and mefloquine, halofantrine, pyrimethamine, terminate clinical attacks of malaria.) atovaquone, chloroguanide 84. Write adverse effects of rifampicin. (NOV- 2023) Elevated liver function test (LFT) results (up to 14%), Rash (1-5%), Epigastric distress (1-2%), Anorexia (1-2%), Nausea (1-2%), Vomiting (1-2%), Diarrhea (1-2%), Cramps (1-2%), Pseudomembranous colitis (1-2%), Pancreatitis (1-2%). 85. Classification of anti-malarial agents. (NOV- 2023) 86. Name the drugs used for treatment of Helminthiasis. (JUN-2024) UNIT:4 1. CHEMOTHERAPY SHORT ESSAYS (05 MARKS) 88. Describe mechanism of action and therapeutic uses of alkylating agents. (DEC-2020) ALKYLATING AGENTS Alkylating agents are drugs that alkylate (donate an alkyl group to) other molecules by covalent bonds. They also alkylate DNA, RNA and various enzymes and there is interstand cross-linking of DNA. Classification: Alkylating agents Nitrogen mustards: Mechlorethamine (Mustine HCl), Cyclophosphamide, Ifosfamide, Chlorambucil, Melphalan Ethylenimine: Thio-TEPA Alkyl sulfonate: Busulfan Nitrosoureas: Carmustine (BCNU), Lomustine (CCNU) Triazine: Dacarbazine (DTIC), Temozolomide Methylhydrazine: Procarbazine Actions: Alkylating agents exert 1. Cytotoxic effects: Alkylating agents destroy the rapidly multiplying cells—both cancer cells and normal host cells. 2. Immunosuppressant effects: Alkylating agents are good immunosuppressants for which they are used in rheumatoid arthritis and other autoimmune disorders. 3. Radiomimetic effects: The actions of alkylating agents resemble that of radiotherapy. Mechanism of Action On administration, alkylating agents form highly reactive derivatives (carbonium ions) which transfer alkyl groups to various cellular carboxyl, amine and phosphate groups and bind them with covalent bonds. Thus such constituents are not available for normal metabolic reactions. They bind to one or both strands of DNA and also alkylate DNA which results in breakage of the DNA strand. They alkylate DNA at different sites, for example, at N7 position of guanine. Such alkylation leads to miscoding and abnormal base pairing or cross-linking, resulting in DNA strand breakages. Thus, they produce cytotoxicity. Resistance: The cells may acquire resistance to alkylating agents by one of the following ways: i. Repair DNA lesions. ii. Decreased transport of the drug into the cell. iii. Increased production of enzymes which conjugate alkylating agents. Adverse effects Cystitis, stomatitis Bone marrow depression, alopecia, vomiting, amenorrhoea, teratogenicity, Pulmonary fibrosis, Ototoxicity, Renal dysfunction, oedema of hands, Cardiotoxicity, red-coloured urine, Hepatotoxicity, Thrombocytopenia, Neurotoxicity, peripheral neuritis, Muscle weakness, Pancreatitis, Allergic reactions, Diarrhoea. Therapeutic Uses of Alkylating Agents: 1. Hematologic malignancies: o Hodgkin's lymphoma o Non-Hodgkin's lymphoma o Chronic lymphocytic leukemia (CLL). o Multiple myeloma o Acute myeloid leukemia (AML). 2. Solid tumors: o Breast cancer o Ovarian cancer o Lung cancer o Bladder cancer o Brain tumors 3. Autoimmune diseases (Non-oncologic use): o Severe autoimmune disorders: lupus nephritis, systemic lupus erythematosus (SLE), and certain forms of vasculitis (e.g., Wegener’s granulomatosis). 89. Write mechanism of action, adverse effects and uses of methotrexate. (MAR-2021) (NOV- 2021) ANTIMETABOLITES Folate Antagonists: Methotrexate (MTX) is a folic acid (FA) antagonist. It is a prodrug converted in the liver to its polyglutamates in the normal as well as tumour cells and the reaction is catalysed by the enzymes folypolyglutamate synthase (FPGS). Polyglutamates of methotrexate remain in the tumour cells. They are partly selective for tumour cells. Mechanisam of Action: Methotrexate binds to dihydrofolate reductase and prevents the formation of tetrahydrofolate (THF). This THF serves as a coenzyme essential in several reactions in DNA, RNA and protein synthesis (provides methyl groups). The deficiency results in inhibition of DNA, RNA and protein synthesis. Thus rapidly multiplying cells are the most affected. Methotrexate is most effective on cells in the ‘S’ phase of the cell cycle. Resistance to methotrexate may be due to: Decreased drug transport Reduced formation of active metabolites.  Increased synthesis of DHFR Altered DHFR with reduced affinity for methotrexate. Actions Cytotoxic actions: Methotrexate mainly affects the bone marrow, skin and gastrointestinal mucosa and other rapidly dividing cells. It also has immunosuppressant and some anti-inflammatory properties. Pharmacokinetics Methotrexate is well absorbed when given orally with 50% protein binding. It can also be given parenterally (IM, IV, intrathecal). Higher doses should be given IV as absorption is erratic at such doses. It poorly crosses the BBB due to low lipid solubility. Methotrexate is taken up into the cells by the same active transport process as that of folic acid. It is metabolised in the liver to polyglutamates which are inhibitors of DHFR. Methotrexate is excreted largely by the kidneys—hence dose should be reduced in renal failure. Adverse effects: Bone marrow suppression, nausea, vomiting, diarrhoea, alopecia and dermatitis. Methotrexate can cause nephrotoxicity. Allergic pneumonitis can sometimes be fatal. When injected intrathecally, methotrexate can cause myelopathy and encephalopathy. Drug Interactions Salicylates, sulfonamides, penicillin, aspirin and probenecid inhibit the renal tubular secretion of methotrexate. Some of them also displace methotrexate from plasma protein binding sites. Uses 1. Choriocarcinoma 2. Other cancers: Methotrexate is also tried as a component of multi-drug regimens in lymphomas, breast cancer, bone sarcomas and soft tissue sarcomas. 3. Psoriasis. 4. Rheumatoid arthritis 90. Classify alkylating agents and write their mechanism of action. (JUN-2022) REFER QUESTION NO. 88 91. Write about drugs used in treatment of urinary tract infections. (NOV-2022) Urinary tract infections (UTIs) are common bacterial infections that can affect any part of the urinary system, including the bladder, urethra, ureters, and kidneys. The choice of drugs for treating UTIs depends on the type of bacteria causing the infection, the severity of the infection, and whether it is a simple or complicated UTI. The most common bacteria involved in UTIs is Escherichia coli (E. coli), but other bacteria such as Klebsiella, Proteus, and Staphylococcus saprophyticus may also cause UTIs. Commonly Used Drugs for UTI Treatment: 1. Trimethoprim-Sulfamethoxazole (TMP-SMX): o Uses: Often used as first-line therapy for uncomplicated UTIs. o Mechanism: Inhibits folic acid synthesis in bacteria, preventing DNA replication and growth. o Spectrum: Effective against E. coli and other common UTI pathogens. o Limitations: Increasing bacterial resistance has reduced its effectiveness in some regions. 2. Nitrofurantoin: o Uses: Another first-line treatment for uncomplicated lower UTIs, especially cystitis. o Mechanism: Damages bacterial DNA, leading to bacterial death.  o Spectrum: Effective against E. coli, Enterococcus, Klebsiella, and Staphylococcus saprophyticus. o Limitations: Not suitable for pyelonephritis (kidney infection) due to poor tissue penetration. 3. Fosfomycin: o Uses: Often used as a single-dose treatment for uncomplicated cystitis. o Mechanism: Inhibits bacterial cell wall synthesis, leading to bacterial death. o Spectrum: Effective against E. coli and Enterococcus species, including some multidrug- resistant strains. 4. Fluoroquinolones (e.g., Ciprofloxacin, Levofloxacin): o Uses: Reserved for complicated UTIs or cases of pyelonephritis. o Mechanism: Inhibits bacterial DNA gyrase and topoisomerase IV, leading to DNA damage and bacterial death. o Spectrum: Broad-spectrum activity, including E. coli and other Gram-negative bacteria. o Limitations: Concerns about increasing bacterial resistance and potential side effects (tendonitis, CNS toxicity) limit their use as first-line therapy. 5. Beta-lactams (e.g., Amoxicillin-Clavulanate, Cefpodoxime, Cefdinir): o Uses: Second-line agents for uncomplicated UTIs and useful for complicated UTIs. o Mechanism: Inhibit bacterial cell wall synthesis, leading to cell lysis. o Spectrum: Effective against a broad range of bacteria, including E. coli, Klebsiella, and Proteus species. o Limitations: Resistance may occur, particularly with amoxicillin alone. 6. Aminoglycosides (e.g., Gentamicin, Amikacin): o Uses: Typically used in combination with other agents for severe or complicated UTIs, particularly in hospitalized patients. o Mechanism: Inhibit bacterial protein synthesis, leading to bacterial death. o Spectrum: Effective against Gram-negative bacteria like E. coli, Klebsiella, and Proteus. o Limitations: Potential nephrotoxicity and ototoxicity. 7. Carbapenems (e.g., Imipenem, Meropenem): o Uses: Reserved for multidrug-resistant infections or complicated UTIs, particularly in hospitalized patients. o Mechanism: Inhibit bacterial cell wall synthesis. o Spectrum: Broad-spectrum, including extended-spectrum beta-lactamase (ESBL) producing bacteria. o Limitations: Typically reserved for severe cases due to the risk of promoting antibiotic resistance. Special Considerations: Pregnancy: Certain drugs, such as nitrofurantoin and beta-lactams (e.g., amoxicillin-clavulanate), are safer for treating UTIs during pregnancy. Fluoroquinolones and tetracyclines are avoided due to potential harm to the fetus. Recurrent UTIs: In cases of recurrent UTIs, long-term, low-dose prophylaxis with agents like nitrofurantoin or TMP-SMX may be considered. Complicated UTIs: Infections associated with structural abnormalities, catheters, or kidney involvement (pyelonephritis) require broader-spectrum antibiotics like fluoroquinolones or carbapenems. 92. Classifytypes of anti-metabolites with examples. (JUN-2023) Antimetabolites are a class of drugs that interfere with DNA and RNA synthesis by mimicking the building blocks of these molecules. They are commonly used in cancer chemotherapy and to treat certain  autoimmune diseases. Antimetabolites can be classified into several categories based on their mechanism of action and the specific metabolic pathways they affect. Classification of Antimetabolites 1. Folic Acid Antagonists: o Mechanism: Inhibit the synthesis of folic acid, which is essential for the production of nucleotides and DNA. o Examples: ▪ Methotrexate: Used in the treatment of various cancers (e.g., leukemia, lymphoma) and autoimmune diseases (e.g., rheumatoid arthritis). ▪ Pemetrexed: Used primarily for non-small cell lung cancer and mesothelioma. 2. Purine Antagonists: o Mechanism: Interfere with purine metabolism, affecting the synthesis of adenine and guanine nucleotides. o Examples: ▪ Mercaptopurine (6-MP): Used in the treatment of acute lymphoblastic leukemia (ALL) and other hematologic malignancies. ▪ Thioguanine: Also used in the treatment of leukemia. ▪ Fludarabine: Used in the treatment of chronic lymphocytic leukemia (CLL) and non- Hodgkin lymphoma. 3. Pyrimidine Antagonists: o Mechanism: Inhibit the synthesis of pyrimidines, which are essential for DNA and RNA synthesis. o Examples: ▪ Cytarabine (Ara-C): Primarily used in the treatment of acute myeloid leukemia (AML) and lymphomas. ▪ 5-Fluorouracil (5-FU): Used in the treatment of various solid tumors, including colorectal and breast cancer. ▪ Capecitabine: An oral prodrug of 5-FU used for metastatic colorectal cancer and breast cancer. 4. Nucleotide Analogues: o Mechanism: Mimic the structure of nucleotides, leading to faulty DNA or RNA synthesis. o Examples: ▪ Acyclovir: An antiviral drug used to treat infections caused by certain viruses (e.g., herpes simplex virus, varicella-zoster virus) by mimicking deoxyguanosine. ▪ Gemcitabine: Used in the treatment of various cancers, including pancreatic cancer and non-small cell lung cancer. 93. Classify anticancer agents with examples. (NOV-2023) A. Cytotoxic drugs 1. Alkylating agents i. Nitrogen mustards: Mechlorethamine (Mustine HCl), Cyclophosphamide, Ifosfamide, Chlorambucil, Melphalan ii. Ethylenimine: Thio-TEPA iii. Alkyl sulfonate: Busulfan iv. Nitrosoureas: Carmustine (BCNU), Lomustine (CCNU) v. Triazine: Dacarbazine (DTIC), Temozolomide vi. Methylhydrazine: Procarbazine 2. Platinum coordination complexes: Cisplatin, Carboplatin, Oxaliplatin 3. Antimetabolites:  i. Folate Antagonist: Methotrexate (Mtx), Pemetrexed ii. Purine Antagonist: 6-Mercaptopurine (6-MP), 6-Thioguanine (6-TG), Azathioprine, Fludarabine iii. Pyrimidine antagonist: 5-Fluorouracil (5-FU), Capecitabine, Cytarabine (cytosine arabinoside) 4. Microtubule damaging agents: Vincristine (Oncovin), Vinblastine, Vinorelbine Paclitaxel, Docetaxel Estramustine 5. Topoisomerase-2 inhibitors: Etoposide 6. Topoisomerase-1 inhibitors: Topotecan, Irinotecan 7. Antibiotics: Actinomycin D (Dactinomycin), Doxorubicin, Daunorubicin (Rubidomycin), Epirubicin, Mitoxantrone, Bleomycins, Mitomycin C 8. Miscellaneous: Hydroxyurea, L-Asparaginase, Tretinoin, Arsenic trioxide B. Targeted drugs 1. Tyrosine protein- kinase inhibitors: Imatinib, Nilotinib 2. EGF receptor inhibitors: Gefitinib, Erlotinib Cetuximab 3. Angiogenesis inhibitors: Bevacizumab Sunitinib 4. Proteasome inhibitor: Bortezomib 5. Unarmed monoclonal antibody: Rituximab, Trastuzumab C. Hormonal drugs 1. Glucocorticoids: Prednisolone and others 2. Estrogens: Fosfestrol, Ethinylestradiol 3. Selective estrogen receptor modulators: Tamoxifen, Toremifene 4. Selective estrogen receptor down regulators: Fulvestrant 5. Aromatase inhibitors: Letrozole, Anastrozole, Exemestane 6. Antiandrogen: Flutamide, Bicalutamide 7. 5-α reductase inhibitor: Finasteride, Dutasteride 8. GnRH analogues: Nafarelin, Leuprorelin, Triptorelin 9. Progestins: Hydroxyprogesterone acetate, etc. 94. Write the mechanism of action, toxicity and uses of Methotrexate. (JUN-2024) REFER QUESTION NO. 89 SHORT ANSWERS (02 MARKS) 95. Mention common causative organisms for UTI. (DEC-2020) Urinary tract infections (UTIs) are predominantly caused by bacteria, though they can also be caused by fungi and, in rare cases, viruses. The most common causative organisms for UTIs include: Bacterial Causes 1. Escherichia coli (E. coli) 2. Klebsiella pneumoniae: 3. Proteus mirabilis: 4. Enterococcus faecalis: 5. Staphylococcus saprophyticus: 6. Pseudomonas aeruginosa: 7. Enterobacter species: 8. Serratia marcescens: Fungal Causes: Candida species (e.g., Candida albicans): Viral Causes: Adenovirus: 96. Write causative organisms and drug of choice for syphilis and gonorrhoea. (MAR-2021) Syphilis: Causative organism is Treponema pallidum, with benzathine penicillin G as the drug of choice.  Gonorrhea: Causative organism is Neisseria gonorrhoeae, with ceftriaxone (often combined with azithromycin) as the drug of choice. 97. Mention common causative organism of sexually transmitted diseases. (NOV-2021) Bacterial STDs 1. Chlamydia trachomatis: Causes chlamydia. 2. Neisseria gonorrhoeae: Causes gonorrhea. 3. Treponema pallidum: Causes syphilis. 4. Mycoplasma genitalium: Associated with non-gonococcal urethritis and pelvic inflammatory disease. 5. Haemophilus ducreyi: Causes chancroid. Viral STDs 1. Human Immunodeficiency Virus (HIV): Causes HIV/AIDS. 2. Herpes Simplex Virus (HSV): Causes genital herpes (primarily HSV-2, but also HSV-1). 3. Human Papillomavirus (HPV): Causes genital warts and is associated with various cancers, including cervical cancer. 4. Hepatitis B Virus (HBV): Causes hepatitis B. 5. Hepatitis C Virus (HCV): Primarily transmitted through blood but can also be sexually transmitted. Parasitic STDs 1. Trichomonas vaginalis: Causes trichomoniasis. 98. Mention four urinary antiseptics. (JUN-2022) 1. Nitrofurantoin 2. Methenamine 3. Fosfomycin 4. Trimethoprim 99. Write the mechanism of action of alkylating agents. (NOV-2022) On administration, alkylating agents form highly reactive derivatives (carbonium ions) which transfer alkyl groups to various cellular carboxyl, amine and phosphate groups and bind them with covalent bonds. Thus such constituents are not available for normal metabolic reactions. They bind to one or both strands of DNA and also alkylate DNA which results in breakage of the DNA strand. They alkylate DNA at different sites, for example, at N7 position of guanine. Such alkylation leads to miscoding and abnormal base pairing or cross-linking, resulting in DNA strand breakages. Thus, they produce cytotoxicity. 100. Mention the first line of drug therapy for syphilis. (JUN-2023)  The first-line drug therapy for syphilis is Benzathine penicillin G. It is administered as an intramuscular injection and is effective for all stages of syphilis, including primary, secondary, and latent syphilis. For individuals who are allergic to penicillin, alternative treatment options may include doxycycline or tetracycline, but these are not