Antu diabetic drugs classification and mechanism of action

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Antidiabetic Drugs: Classification and Mechanism of Action

Antidiabetic drugs are classified based on their primary mechanism of action. Here is a complete overview from the medical library:

1. Biguanides

Drug: Metformin (only available biguanide)

Mechanism:

Activates AMP-activated protein kinase (AMPK)
Reduces hepatic insulin resistance → decreases gluconeogenesis and hepatic glucose production
Some peripheral insulin sensitization (inconsistent)

Key points: Preferred first-line agent in type 2 diabetes. No hypoglycemia risk (does not increase insulin). Contraindicated in eGFR <30 mL/min. Rare risk of lactic acidosis.

2. Sulfonylureas (Insulin Secretagogues)

Drugs:

1st generation: Chlorpropamide, tolbutamide, tolazamide, acetohexamide
2nd generation: Glipizide, glyburide, gliclazide, glimepiride

Mechanism:

Bind to the sulfonylurea receptor (a subunit of the ATP-sensitive K+ channel) on pancreatic β-cell membrane
Close the K+ channel → membrane depolarization → Ca²+ influx → exocytosis of insulin granules (insulin secretion)

Key points: Oldest oral antidiabetic class. Major adverse effects - hypoglycemia (highest risk with glyburide) and weight gain.

3. Meglitinides / Glinides (Insulin Secretagogues)

Drugs: Repaglinide, Nateglinide

Mechanism:

Bind to pancreatic β-cells and stimulate insulin secretion (similar site to sulfonylureas but structurally distinct)
Repaglinide: faster absorption, briefer insulin stimulus, effect mainly on fasting glucose
Nateglinide: very short action, specific effect on postprandial glucose

Key points: Taken with meals. Repaglinide has biliary elimination - safe in renal insufficiency.

4. Thiazolidinediones (TZDs) / Glitazones (Insulin Sensitizers)

Drugs: Pioglitazone, Rosiglitazone

Mechanism:

Bind to and modulate peroxisome proliferator-activated receptor-gamma (PPAR-γ) in muscle, fat, and liver
PPAR-γ activation influences differentiation of fibroblasts into adipocytes and lowers free fatty acid levels
Result: improved insulin sensitivity + reduced free fatty acid levels

Key points: No hypoglycemia risk. Adverse effects include weight gain, fluid retention, risk of bone fractures (postmenopausal women, older males), and congestive heart failure. Contraindicated in active hepatocellular disease.

5. Alpha-Glucosidase Inhibitors (Carbohydrate Absorption Blockers)

Drugs: Acarbose, Miglitol

Mechanism:

Competitively inhibit α-glucosidases at the brush border of intestinal epithelium
Block the final step of carbohydrate digestion → delay carbohydrate absorption
Decrease postprandial glucose peak and insulin response

Key points: No hypoglycemia risk, no weight gain. Main adverse effects are flatulence and diarrhea. Use cautiously in chronic renal disease.

6. GLP-1 Receptor Agonists (Incretin Mimetics)

Drugs: Exenatide, Liraglutide, Dulaglutide, Semaglutide

Mechanism:

Mimic glucagon-like peptide-1 (GLP-1), which mediates the incretin effect (oral glucose → greater insulin stimulation than parenteral glucose)
Suppress glucagon secretion
Slow gastric emptying
Reduce food intake
Promote β-cell proliferation and secretion
Increase insulin secretion only in the presence of hyperglycemia (glucose-dependent) → low hypoglycemia risk

Key points: Injectable (mostly). Cause weight loss. Contraindicated in medullary thyroid cancer and MEN. Pancreatitis is a reported risk.

7. DPP-4 Inhibitors (Gliptins)

Drugs: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, Vildagliptin

Mechanism:

Inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades endogenous GLP-1
Prolonging native GLP-1 action → increased glucose-dependent insulin secretion + decreased glucagon secretion

Key points: Oral, once-daily. No hypoglycemia risk. Most require renal dose adjustment except linagliptin. Risk of pancreatitis. Saxagliptin has a safety alert for possible heart failure association.

8. SGLT-2 Inhibitors (Gliflozins)

Drugs: Canagliflozin, Dapagliflozin, Empagliflozin

Mechanism:

Inhibit sodium-glucose cotransporter 2 (SGLT-2) in the proximal nephron
Insulin-independent mechanism
Block renal glucose reabsorption → glucosuria → reduces blood glucose
Also causes natriuresis → lowers blood pressure

Key points: Reduce HbA1c AND systolic/diastolic BP. Efficacy decreases in renal impairment (eGFR <45-60 mL/min/1.73 m²). Risk of genitourinary infections and euglycemic DKA.

9. Amylin Mimetics

Drug: Pramlintide

Mechanism:

Mimics amylin (co-secreted with insulin from β-cells)
Decreases glucagon secretion
Slows gastric emptying

Key points: Injectable, used adjunctively with insulin. Modest efficacy. Causes nausea and vomiting.

10. Insulin

Mechanism:

Binds insulin receptors (tyrosine kinase receptors) on target cells
Promotes glucose uptake in muscle and fat, suppresses hepatic glucose production, promotes glycogen synthesis
Available as rapid-acting, short-acting, intermediate-acting, and long-acting formulations

Key points: Used when β-cell function declines and oral agents are insufficient, or in acute hyperglycemic crises.

11. Other Agents (Modest Efficacy)

Drug	Mechanism
Bromocriptine (dopamine agonist)	Unknown mechanism; modest A1C reduction
Colesevelam (bile acid sequestrant)	Unknown mechanism; modest A1C reduction

Summary Table

Drug Class	Mechanism	Hypoglycemia Risk	Examples
Biguanides	Suppress hepatic glucose production	No	Metformin
Sulfonylureas	Potentiate insulin secretion (K+ channel closure)	Yes	Glyburide, Glipizide, Glimepiride
Meglitinides	Potentiate insulin secretion (short-acting)	Yes (rare)	Repaglinide, Nateglinide
TZDs	Improve insulin sensitivity via PPAR-γ	No	Pioglitazone, Rosiglitazone
α-Glucosidase inhibitors	Delay carbohydrate absorption	No	Acarbose, Miglitol
GLP-1 agonists	Incretin effect - increase insulin, decrease glucagon, slow gastric emptying	No	Exenatide, Liraglutide
DPP-4 inhibitors	Prolong GLP-1 action	No	Sitagliptin, Linagliptin
SGLT-2 inhibitors	Block renal glucose reabsorption	No	Canagliflozin, Dapagliflozin, Empagliflozin
Amylin mimetics	Decrease glucagon, slow gastric emptying	No	Pramlintide
Insulin	Direct insulin receptor activation	Yes	Various formulations

Sources: Tintinalli's Emergency Medicine: A Comprehensive Study Guide, p. 1471-1472; Lippincott Illustrated Reviews: Pharmacology, p. 821

Anti tubercular drugs and mechanism of action

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Anti-Tubercular Drugs: Classification and Mechanism of Action

Antitubercular drugs are divided into first-line (preferred, most effective, least toxic) and second-line (for resistant or intolerant cases) agents.

FIRST-LINE DRUGS

The standard regimen is RIPE: Rifampin + Isoniazid + Pyrazinamide + Ethambutol

1. Isoniazid (INH)

Mechanism of Action:

A prodrug - activated by the mycobacterial catalase-peroxidase enzyme KatG
The activated form forms a covalent complex with AcpM (acyl carrier protein) and KasA (β-ketoacyl carrier protein synthetase)
This blocks mycolic acid synthesis - mycolic acids are essential long-chain fatty acid components of the mycobacterial cell wall
Bactericidal against actively growing bacilli; active against both extracellular and intracellular organisms

Resistance: Mutations in katG (high-level resistance), overexpression of inhA (low-level resistance + cross-resistance to ethionamide), mutations in kasA or ahpC.

Key adverse effects:

Hepatotoxicity (most important - risk increases with age and alcohol use)
Peripheral neuropathy (due to pyridoxine/B6 depletion - prevented by giving pyridoxine 10 mg/d)
Drug-induced lupus

2. Rifampin (Rifampicin)

Mechanism of Action:

Binds to the β-subunit of bacterial DNA-dependent RNA polymerase (encoded by rpoB gene)
Inhibits RNA synthesis (transcription)
Human RNA polymerase is not inhibited (selectivity)
Bactericidal; active against both intracellular and extracellular bacilli

Resistance: Point mutations in the rpoB gene → reduced binding of rifampin to RNA polymerase. Complete cross-resistance with rifabutin and rifapentine.

Key adverse effects:

Orange discoloration of urine, sweat, tears (harmless)
Hepatitis, cholestatic jaundice
Thrombocytopenia, rash
Influenza-like syndrome (if given less than twice weekly)
Potent CYP450 inducer (CYP1A2, 2C9, 2C19, 2D6, 3A4) - reduces levels of many drugs (oral contraceptives, anticoagulants, protease inhibitors, etc.)

3. Pyrazinamide (PZA)

Mechanism of Action:

Another prodrug - converted to pyrazinoic acid by mycobacterial pyrazinamidase (PncA)
Pyrazinoic acid acidifies the intracellular environment of mycobacteria
Disrupts membrane potential and interferes with fatty acid synthesis (FAS-I)
Active only in acidic environments (e.g., intracellular compartments, caseous necrosis)
Bactericidal against semi-dormant intracellular bacilli - uniquely effective in the first 2 months to sterilize lesions
Only active against M. tuberculosis (not atypical mycobacteria)

Resistance: Mutations in the pncA gene (loss of pyrazinamidase activity).

Key adverse effects:

Hyperuricemia (most common) → gout
Hepatotoxicity
Arthralgia, rash

4. Ethambutol (EMB)

Mechanism of Action:

Inhibits arabinosyl transferases (encoded by embCAB genes)
Blocks synthesis of arabinogalactan - a major polysaccharide component of the mycobacterial cell wall
Primarily bacteriostatic
Used mainly to prevent emergence of resistance to other drugs

Resistance: Mutations in embB gene.

Key adverse effects:

Optic neuritis (dose-dependent) - loss of visual acuity, red-green colour blindness (reversible if stopped early)
Hyperuricemia

5. Rifapentine

Mechanism:

Analog of rifampin; same mechanism - inhibits bacterial RNA polymerase (β-subunit)
Complete cross-resistance with rifampin
Longer half-life than rifampin → allows less frequent dosing
Less potent CYP inducer when given intermittently

6. Moxifloxacin (now classified as first-line in newer regimens)

Mechanism:

Fluoroquinolone - inhibits DNA gyrase (topoisomerase II) and topoisomerase IV
Prevents DNA supercoiling and strand separation → blocks DNA replication and transcription
Bactericidal

SECOND-LINE DRUGS

Used for multidrug-resistant TB (MDR-TB), drug intolerance, or treatment failure.

7. Streptomycin

Mechanism:

Aminoglycoside antibiotic
Binds 30S ribosomal subunit (16S rRNA and S12 protein)
Causes misreading of mRNA → production of faulty proteins
Bactericidal
Active mainly against extracellular bacilli (poor intracellular penetration)

Resistance: Point mutations in rpsL (S12 protein) or rrs (16S rRNA) genes.

Key adverse effects: Ototoxicity (vestibular > cochlear), nephrotoxicity.

8. Cycloserine

Mechanism:

Structural analog of D-alanine
Inhibits D-alanine racemase and D-alanyl-D-alanine synthetase
Blocks synthesis of D-alanyl-D-alanine, a key component of the peptidoglycan cell wall

Key adverse effects: CNS toxicity (psychosis, seizures, depression) - most serious. Pyridoxine can reduce CNS effects.

9. Ethionamide

Mechanism:

Also a prodrug; activated by EthA (a flavin monooxygenase)
Inhibits mycolic acid synthesis (similar target to INH via inhA)
Cross-resistance with isoniazid when resistance is due to inhA overexpression

Key adverse effects: GI intolerance (most common), hepatotoxicity, peripheral neuropathy, hypothyroidism.

10. Bedaquiline

Mechanism:

Diarylquinoline - first new drug class approved since 1971
Inhibits mycobacterial ATP synthase (subunit c of the F0 portion)
Blocks ATP production → energy starvation and death
Active against both replicating and non-replicating bacilli
Used in MDR and XDR-TB (combined with linezolid + pretomanid - the BPaL regimen)

Key adverse effects: QT prolongation (ECG monitoring required), nausea, hepatotoxicity. Long half-life (>5 months).

11. Pretomanid

Mechanism:

A nitroimidazole (similar to metronidazole)
Kills replicating bacilli by generating reactive nitrogen intermediates (NO) → disrupts cell wall lipid synthesis and respiratory function
Also kills non-replicating bacilli under anaerobic conditions

Key adverse effects: Peripheral neuropathy (especially combined with linezolid), hepatotoxicity, QT prolongation, acne.

12. Linezolid

Mechanism:

Oxazolidinone antibiotic
Binds 23S rRNA of the 50S ribosomal subunit
Blocks formation of the 70S initiation complex → inhibits protein synthesis
Bacteriostatic against most organisms, but has useful bactericidal activity against M. tuberculosis
Used in MDR/XDR-TB as part of BPaL regimen

Key adverse effects: Bone marrow suppression, peripheral neuropathy, optic neuropathy (risk with prolonged use). Serotonin syndrome risk with serotonergic agents.

13. Rifabutin

Mechanism:

Rifamycin derivative; same mechanism as rifampin - inhibits bacterial RNA polymerase
Less potent CYP inducer than rifampin
Preferred over rifampin in HIV patients on antiretrovirals (protease inhibitors, NNRTIs, integrase inhibitors)

14. Aminosalicylic Acid (PAS)

Mechanism:

Structural analog of para-aminobenzoic acid (PABA)
Competitively inhibits dihydropteroate synthase → blocks folate synthesis in mycobacteria
Bacteriostatic; used mainly to prevent resistance

15. Capreomycin / Amikacin / Kanamycin

Mechanism:

Polypeptide (capreomycin) / aminoglycosides
Inhibit protein synthesis at the 30S ribosomal subunit
Used for MDR-TB when injectable agents are needed

Summary Table

Drug	Class	Mechanism	Bactericidal/static	Key Toxicity
Isoniazid	Hydrazide	Inhibits mycolic acid synthesis (via KatG activation)	Bactericidal	Hepatitis, peripheral neuropathy (B6 deficiency)
Rifampin	Rifamycin	Inhibits RNA polymerase (β-subunit)	Bactericidal	Orange secretions, hepatitis, CYP inducer
Pyrazinamide	Pyrazine	Disrupts membrane potential, fatty acid synthesis (acidic pH)	Bactericidal (intracellular)	Hyperuricemia, hepatotoxicity
Ethambutol	Ethanolamine	Inhibits arabinosyl transferase → blocks arabinogalactan	Bacteriostatic	Optic neuritis
Rifapentine	Rifamycin	Inhibits RNA polymerase	Bactericidal	Similar to rifampin
Moxifloxacin	Fluoroquinolone	Inhibits DNA gyrase/topoisomerase IV	Bactericidal	QT prolongation
Streptomycin	Aminoglycoside	Inhibits 30S ribosome → misreads mRNA	Bactericidal	Ototoxicity, nephrotoxicity
Cycloserine	Structural analog	Inhibits D-Ala racemase and synthetase → blocks cell wall	Bacteriostatic	CNS toxicity, seizures
Ethionamide	Thioamide	Inhibits mycolic acid synthesis (inhA)	Bacteriostatic	GI intolerance, hepatitis
Bedaquiline	Diarylquinoline	Inhibits ATP synthase	Bactericidal	QT prolongation
Pretomanid	Nitroimidazole	Generates reactive NO species; disrupts cell wall and respiration	Bactericidal	Neuropathy, QT
Linezolid	Oxazolidinone	Inhibits 50S ribosome (70S initiation)	Bacteriostatic/cidal	Bone marrow suppression, neuropathy
Rifabutin	Rifamycin	Inhibits RNA polymerase	Bactericidal	Leukopenia, optic neuritis
PAS	PABA analog	Inhibits folate synthesis	Bacteriostatic	GI intolerance
Streptomycin/Amikacin	Aminoglycosides	Inhibit 30S ribosome	Bactericidal	Ototoxicity, nephrotoxicity

Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 1312-1321

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