Insulin preparation and analogues -enumerate Diabetic ketoacidosis outline treatment and management of diabetic ketoacidosis detail Oral hypoglycemic agents classify;biguanides moa,adverse effect, uses ; sulfonylureas moa, adverse effect, uses ;thiazolidinediones moa, pharmacological actions, adverse effect and uses : metformin moa adverse effect, uses Insulin different sources, indications, human insulin over conventional insulin advantages detail answer each for 2nd yr mbbs pharmacology refer kd tripathi add flowcharts and diagram

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INSULIN AND ORAL HYPOGLYCAEMIC AGENTS

2nd Year MBBS Pharmacology | Ref: KD Tripathi / Lippincott Pharmacology

SECTION 1: INSULIN - SOURCES

Insulin is obtained from three sources:

Source	Details
Bovine (Beef) insulin	Differs from human insulin at 3 amino acid positions (A8, A10, B30). More antigenic.
Porcine (Pork) insulin	Differs at only 1 position (B30: alanine instead of threonine). Less antigenic than bovine.
Human insulin	Produced by recombinant DNA technology using E. coli or Saccharomyces cerevisiae, or by enzymatic conversion of pork insulin. Least antigenic.

SECTION 2: ADVANTAGES OF HUMAN INSULIN OVER CONVENTIONAL (ANIMAL) INSULIN

Feature	Human Insulin	Conventional (Animal) Insulin
Antigenicity	Very low - structurally identical to endogenous insulin	Higher - amino acid differences cause immune reactions
Insulin resistance	Rare	More common (antibody-mediated)
Lipodystrophy	Less frequent at injection sites	More frequent
Allergy	Very rare	Local/systemic reactions possible
Onset of action	Slightly faster absorption	Slightly slower
Availability	Produced in unlimited quantities via recombinant DNA	Limited by animal sources
Purity	Highly purified, monocomponent	May contain proinsulin and other peptides
Immunological complications	Minimal	More - anti-insulin antibodies, insulin resistance

Key advantage: Human insulin eliminates the risk of immunological complications and insulin resistance that arise with bovine/porcine insulins due to structural differences. It also does not carry risk of animal-derived pathogens.

SECTION 3: INSULIN PREPARATIONS - CLASSIFICATION AND ENUMERATION

Classification by Duration of Action

INSULIN PREPARATIONS
├── RAPID-ACTING (Bolus/Prandial)
│   ├── Insulin Lispro (Humalog)
│   ├── Insulin Aspart (NovoLog/NovoRapid)
│   ├── Insulin Glulisine (Apidra)
│   └── Inhaled Insulin (Afrezza)
│
├── SHORT-ACTING
│   └── Regular Insulin (Soluble/Plain insulin) (Humulin R)
│
├── INTERMEDIATE-ACTING (Basal)
│   └── NPH Insulin (Neutral Protamine Hagedorn / Isophane insulin) (Humulin N)
│
├── LONG-ACTING (Basal)
│   ├── Insulin Glargine (Lantus) - "peakless"
│   ├── Insulin Detemir (Levemir)
│   └── Insulin Degludec (Tresiba) - ultra-long acting (>42 h)
│
└── MIXTURES (Premixed)
    ├── NPH/Regular 70/30
    ├── Insulin lispro protamine/lispro 75/25
    └── Insulin aspart protamine/aspart 70/30

Pharmacokinetic Summary Table

Type	Agent	Onset	Peak	Duration	Route
Rapid-acting	Lispro, Aspart, Glulisine	15-30 min	30-90 min	3-5 h	SC
Short-acting	Regular insulin	30-60 min	50-120 min	5-8 h	SC/IV/IM
Intermediate	NPH (Isophane)	1-2 h	4-8 h	12-20 h	SC
Long-acting	Glargine	2-4 h	Peakless	~24 h	SC only
Long-acting	Detemir	1-2 h	6-8 h	6-23 h	SC
Ultra-long	Degludec	1 h	Peakless	>42 h	SC

Insulin Onset/Duration Graph (from Lippincott Pharmacology)

Onset and duration of action of human insulin and insulin analogs

Figure: Onset and duration of human insulin and insulin analogs. NPH = Neutral Protamine Hagedorn.

Insulin Analogues - How are they made?

Regular insulin is modified at amino acid sequences to create analogues with altered pharmacokinetics:

Rapid-acting analogues (Lispro, Aspart, Glulisine): Amino acid sequence changes reduce self-association into hexamers → monomer/dimer form absorbed faster from SC tissue
Glargine: Asparagine replaced by glycine at A21; 2 arginines added at B30 end → low pH formulation precipitates at injection site → slow, sustained release → PEAKLESS profile
Detemir: Fatty acid (myristic acid) attached to B29 lysine → binds albumin → prolonged action
Degludec: Forms multi-hexamer depots at SC site → ultra-long duration (>42 h), truly flat profile

SECTION 4: INDICATIONS FOR INSULIN

INDICATIONS FOR INSULIN
┌─────────────────────────────────────────────────────────────┐
│  ABSOLUTE INDICATIONS                                        │
│  • Type 1 Diabetes Mellitus (mandatory - no beta cells)     │
│  • Diabetic Ketoacidosis (DKA)                              │
│  • Hyperosmolar Hyperglycaemic State (HHS)                  │
│  • Gestational Diabetes (when diet fails)                   │
│  • Diabetes with severe hepatic/renal disease               │
│  • Diabetes with serious infections, surgery, trauma        │
└─────────────────────────────────────────────────────────────┘
┌─────────────────────────────────────────────────────────────┐
│  RELATIVE INDICATIONS                                        │
│  • Type 2 DM: when oral agents fail or contraindicated      │
│  • Type 2 DM with advanced complications                    │
│  • Pancreatectomy / secondary diabetes                      │
│  • Diabetic patients undergoing major surgery               │
│  • Severely malnourished / wasting diabetes                 │
└─────────────────────────────────────────────────────────────┘

SECTION 5: DIABETIC KETOACIDOSIS (DKA)

Definition and Diagnostic Criteria

DKA is an acute metabolic emergency characterized by the triad:

Hyperglycaemia - Blood glucose >250 mg/dL (usually)
Ketoacidosis - Serum bicarbonate <18 mEq/L; pH <7.3; ketonaemia/ketonuria
Anion gap metabolic acidosis - Anion gap >12

Pathophysiology (Brief)

INSULIN DEFICIENCY + GLUCAGON EXCESS
           ↓
┌──────────────────────────────────────────┐
│  Glucose cannot enter cells              │
│  ↑ Glycogenolysis + ↑ Gluconeogenesis    │
│  → HYPERGLYCAEMIA                        │
│                                          │
│  ↑ Lipolysis → Free Fatty Acids          │
│  → Beta-oxidation → Acetyl CoA excess    │
│  → KETONE BODY formation                 │
│  (Acetoacetate, Beta-hydroxybutyrate,    │
│   Acetone)                               │
│  → METABOLIC ACIDOSIS                    │
│                                          │
│  Glucose osmotic diuresis →              │
│  Na⁺, K⁺, H₂O, PO₄ losses              │
│  → DEHYDRATION + ELECTROLYTE LOSS        │
└──────────────────────────────────────────┘

Precipitating Factors (The "I's")

Infection (most common - ~40%)
Insulin omission / non-compliance
Ischemia (MI, stroke)
Intoxication (alcohol, cocaine)
Inflammation (pancreatitis)
Infarction (mesenteric)
Iatrogenic (steroids, thiazides)
New-onset DM Type 1

MANAGEMENT OF DKA - DETAILED

Flowchart: DKA Management

PATIENT PRESENTS WITH SUSPECTED DKA
           ↓
IMMEDIATE ASSESSMENT (ABCs + IV Access)
           ↓
DIAGNOSTIC CONFIRMATION
• Serum glucose, electrolytes (Na, K, Cl, HCO₃)
• ABG (pH, pCO₂, HCO₃)
• Urine/serum ketones
• CBC with differential
• Serum BUN, creatinine
• ECG, CXR, Urine culture
• Blood cultures if infection suspected
           ↓
SEVERITY CLASSIFICATION
┌──────────┬──────────┬──────────┐
│          │  Mild    │ Moderate │ Severe
│ pH       │ 7.25-7.30│ 7.00-7.24│ <7.00
│ HCO₃     │ 15-18    │ 10-15    │ <10
│ Anion Gap│ >10      │ >12      │ >12
│ Sensorium│ Alert    │ Drowsy   │ Stupor/Coma
└──────────┴──────────┴──────────┘
           ↓
┌─────────────────────────────────────────────────────────┐
│                   FOUR PILLARS OF TREATMENT              │
│                                                          │
│  1. FLUID REPLACEMENT                                    │
│  2. INSULIN THERAPY                                      │
│  3. ELECTROLYTE REPLACEMENT (esp. POTASSIUM)             │
│  4. TREAT PRECIPITATING CAUSE                            │
└─────────────────────────────────────────────────────────┘

PILLAR 1: FLUID REPLACEMENT

Goal: Correct dehydration (fluid deficit typically 4-6 L), restore circulating volume, dilute glucose and ketones

Step	Fluid	Rate
First 1-2 hours	0.9% Normal Saline (NS)	1 L bolus, then 500-1000 mL/h
After volume restored	0.45% NS (or 0.9% NS if hyponatraemic)	150-500 mL/h
When glucose <250 mg/dL	Switch to Dextrose 5% in 0.45% NS	To prevent hypoglycaemia while continuing insulin

Note: Correct no faster than 3 mOsm/kg/h to prevent cerebral oedema (especially in children).

PILLAR 2: INSULIN THERAPY

Agent: Regular insulin IV (NEVER NPH or long-acting in acute DKA)

INSULIN PROTOCOL IN DKA
        ↓
CHECK SERUM K⁺ FIRST
        ↓
   K⁺ < 3.3 mEq/L?        K⁺ ≥ 3.3 mEq/L?
        ↓                       ↓
  HOLD INSULIN           GIVE INSULIN BOLUS
  Replace K⁺ first       0.1 units/kg IV bolus
        ↓                       ↓
                        INSULIN INFUSION
                        0.1 units/kg/h IV
                        (Regular insulin: 100 units
                         in 100 mL 0.9% saline
                         at 10 mL/h = 10 units/h)
                               ↓
                    GOAL: ↓ BG by 50-75 mg/dL/h
                    (NOT faster than 100 mg/dL/h
                     → risk of cerebral oedema)
                               ↓
                   When BG reaches 250 mg/dL:
                   • Add D5W to IV fluids
                   • Reduce insulin to 0.05 units/kg/h
                   • Continue until: pH >7.3,
                     HCO₃ >15 mEq/L, anion gap closed
                               ↓
                   Transitioning to Subcutaneous:
                   Give SC basal insulin 2 h BEFORE
                   stopping IV insulin infusion

PILLAR 3: POTASSIUM REPLACEMENT

Why K⁺ is critical: Total body K⁺ is depleted (from osmotic diuresis), but serum K⁺ may be normal or HIGH initially (due to acidosis shifting K⁺ extracellularly). Insulin drives K⁺ back INTO cells → serum K⁺ FALLS → can cause life-threatening hypokalaemia.

Serum K⁺	Action
< 3.3 mEq/L	HOLD insulin; give 40 mEq/h KCl until K⁺ ≥ 3.3
3.3 - 5.5 mEq/L	Add 20-40 mEq KCl to each litre of IV fluids
> 5.5 mEq/L	Do not give K⁺; monitor every 2 hours

Other Treatments

Bicarbonate:

NOT routinely recommended
Consider ONLY if pH < 7.0 or severe hyperkalaemia with ECG changes
Risks: paradoxical CNS acidosis, hypokalaemia, cerebral oedema

Phosphate:

Not routinely replaced
May replace if severe hypophosphataemia (<1 mg/dL) with cardiac or respiratory complications

Monitoring:

Blood glucose: hourly
Electrolytes (K⁺, Na⁺, HCO₃⁻, Cl⁻): every 2-4 hours
ABG: every 4-6 hours
Urine output: continuously

Resolution Criteria (DKA is resolved when ALL of):

Blood glucose < 200 mg/dL
Serum HCO₃ ≥ 15 mEq/L
Venous pH > 7.3
Anion gap ≤ 12 mEq/L

SECTION 6: ORAL HYPOGLYCAEMIC AGENTS (OHAs) - CLASSIFICATION

ORAL HYPOGLYCAEMIC AGENTS
│
├── INSULIN SECRETAGOGUES (stimulate insulin release)
│   ├── Sulfonylureas - 1st gen: Tolbutamide, Chlorpropamide
│   │                  2nd gen: Glibenclamide (Glyburide), Glipizide
│   │                  3rd gen: Glimepiride
│   └── Meglitinides (Glinides) - Repaglinide, Nateglinide
│
├── INSULIN SENSITIZERS
│   ├── Biguanides - Metformin (only available biguanide)
│   └── Thiazolidinediones (TZDs/Glitazones) - Pioglitazone, Rosiglitazone
│
├── ALPHA-GLUCOSIDASE INHIBITORS
│   └── Acarbose, Miglitol, Voglibose
│
├── INCRETIN-BASED THERAPIES
│   ├── DPP-4 Inhibitors (Gliptins) - Sitagliptin, Vildagliptin, Saxagliptin
│   └── GLP-1 Receptor Agonists (injectable) - Exenatide, Liraglutide
│
└── SGLT-2 INHIBITORS (Gliflozins)
    └── Canagliflozin, Dapagliflozin, Empagliflozin

SECTION 7: BIGUANIDES

Only available member: METFORMIN (Glucophage)

(Phenformin and Buformin withdrawn due to fatal lactic acidosis)

Mechanism of Action

METFORMIN MOA
        ↓
Activates AMP-activated Protein Kinase (AMPK)
        ↓
┌──────────────────────────────────────────────────┐
│  LIVER (PRIMARY ACTION)                          │
│  • ↓ Hepatic gluconeogenesis (PRIMARY effect)    │
│  • ↓ Glycogenolysis                              │
│  Net: ↓ Hepatic glucose output (~30%)            │
│                                                  │
│  PERIPHERAL TISSUES (Muscle/Fat)                 │
│  • ↑ Peripheral glucose uptake                   │
│  • ↑ Insulin sensitivity                         │
│  • ↑ GLUT-4 translocation to cell surface        │
│                                                  │
│  GI TRACT                                        │
│  • ↓ Glucose absorption from intestine           │
│  • ↑ GLP-1 secretion (possible mechanism)        │
│                                                  │
│  DOES NOT stimulate insulin secretion            │
│  → NO risk of hypoglycaemia as monotherapy       │
└──────────────────────────────────────────────────┘

Additional effects: Modest weight loss or neutral, cardioprotective (reduces CV events in Type 2 DM - UKPDS study), lowers triglycerides and LDL slightly.

Adverse Effects of Metformin

System	Adverse Effect	Notes
GI (most common)	Nausea, vomiting, diarrhoea, metallic taste, abdominal discomfort	Occurs in up to 30%; take with food; usually transient
Rare but serious	Lactic acidosis	Risk in renal/hepatic failure, heart failure, alcoholism - due to accumulation
Metabolic	Vitamin B₁₂ deficiency (with long-term use)	Reduces absorption via intrinsic factor mechanism
No hypoglycaemia	As monotherapy (does not stimulate insulin)	Safe in this regard

Contraindications:

Serum creatinine >1.5 mg/dL (men) or >1.4 mg/dL (women) / eGFR <30
Severe hepatic disease
Acute heart failure, respiratory failure
Prior to contrast dye procedures (hold 48 h)
Alcoholism
During major surgery

Uses of Metformin

First-line drug for Type 2 DM (ADA/WHO recommendation)
Type 2 DM in obese patients (does not cause weight gain)
Prevention of T2DM in high-risk individuals (prediabetes)
Polycystic Ovarian Syndrome (PCOS) - improves insulin resistance and ovulation
Gestational diabetes (limited use, some guidelines)
Combination therapy with other OHAs or insulin

SECTION 8: SULFONYLUREAS

Members

Generation	Drugs
1st Generation	Tolbutamide, Chlorpropamide, Tolazamide, Acetohexamide
2nd Generation	Glibenclamide (Glyburide), Glipizide, Gliclazide
3rd Generation	Glimepiride (longest-acting, once daily)

Mechanism of Action

SULFONYLUREA MOA
        ↓
Bind to SUR-1 subunit of ATP-sensitive K⁺ channels
on pancreatic β-cell membrane
        ↓
Block K_ATP channel → Membrane depolarization
        ↓
Opening of voltage-gated Ca²⁺ channels
        ↓
↑ Intracellular Ca²⁺
        ↓
Stimulates exocytosis of insulin granules
        ↓
↑ INSULIN SECRETION (glucose-independent)

Note: Action is GLUCOSE-INDEPENDENT - they stimulate insulin release even without elevated glucose → risk of hypoglycaemia.

Extra-pancreatic effects (minor): ↑ Peripheral insulin sensitivity, ↓ hepatic glucose output.

Adverse Effects of Sulfonylureas

Adverse Effect	Details
Hypoglycaemia	Most important; more with long-acting agents (chlorpropamide, glibenclamide); elderly at higher risk
Weight gain	Due to increased insulin; important concern in obese T2DM
Hyponatraemia	Chlorpropamide - augments ADH action (SIADH-like)
Disulfiram-like reaction	Chlorpropamide - flushing with alcohol
Cholestatic jaundice	Rare
Blood dyscrasias	Leucopenia, agranulocytosis, thrombocytopenia (rare)
GI upset	Nausea, vomiting (less common)
Teratogenicity	Avoid in pregnancy

Uses of Sulfonylureas

Type 2 DM when diet + metformin alone is insufficient
Combination therapy with metformin/TZDs/DPP-4 inhibitors
MODY (Maturity Onset Diabetes of the Young) type 2 - glibenclamide very effective
Not used in Type 1 DM (no beta cells to stimulate)

SECTION 9: THIAZOLIDINEDIONES (TZDs / Glitazones)

Members: Pioglitazone (Actos), Rosiglitazone (Avandia - restricted)

Mechanism of Action

THIAZOLIDINEDIONE MOA
        ↓
Bind and activate PPAR-γ
(Peroxisome Proliferator-Activated Receptor gamma)
- a nuclear transcription factor
        ↓
Located in ADIPOSE TISSUE (primarily), 
also liver, muscle
        ↓
Changes in gene expression:
• ↑ Expression of GLUT-4 and GLUT-1 transporters
• ↑ Adipogenesis (differentiation of pre-adipocytes)
• Redistribution of fat from visceral to subcutaneous
• ↓ TNF-α and other insulin-resistance mediators
        ↓
PERIPHERAL INSULIN SENSITIZATION
(muscle, adipose, liver)
        ↓
↓ Insulin resistance → better glucose uptake

Key point: TZDs do NOT stimulate insulin secretion - they make tissues MORE SENSITIVE to existing insulin.

Pharmacological Actions of TZDs

Action	Details
Glycaemic control	↓ Fasting and postprandial glucose; ↓ HbA1c by 1-1.5%
Lipid effects	Pioglitazone: ↑ HDL, ↓ triglycerides; Rosiglitazone: ↑ LDL (unfavourable)
Blood pressure	Slight reduction
Inflammatory markers	↓ CRP, ↑ adiponectin
Insulin secretion	NOT stimulated → no hypoglycaemia as monotherapy
Weight	Cause weight gain (fluid retention + fat redistribution)
NAFLD	Pioglitazone improves non-alcoholic fatty liver disease

Adverse Effects of TZDs

Adverse Effect	Notes
Weight gain	Due to fluid retention and fat redistribution
Oedema	Peripheral oedema (fluid retention); increases risk of heart failure
Heart failure	Contraindicated in NYHA Class III/IV heart failure
Hepatotoxicity	Rare (troglitazone withdrawn due to this; monitor LFTs)
Bone fractures	↑ risk of fractures, especially in women (distal long bones); ↓ osteoblast activity
Bladder cancer	Pioglitazone - slight increased risk with prolonged use (>2 years)
Anaemia	Dilutional (plasma volume expansion)
Rosiglitazone	Increased CV risk (controversial - now restricted in many countries)

Uses of TZDs

Type 2 DM as monotherapy or in combination
Particularly useful in obese, insulin-resistant patients
PCOS (improve insulin sensitivity)
Non-alcoholic fatty liver disease / steatohepatitis (pioglitazone)
Metabolic syndrome
NOT used in Type 1 DM

COMBINED ORAL HYPOGLYCAEMIC AGENT SUMMARY

SITE/MECHANISM OF OHA ACTION

                    PANCREAS
                  [Sulfonylureas]
                  [Glinides]
                  ↑ Insulin secretion
                       │
                       ▼
                  BLOOD GLUCOSE
                       │
    ┌──────────────────┼──────────────────┐
    ▼                  ▼                  ▼
  LIVER           MUSCLE/FAT           GUT
[Metformin]     [Metformin]        [Acarbose]
↓ Gluconeo-     [TZDs]             ↓ Glucose
genesis         ↑ Glucose          absorption
↓ Hepatic       uptake/sensitivity
glucose output  [DPP-4i, GLP-1]

QUICK REFERENCE: OHA COMPARISON TABLE

Feature	Metformin	Sulfonylureas	TZDs
Primary site	Liver	Pancreas	Adipose/Peripheral
MOA	↓ Gluconeogenesis, ↑ AMPK	↑ Insulin secretion via K_ATP block	PPAR-γ activation → insulin sensitization
Hypoglycaemia	No (monotherapy)	Yes (significant risk)	No (monotherapy)
Weight	Neutral / mild loss	Gain	Gain
HbA1c reduction	1.5-2%	1.5-2%	0.5-1.5%
CV effects	Cardioprotective (UKPDS)	Variable	Rosiglitazone - ↑ risk; Pioglitazone - may be neutral
Use in renal impairment	Contraindicated (eGFR <30)	Avoid	Use with caution
Pregnancy	Class B / limited use	Avoid (teratogenic)	Avoid
1st line	YES	2nd line	2nd line (adjunct)

KEY POINTS FOR EXAM (2nd Year MBBS)

Insulin lispro/aspart/glulisine = rapid-acting analogues; given 15 min before meals; safe in insulin pumps
Glargine = "peakless" long-acting; precipitates at physiological pH; never mix with other insulins
NPH insulin = zinc + protamine + regular insulin; NEVER give IV
Regular insulin = the ONLY insulin given IV (used in DKA, surgery)
DKA treatment = Fluids first → then insulin (only after K⁺ ≥ 3.3 mEq/L) → K⁺ replacement
Metformin = first-line T2DM; main risk = lactic acidosis; primary action = ↓ hepatic gluconeogenesis
Sulfonylureas = bind SUR-1, close K_ATP channels; main risk = hypoglycaemia + weight gain
TZDs = PPAR-γ agonists; main risks = oedema, heart failure, fractures, bladder cancer (pioglitazone)
Human insulin > animal insulin: Less antigenic, no allergy, no insulin resistance, produced in unlimited quantities

*Sources: Lippincott Illustrated Reviews: Pharmacology; KD Tripathi Essentials of Medical Pharmacology; Washington Manual of Medical Therapeutics (DKA section); Rosen's Emergency Medicine (DKA management).*Here is your complete, exam-ready pharmacology notes for 2nd Year MBBS. All topics are covered in detail:

What's covered above:

1. Insulin Sources

Three sources: Bovine, Porcine, Human (recombinant DNA)

2. Human Insulin Advantages (detailed table)

Less antigenic, no immune resistance, no lipodystrophy, unlimited supply, no animal-pathogen risk

3. Insulin Preparations - Full Enumeration

Rapid-acting: Lispro, Aspart, Glulisine, Inhaled insulin Short-acting: Regular insulin (only one given IV) Intermediate: NPH (Isophane) insulin Long-acting: Glargine (peakless), Detemir, Degludec (ultra-long, >42 h) Mixtures: 70/30 combinations

The pharmacokinetic graph from Lippincott is included showing onset/peak/duration curves for all types.

4. Insulin Analogues

How structural modifications produce altered kinetics (lispro - reversed B28/B29; glargine - precipitates at pH 7.4; detemir - fatty acid + albumin binding)

5. DKA - Complete Management

Outlined with pathophysiology flowchart, precipitating factors ("I's mnemonic"), the 4 pillars (Fluids → Insulin → K⁺ → Treat cause), step-by-step insulin protocol, K⁺ replacement rules, bicarbonate guidelines, and resolution criteria

6. Oral Hypoglycaemic Agents - Full Classification

All 6 classes enumerated with complete structure

7. Biguanides/Metformin

AMPK activation → ↓ hepatic gluconeogenesis (primary), MOA diagram, adverse effects (GI, lactic acidosis, B12 deficiency), uses

8. Sulfonylureas

SUR-1/K_ATP channel mechanism flowchart, adverse effects (hypoglycaemia most important, weight gain, chlorpropamide-specific: SIADH, disulfiram), uses

9. Thiazolidinediones (TZDs)

PPAR-γ mechanism, pharmacological actions (lipid, BP, inflammatory), adverse effects (oedema, heart failure, fractures, bladder cancer for pioglitazone), uses

10. Comparison Tables

All OHAs compared by MOA, site, hypoglycaemia risk, weight, HbA1c reduction

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PHARMACOLOGY OF INSULIN AND ORAL HYPOGLYCAEMIC AGENTS

2nd Year MBBS | Ref: KD Tripathi's Essentials of Medical Pharmacology + Lippincott Illustrated Reviews: Pharmacology + Katzung's Basic & Clinical Pharmacology

PART 1: INSULIN

1.1 SOURCES OF INSULIN

Insulin is derived from three sources:

Source	Species	Differences from Human Insulin	Antigenicity
Bovine (Beef)	Cattle	3 amino acid positions differ (A8, A10, B30)	Highest - most antigenic
Porcine (Pork)	Pig	1 amino acid difference (B30: Ala instead of Thr)	Intermediate
Human	Recombinant DNA (E. coli or Saccharomyces cerevisiae); or enzymatic conversion of pork insulin	Identical to endogenous insulin	Least - near zero antigenicity

Note (KD Tripathi): Animal insulins (bovine and porcine) have been largely replaced by human insulin and insulin analogues in clinical practice due to superior immunological profile of human insulin.

1.2 ADVANTAGES OF HUMAN INSULIN OVER CONVENTIONAL (ANIMAL) INSULIN

Feature	Human Insulin	Animal (Bovine/Porcine) Insulin
Antigenicity	Very low - structurally identical to endogenous insulin	Higher - structural differences trigger immune response
Insulin resistance	Rare (almost none)	More common - anti-insulin IgG antibodies form, binding and inactivating insulin
Immunological reactions	Minimal - local or systemic allergic reactions extremely rare	More common - urticaria, angioedema, anaphylaxis reported
Lipodystrophy at injection site	Less frequent	More frequent (lipoatrophy or lipohypertrophy)
Onset of action	Slightly faster SC absorption	Slightly slower due to less predictable absorption
Purity	Monocomponent - free of proinsulin, C-peptide contaminants	May contain proinsulin and other pancreatic peptides
Availability/Supply	Unlimited - produced by recombinant DNA technology	Limited by animal source availability
Species-transmitted disease risk	None	Theoretical risk (prion diseases, viral contaminants)
Patient acceptability	Better - no ethical concerns	Some religious/ethical objections to pork or beef insulin
Dose requirement	Lower (more predictable)	May need higher doses due to antibody binding

Clinical bottom line (KD Tripathi): Human insulin is preferred because it reduces the risk of immunological insulin resistance, eliminates allergic reactions, and is available in unlimited quantities. In countries where it is affordable, it has completely replaced animal-source insulins.

1.3 INSULIN PREPARATIONS - ENUMERATION

Insulin preparations are classified by their duration of action into four groups:

╔══════════════════════════════════════════════════════════════╗
║              CLASSIFICATION OF INSULIN PREPARATIONS          ║
╠═══════════════════╦══════════════════════════════════════════╣
║ RAPID-ACTING      ║ Insulin Lispro (Humalog)                 ║
║ (Bolus/Prandial)  ║ Insulin Aspart (NovoRapid/NovoLog)       ║
║                   ║ Insulin Glulisine (Apidra)               ║
║                   ║ Inhaled Insulin (Afrezza/Technosphere)   ║
╠═══════════════════╬══════════════════════════════════════════╣
║ SHORT-ACTING      ║ Regular (Soluble) Insulin                ║
║                   ║ (Humulin R / Actrapid)                   ║
║                   ║ U-500 Regular Insulin (concentrated)     ║
╠═══════════════════╬══════════════════════════════════════════╣
║ INTERMEDIATE-     ║ NPH Insulin / Isophane Insulin           ║
║ ACTING (Basal)    ║ (Humulin N / Insulatard)                 ║
╠═══════════════════╬══════════════════════════════════════════╣
║ LONG-ACTING       ║ Insulin Glargine (Lantus) - ~24 h        ║
║ (Basal)           ║ Insulin Detemir (Levemir) - ~17-24 h     ║
║                   ║ Insulin Degludec (Tresiba) - >42 h       ║
╠═══════════════════╬══════════════════════════════════════════╣
║ PREMIXED          ║ NPH/Regular 70/30                        ║
║ COMBINATIONS      ║ Lispro protamine/Lispro 75/25            ║
║                   ║ Aspart protamine/Aspart 70/30            ║
╚═══════════════════╩══════════════════════════════════════════╝

Pharmacokinetic Comparison Table (from Katzung)

Insulin	Onset	Peak	Effective Duration	Route
Lispro / Aspart / Glulisine	5-15 min	1-1.5 h	3-4 h	SC
Regular (Soluble)	30-60 min	2 h	6-8 h	SC / IV / IM
Inhaled (Afrezza)	5-15 min	1 h	3 h	Inhaled
NPH (Isophane)	2-4 h	6-7 h	10-20 h	SC only
Glargine	0.5-1 h	Flat (peakless)	~24 h	SC only
Detemir	0.5-1 h	Flat	~17 h	SC only
Degludec	0.5-1.5 h	Flat (peakless)	>42 h	SC only

Onset and Duration Graph (Lippincott Illustrated Reviews: Pharmacology)

Onset and duration of action of human insulin and insulin analogs - NPH = Neutral Protamine Hagedorn

1.4 INSULIN ANALOGUES - DETAILS

What is an analogue?

An insulin analogue is a modified form of human insulin in which one or more amino acids have been altered to produce a different pharmacokinetic profile while retaining biological activity.

Rapid-Acting Analogues

Analogue	Structural Change	Effect	Onset
Insulin Lispro	B28 (Pro) and B29 (Lys) positions swapped (reversed)	Monomers don't self-associate into hexamers → faster absorption	15-30 min
Insulin Aspart	B28 Pro replaced by Asp (aspartic acid)	Reduces self-association → rapid absorption	15-30 min
Insulin Glulisine	B3 Asn→Lys; B29 Lys→Glu	Faster absorption from SC tissue	15-30 min

Clinical use: These mimic the physiological prandial (mealtime) insulin spike. Given 15-20 minutes before (or immediately after starting) a meal. Used in insulin pumps (CSII).

Long-Acting Analogues

Analogue	Structural Change	Mechanism of prolonged action
Insulin Glargine	A21 Asn→Gly + 2 Arg added to B-chain C-terminus	Low pH formulation (pH 4) → precipitates at physiological pH 7.4 at SC injection site → slow, steady release → truly peakless
Insulin Detemir	B30 Thr deleted + myristic acid (C14 fatty acid) attached to B29 Lys	Fatty acid chain binds reversibly to albumin → prolonged absorption + circulatory buffering
Insulin Degludec	B30 Thr deleted + C18 fatty acid attached via linker to B29 Lys	Forms multi-hexamer depot chains at SC site → extremely slow release → >42 h duration

Key exam fact: Glargine is peakless (flat profile). It must NOT be mixed with other insulins in the same syringe (its low pH will alter other insulins). Never give IV.

1.5 INDICATIONS FOR INSULIN

┌─────────────────────────────────────────────────────────────┐
│           INDICATIONS FOR INSULIN THERAPY                   │
├─────────────────────────────────────────────────────────────┤
│ ABSOLUTE INDICATIONS                                        │
│ • Type 1 Diabetes Mellitus (mandatory - no beta cells)      │
│ • Diabetic Ketoacidosis (DKA)                               │
│ • Hyperosmolar Hyperglycaemic State (HHS)                   │
│ • Gestational Diabetes Mellitus (when diet fails)           │
│ • Diabetes with acute complications (infection, surgery,    │
│   trauma, MI) - oral drugs insufficient                     │
│ • Severe hepatic or renal disease (OHAs contraindicated)    │
├─────────────────────────────────────────────────────────────┤
│ RELATIVE INDICATIONS                                        │
│ • Type 2 DM: failure of oral agents                        │
│ • Type 2 DM: HbA1c ≥ 9% with symptoms at diagnosis         │
│ • Secondary diabetes (pancreatectomy, Cushing's, etc.)      │
│ • Severely malnourished diabetics                           │
│ • Allergy / intolerance to all oral agents                  │
└─────────────────────────────────────────────────────────────┘

PART 2: DIABETIC KETOACIDOSIS (DKA)

2.1 DEFINITION AND DIAGNOSTIC TRIAD

DKA is defined by the triad (Goldman-Cecil Medicine):

D - Diabetes / Hyperglycaemia (glucose usually >250 mg/dL; may be normal in euglycaemic DKA)
K - Ketonaemia/Ketonuria (serum ketones ≥3.0 mmol/L or urine ketones 2+ or more)
A - Acidosis (arterial/venous pH <7.3, serum HCO₃ <18 mEq/L)

2.2 SEVERITY CLASSIFICATION

Parameter	Mild	Moderate	Severe
Blood glucose	>250 mg/dL	>250 mg/dL	>250 mg/dL
Arterial pH	7.25-7.30	7.00-7.24	<7.00
Serum HCO₃	15-18 mEq/L	10-14 mEq/L	<10 mEq/L
Urine/Serum ketones	Positive	Positive	Positive
Anion gap	>10	>12	>12
Mental status	Alert	Drowsy/Alert	Stupor/Coma

2.3 PATHOPHYSIOLOGY OUTLINE

ABSOLUTE/RELATIVE INSULIN DEFICIENCY
+ COUNTER-REGULATORY HORMONE EXCESS
(Glucagon ↑, Cortisol ↑, Catecholamines ↑, GH ↑)
                    │
        ┌───────────┼───────────┐
        ▼           ▼           ▼
   LIVER          FAT         MUSCLE
     │              │            │
↑ Gluconeogenesis  ↑ Lipolysis   ↑ Proteolysis
↑ Glycogenolysis   → FFA →      → Amino acids
     │           Beta-oxidation      │
     │           → Acetyl CoA ────────┘
     │           (excess) →
     │           KETONE BODIES
     │           (β-hydroxybutyrate,
     │           Acetoacetate, Acetone)
     ▼                │
HYPERGLYCAEMIA    KETONAEMIA
     │                │
Osmotic diuresis    H⁺ accumulation
  │                     │
Na⁺, K⁺, H₂O,     METABOLIC ACIDOSIS
PO₄ loss            (↓ pH, ↓ HCO₃)
  │                     │
DEHYDRATION       Kussmaul breathing
HYPOVOLAEMIA      (respiratory compensation)

Precipitating Factors (Goldman-Cecil):

Most common: Infection (~40%), Insulin omission/non-compliance, New-onset T1DM
Others: Acute coronary syndrome, CVA, acute pancreatitis, alcohol intoxication
Drugs: Corticosteroids, thiazide diuretics, SGLT-2 inhibitors (euglycaemic DKA), clozapine, cocaine

2.4 CLINICAL FEATURES

Prodrome (hours to days): Polyuria, polydipsia, polyphagia, weakness, nausea, vomiting
Examination: Dry skin and mucous membranes, tachycardia, hypotension, reduced JVP (dehydration)
Kussmaul breathing - deep, rapid respirations (respiratory compensation for metabolic acidosis)
Fruity (acetone) breath
Abdominal pain (can mimic acute abdomen - due to gastric stasis/ileus)
Altered sensorium - confusion to frank coma in severe DKA

2.5 INVESTIGATIONS

Serum glucose, electrolytes (Na, K, Cl, HCO₃), urea, creatinine
ABG (pH, pCO₂, HCO₃)
Serum/urine ketones (beta-hydroxybutyrate is gold standard)
CBC with differential (leukocytosis - may be from acidosis itself, not necessarily infection)
ECG (hyperkalaemia changes), CXR
Blood and urine cultures if infection suspected
Serum lipase (if pancreatitis suspected)
Note: Serum Na⁺ is artifactually low (osmotic shift); serum K⁺ may be falsely normal/high initially despite total body depletion

2.6 TREATMENT OF DKA - DETAILED

DKA Management Flowchart

SUSPECTED DKA
      │
      ▼
IMMEDIATE: IV access + blood tests + ABG + urinalysis
      │
      ▼
CONFIRM DIAGNOSIS (hyperglycaemia + ketonaemia + acidosis)
      │
      ▼
ASSESS SEVERITY + IDENTIFY PRECIPITANT
      │
      ▼
┌─────────────────────────────────────────────────────┐
│           FOUR THERAPEUTIC PILLARS                  │
│                                                     │
│  1. FLUID REPLACEMENT                               │
│  2. POTASSIUM MONITORING AND REPLACEMENT            │
│  3. INSULIN THERAPY                                 │
│  4. TREAT PRECIPITATING CAUSE                       │
└─────────────────────────────────────────────────────┘
      │
      ▼
MONITOR: hourly glucose; 2-4 hourly electrolytes + ABG
      │
      ▼
RESOLUTION: glucose <200 + pH >7.3 + HCO₃ >15 + AG closed
      │
      ▼
TRANSITION TO SUBCUTANEOUS INSULIN
(give SC basal insulin 2 h BEFORE stopping IV infusion)

PILLAR 1: FLUID REPLACEMENT

Goal: Correct dehydration (typical deficit 4-6 L, approximately 7-9% body weight), restore circulating volume, dilute glucose and ketones.

Step	Fluid	Volume/Rate
Phase 1 (first 1-2 h)	0.9% Normal Saline (isotonic)	1-2 L bolus; then 500-1000 mL/h
Phase 2 (after volume restored)	0.45% NS (hypotonic) [or 0.9% NS if hyponatraemic]	150-500 mL/h (guided by BP, urine output)
When BG ≤ 250 mg/dL	Switch to 5% Dextrose in 0.45% NS	To prevent hypoglycaemia while insulin continues

Caution: Correct no faster than 3 mOsm/kg/h to prevent cerebral oedema (especially important in children).

PILLAR 2: POTASSIUM MANAGEMENT

Why critical: Total body K⁺ is always depleted (from osmotic diuresis) even when serum K⁺ appears normal or high (acidosis shifts K⁺ extracellularly). Insulin therapy drives K⁺ INTO cells → rapid drop in serum K⁺ → life-threatening hypokalaemia.

CHECK SERUM K⁺ BEFORE STARTING INSULIN
              │
    ┌─────────┼──────────┐
    ▼         ▼          ▼
K⁺ < 3.3   K⁺ 3.3-5.5  K⁺ > 5.5
    │         │          │
HOLD        Give K⁺    Do NOT give K⁺
INSULIN     20-40 mEq  Monitor 2-hourly
Replace K⁺  per litre
40 mEq/h    IV fluid
until ≥ 3.3

PILLAR 3: INSULIN THERAPY

Agent: Regular (soluble) insulin IV - ONLY insulin used in DKA. Never NPH or analogues for acute DKA.

INSULIN PROTOCOL IN DKA
      │
Ensure K⁺ ≥ 3.3 mEq/L first
      │
      ▼
IV BOLUS: 0.1 units/kg regular insulin
      │
      ▼
IV INFUSION: 0.1 units/kg/h
(Standard: 100 units in 100 mL 0.9% saline = 1 unit/mL
 Run at 10 mL/h = 10 units/h)
      │
      ▼
TARGET: Glucose falls 50-75 mg/dL/h
(Do NOT correct faster than 100 mg/dL/h → cerebral oedema risk)
      │
      ▼
When BG reaches 250 mg/dL:
• ADD dextrose to IV fluid
• REDUCE insulin to 0.05 units/kg/h
• CONTINUE insulin until DKA resolution
  (NOT just when glucose normalises)
      │
      ▼
DKA Resolution criteria (ALL must be met):
• BG < 200 mg/dL
• pH > 7.3
• HCO₃ ≥ 15 mEq/L
• Anion gap ≤ 12
      │
      ▼
TRANSITION: Give SC basal insulin 2 h before
stopping IV insulin infusion

PILLAR 4: BICARBONATE (Controversial)

NOT routinely recommended (Rosen's / Goldman-Cecil)
May be considered only if:
- pH < 7.0, OR
- Life-threatening hyperkalaemia with ECG changes
Risks of bicarbonate: Paradoxical CNS acidosis; hypokalaemia; cerebral oedema; shifts oxygen-dissociation curve

Phosphate and Magnesium

Phosphate: Not routinely replaced; only if severe hypophosphataemia (<1 mg/dL) with cardiac/respiratory dysfunction
Magnesium: Correct only if levels are low (1-2 g MgSO₄ IV)

PART 3: ORAL HYPOGLYCAEMIC AGENTS (OHAs)

3.1 CLASSIFICATION

ORAL HYPOGLYCAEMIC AGENTS
│
├── A. INSULIN SECRETAGOGUES (↑ insulin release from β-cells)
│   ├── 1. SULFONYLUREAS
│   │      1st Gen: Tolbutamide, Chlorpropamide, Tolazamide
│   │      2nd Gen: Glibenclamide (Glyburide), Glipizide, Gliclazide
│   │      3rd Gen: Glimepiride
│   └── 2. MEGLITINIDES (Glinides)
│          Repaglinide, Nateglinide
│
├── B. INSULIN SENSITIZERS (↑ tissue response to insulin)
│   ├── 3. BIGUANIDES
│   │      Metformin (only available member)
│   └── 4. THIAZOLIDINEDIONES (TZDs / Glitazones)
│          Pioglitazone, Rosiglitazone
│
├── C. ALPHA-GLUCOSIDASE INHIBITORS (↓ carbohydrate absorption)
│      Acarbose, Miglitol, Voglibose
│
├── D. INCRETIN-BASED THERAPIES
│   ├── 5. DPP-4 INHIBITORS (Gliptins)
│   │      Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
│   └── 6. GLP-1 RECEPTOR AGONISTS (injectable - not strictly oral)
│          Exenatide, Liraglutide, Dulaglutide
│
└── E. SGLT-2 INHIBITORS (Gliflozins)
       Canagliflozin, Dapagliflozin, Empagliflozin

3.2 BIGUANIDES

Only clinically used member: METFORMIN

(Phenformin and Buformin were withdrawn due to high incidence of fatal lactic acidosis)

Mechanism of Action

METFORMIN MOA
      │
Enters hepatocytes via OCT1 transporter
      │
      ▼
Inhibits Complex I of mitochondrial respiratory chain
      │
↓ ATP/↑ AMP ratio
      │
      ▼
Activates AMPK (AMP-Activated Protein Kinase)
      │
┌─────────────────────────────────────────────────┐
│ PRIMARY - LIVER                                 │
│ ↓ Hepatic gluconeogenesis (main mechanism)      │
│ ↓ Glycogenolysis                                │
│ → ↓ Fasting blood glucose (accounts for 30%↓)  │
│                                                 │
│ PERIPHERAL TISSUES (Muscle & Adipose)           │
│ ↑ Peripheral glucose uptake                     │
│ ↑ Insulin-stimulated GLUT-4 translocation       │
│ → ↑ Insulin sensitivity                         │
│                                                 │
│ GI TRACT                                        │
│ ↓ Intestinal glucose absorption                 │
│ ↑ GLP-1 secretion (incretin effect)             │
└─────────────────────────────────────────────────┘
      │
      ▼
DOES NOT stimulate insulin secretion
→ NO hypoglycaemia as monotherapy
→ NO weight gain (often mild weight loss)

Adverse Effects of Metformin

System	Adverse Effect	Notes
GI (most common ~30%)	Nausea, vomiting, diarrhoea, metallic taste, anorexia, abdominal cramps	Dose-related; take with food; usually transient; titrate dose slowly
Serious/Rare	Lactic acidosis	Potentially fatal; due to metformin accumulation; risk in renal failure, liver failure, cardiac failure, sepsis, dehydration, alcoholism
Metabolic	Vitamin B₁₂ deficiency	Long-term use; reduces ileal absorption; monitor B₁₂ levels especially with anaemia/neuropathy
Weight	Neutral or mild loss	Advantage over sulfonylureas/TZDs

Contraindications:

eGFR <30 mL/min/1.73 m² (or serum Cr >1.5 mg/dL men; >1.4 mg/dL women)
Severe hepatic disease
Acute MI, decompensated cardiac failure, sepsis (risk of acute renal failure)
Contrast media procedures (hold 48 h before and after)
Alcoholism
General anaesthesia / major surgery

Uses of Metformin

First-line drug for Type 2 DM (ADA, WHO, IDF guidelines) - should be started at diagnosis
Obese T2DM patients (no weight gain, possible weight loss)
Prevention of T2DM in prediabetes / high-risk individuals
Polycystic Ovarian Syndrome (PCOS) - reduces insulin resistance, restores menstrual cycles
Combination therapy with other OHAs (sulfonylureas, TZDs, DPP-4 inhibitors, insulin)
Gestational diabetes (limited use - some guidelines support it)

3.3 SULFONYLUREAS

Mechanism of Action

Sulfonylurea MOA - beta cell K-ATP channel mechanism (Katzung)

SULFONYLUREA MOA (Katzung's Basic & Clinical Pharmacology)

Sulfonylurea binds to SUR-1 subunit of
ATP-sensitive K⁺ channel (K_ATP) on β-cell membrane
              │
              ▼
BLOCKS K_ATP channel
(same effect as ↑ ATP from glucose metabolism)
              │
              ▼
K⁺ CANNOT leave cell
→ Cell membrane DEPOLARIZES
              │
              ▼
Voltage-gated Ca²⁺ channels OPEN
              │
              ▼
↑ Intracellular Ca²⁺
              │
              ▼
Triggers EXOCYTOSIS of insulin granules
              │
              ▼
↑ INSULIN SECRETION
(glucose-independent - occurs even at LOW glucose)

Key point: Sulfonylureas stimulate insulin release independently of blood glucose → risk of hypoglycaemia even in fasting state.

Extra-pancreatic effects (minor): ↑ Peripheral insulin sensitivity; ↓ hepatic glucose output; ↑ insulin receptor number.

Adverse Effects of Sulfonylureas

Adverse Effect	Details
Hypoglycaemia	Most important and most common serious ADR; risk ↑ with long-acting agents (glibenclamide, chlorpropamide); elderly, renal impairment, missed meals, alcohol
Weight gain	Due to increased insulin secretion and anabolic effects; problematic in obese T2DM
Hyponatraemia (SIADH)	Chlorpropamide specifically - augments ADH action on renal collecting duct
Disulfiram-like reaction	Chlorpropamide + alcohol → facial flushing, tachycardia (due to acetaldehyde accumulation)
Haematological	Leucopenia, thrombocytopenia, agranulocytosis, haemolytic anaemia (rare)
Hepatotoxicity	Cholestatic jaundice (rare)
GI	Nausea, vomiting, cholestasis
Teratogenicity	Contraindicated in pregnancy (cross placenta → fetal hypoglycaemia)
Cross-reactions	Sulfa drug allergy may react (sulfonamide structure)

Uses of Sulfonylureas

Type 2 DM as second-line (when metformin alone is insufficient) or when metformin is contraindicated
MODY type 2 (Maturity Onset Diabetes of Young) - highly responsive to sulfonylureas
Combination with metformin, TZDs, DPP-4 inhibitors
Not used in: Type 1 DM (no functional beta cells), pregnancy, severe hepatic/renal failure, DKA

3.4 THIAZOLIDINEDIONES (TZDs / Glitazones)

Members: Pioglitazone (Actos), Rosiglitazone (Avandia - restricted)

(Troglitazone was withdrawn due to fatal hepatotoxicity)

Mechanism of Action

THIAZOLIDINEDIONE MOA

TZD enters cell
      │
      ▼
Binds and activates PPAR-γ
(Peroxisome Proliferator-Activated Receptor gamma)
- Nuclear receptor (transcription factor)
- Mainly expressed in ADIPOSE TISSUE
  (also liver, skeletal muscle, endothelium)
      │
      ▼
PPAR-γ + Retinoid X Receptor (RXR)
→ Heterodimer complex
→ Binds to PPRE (PPAR Response Element) in DNA
      │
      ▼
↑ Transcription of insulin-responsive genes:
• ↑ GLUT-1 and GLUT-4 expression
• ↑ Adiponectin secretion
• ↓ TNF-α, ↓ FFA, ↓ Resistin
• ↑ Adipogenesis (small fat cells = more insulin-sensitive)
• Redistribution of fat: visceral → subcutaneous
      │
      ▼
↑ INSULIN SENSITIVITY in:
• Adipose tissue (primary)
• Skeletal muscle
• Liver
      │
      ▼
↓ Blood glucose (fasting + postprandial)

Pharmacological Actions of TZDs

Action	Details
Glycaemic control	↓ Fasting and postprandial glucose; ↓ HbA1c by 0.5-1.5%
Lipid effects	Pioglitazone: ↑ HDL-C, ↓ TG (favourable); Rosiglitazone: ↑ LDL-C (unfavourable)
BP	Mild reduction in blood pressure
Anti-inflammatory	↓ CRP, ↓ IL-6, ↓ PAI-1; ↑ adiponectin
NAFLD/NASH	Pioglitazone improves non-alcoholic steatohepatitis
Insulin secretion	NOT increased → No hypoglycaemia as monotherapy
Weight	Causes weight GAIN (fluid retention + fat redistribution)
Ovulation	Improve ovarian function in PCOS

Adverse Effects of TZDs

Adverse Effect	Details
Fluid retention / Oedema	Due to ↑ renal sodium and water reabsorption; peripheral oedema
Heart failure	Contraindicated in NYHA Class III-IV cardiac failure; may precipitate/worsen CHF
Weight gain	Due to fluid retention and fat redistribution
Bone fractures	↑ Risk particularly in women (distal radius, humerus, ankle); ↓ osteoblast differentiation via PPAR-γ
Bladder cancer	Pioglitazone with prolonged use (>2 years) - small but significant increased risk; contraindicated in bladder cancer history
Hepatotoxicity	Rare (troglitazone was withdrawn for this); monitor LFTs with pioglitazone
Anaemia	Dilutional - due to plasma volume expansion
Macular oedema	Reported with both agents
Rosiglitazone	↑ Cardiovascular risk (MI) - restricted/withdrawn in many countries

Uses of TZDs

Type 2 DM as monotherapy or in combination (with metformin, sulfonylureas, insulin)
Obese insulin-resistant T2DM patients
PCOS (improve insulin sensitivity, restore ovulation)
NASH/NAFLD (pioglitazone - improving liver histology)
NOT used in: Type 1 DM; heart failure NYHA III-IV; bladder cancer; hepatic disease; pregnancy

3.5 OHA ADVERSE EFFECTS - VISUAL SUMMARY (Lippincott)

OHA adverse effects summary - Lippincott Illustrated Reviews Pharmacology

3.6 OHA SITES OF ACTION - DIAGRAM

Type 2 Diabetes - insulin resistance in peripheral tissues and inadequate beta-cell insulin secretion

WHERE EACH OHA ACTS:

PANCREAS (β-cells)        LIVER              PERIPHERAL TISSUES       GUT
[Sulfonylureas]       [Metformin]          [TZDs + Metformin]    [Acarbose]
[Glinides]          ↓ Gluconeogenesis      ↑ Glucose uptake      ↓ Glucose
↑ Insulin           ↓ Glycogenolysis       ↑ GLUT-4               absorption
 secretion          ↓ Hepatic glucose      ↑ Insulin sensitivity
                       output
[DPP-4 inhibitors / GLP-1 agonists] → ↑ Glucose-dependent insulin secretion
[SGLT-2 inhibitors] → ↑ Urinary glucose excretion (glycosuria)

MASTER COMPARISON TABLE: ORAL HYPOGLYCAEMIC AGENTS

Feature	Metformin	Sulfonylureas	TZDs
Class	Biguanide	Insulin secretagogue	Insulin sensitizer
Primary site	Liver	Pancreas (β-cells)	Adipose/Peripheral
MOA	↓ Hepatic gluconeogenesis (AMPK activation)	Block K_ATP → ↑ Ca²⁺ → ↑ insulin exocytosis	PPAR-γ activation → ↑ insulin sensitivity
Insulin secretion	Not stimulated	Stimulated (glucose-independent)	Not stimulated
Hypoglycaemia	No (monotherapy)	Yes (significant)	No (monotherapy)
Weight	Neutral/loss	Gain	Gain
HbA1c reduction	1.5-2%	1.5-2%	0.5-1.5%
CV effects	Cardioprotective (UKPDS)	Variable	Rosiglitazone - ↑MI risk; Pioglitazone - neutral/beneficial
Serious ADR	Lactic acidosis	Hypoglycaemia	Heart failure, fractures, bladder Ca
Renal impairment	Contraindicated (eGFR<30)	Avoid (accumulation)	Use with caution
Pregnancy	Avoid (limited data)	Contraindicated	Contraindicated
1st line T2DM	YES	2nd line	2nd line adjunct

HIGH-YIELD EXAM POINTS (KD Tripathi / 2nd MBBS)

Only insulin given IV = Regular (soluble) insulin - used in DKA, surgery, ICU
Peakless insulins = Glargine and Degludec - never mix in same syringe
NPH insulin = zinc + protamine + regular insulin; SC only; never IV
DKA rule = Never give insulin if K⁺ < 3.3 mEq/L → replace K⁺ first
Metformin = 1st line T2DM; reduces hepatic gluconeogenesis; lactic acidosis = serious but rare ADR
Sulfonylureas = bind SUR-1/K_ATP; cause hypoglycaemia + weight gain; chlorpropamide → SIADH + disulfiram reaction
TZDs = PPAR-γ agonists; cause oedema/heart failure/fractures; pioglitazone → bladder cancer
Human > animal insulin: Less antigenic, no immune resistance, purer, unlimited supply
Insulin lispro/aspart/glulisine = given 15 min before meals; safe in CSII pumps
Glargine = pH 4 formulation; precipitates at body pH → peakless 24 h coverage

*Sources: KD Tripathi's Essentials of Medical Pharmacology (10th ed.); Lippincott Illustrated Reviews: Pharmacology (8th ed.); Katzung's Basic and Clinical Pharmacology (16th ed.); Goldman-Cecil Medicine (26th ed.); Rosen's Emergency Medicine (9th ed.)*Here is your complete, exam-ready 2nd Year MBBS Pharmacology notes. Everything is covered with full detail:

What's in these notes:

PART 1: INSULIN

Sources (3 types):

Bovine (3 AA differences - most antigenic), Porcine (1 AA difference), Human (recombinant DNA - least antigenic)

Human vs Conventional Insulin - 8 detailed advantages: Less antigenicity, no immune resistance, fewer allergic reactions, no lipodystrophy, faster absorption, monocomponent purity, unlimited supply, no animal pathogen risk

Insulin Preparations - Full Enumeration with table:

Rapid-acting: Lispro, Aspart, Glulisine, Inhaled (onset 5-15 min)
Short-acting: Regular insulin (onset 30-60 min) - the ONLY insulin for IV use
Intermediate: NPH/Isophane (SC only, never IV)
Long-acting: Glargine (peakless, 24 h), Detemir (~17 h), Degludec (>42 h, ultra-long)
Premixed combinations

Insulin Analogues - structural changes explained for each (lispro B28/B29 swap; glargine pH 4 precipitation; detemir fatty acid-albumin binding; degludec multi-hexamer depot)

Indications - absolute and relative

Two key diagrams included: Onset/duration curves from Lippincott + Katzung sulfonylurea K_ATP mechanism diagram

PART 2: DKA

Full outline: Definition, diagnostic triad (D-K-A), severity classification table, pathophysiology flowchart, precipitating factors, clinical features (Kussmaul breathing, fruity breath, pseudoacute abdomen)

Management - 4 pillars in detail:

Fluids: Phase 1 (0.9% NS bolus) → Phase 2 (0.45% NS) → D5W when BG ≤250
Potassium: Critical decision tree - hold insulin if K⁺ <3.3, replace 20-40 mEq/L if 3.3-5.5
Insulin: Regular IV only, 0.1 units/kg bolus then 0.1 units/kg/h, target ↓50-75 mg/dL/h
Bicarbonate: NOT routine; only if pH <7.0
Resolution criteria, monitoring schedule, transition to SC insulin

PART 3: ORAL HYPOGLYCAEMIC AGENTS

Full Classification (6 classes in a clean tree diagram)

Metformin (Biguanide): AMPK → ↓ hepatic gluconeogenesis (primary), full MOA flowchart, adverse effects (GI, lactic acidosis, B₁₂ deficiency), contraindications, uses

Sulfonylureas: SUR-1/K_ATP mechanism with diagram, generation-wise drugs, ADRs (hypoglycaemia #1, weight gain, chlorpropamide-specific SIADH + disulfiram), uses

Thiazolidinediones: PPAR-γ nuclear receptor mechanism, pharmacological actions (glycaemic, lipid, anti-inflammatory, NAFLD), ADRs (oedema, heart failure, fractures, bladder cancer), uses

Master comparison table for all 3 + visual adverse effects diagram from Lippincott

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