Developmental Disorders

Type 2 DM is characterised by a dual defect: peripheral insulin resistance and progressive β-cell dysfunction. The liver fails to suppress gluconeogenesis despite hyperinsulinaemia. Adipose tissue releases excess free fatty acids (FFAs), impairing insulin signalling via the PKC and IKKβ pathways.

Type 2 DM is characterised by a dual defect: peripheral insulin resistance and progressive β-cell dysfunction. The liver fails to suppress gluconeogenesis despite hyperinsulinaemia. Adipose tissue releases excess free fatty acids (FFAs), impairing insulin signalling via the PKC and IKKβ pathways.

In Type 2 DM onset is insidious — many patients are diagnosed incidentally on routine blood tests, never having noticed the classic triad.

Diffuse alveolar damage
Neutrophilic inflammation
Protein-rich pulmonary edema
Hyaline membrane formation
Severe hypoxemia

ADRENERGIC AGONISTS — INBDE HIGH-YIELD 1. Adrenergic Receptors

2. Classification Direct-acting

• Phenylephrine → α₁

• Clonidine → α₂

• Dobutamine → β₁

• Albuterol, terbutaline, salmeterol → β₂

• Epinephrine → α₁, α₂, β₁, β₂

• Norepinephrine → α₁, α₂, β₁

• Isoproterenol → β₁, β₂

Indirect-acting

• Amphetamine

• Methamphetamine

• Tyramine

Mixed-acting

• Ephedrine → direct stimulation + ↑ NE release

KEY DRUGS Phenylephrine — α₁

α₁ → vasoconstriction → ↑ SVR/BP

Uses:

• Vasodilatory hypotension

• Topical nasal decongestion

• Mydriasis

Adverse effect:

• Reflex bradycardia

⭐ Phenylephrine = vasoconstriction

Clonidine — α₂

Central α₂ stimulation → ↓ sympathetic outflow → ↓ BP/HR

Uses:

• Hypertension

• ADHD

Adverse effects:

• Sedation

• Xerostomia

• Bradycardia

• Hypotension

⚠️ Abrupt withdrawal → rebound hypertension

🦷 Xerostomia → ↑ caries risk.

Dobutamine — β₁

β₁ → ↑ myocardial contractility → ↑ cardiac output

Uses:

• Acute heart failure

• Cardiogenic/low-output states

• Pharmacologic stress testing

Adverse effects:

• Tachycardia

• Arrhythmias

⭐ Dobutamine = boosts the heart

β₂ AGONISTS Albuterol / Salbutamol

SABA

β₂ → ↑ cAMP → bronchial smooth-muscle relaxation

Uses:

• Acute bronchospasm

• Rapid asthma symptom relief

• Exercise-induced bronchoconstriction

Adverse effects:

• Tremor

• Tachycardia/palpitations

• Hypokalemia

🦷 Acute bronchospasm in dental chair → stop treatment + upright position + rapid-acting inhaled bronchodilator; give oxygen/activate EMS if severe or not improving.

Salmeterol

LABA

• Long-term asthma maintenance with an ICS-containing regimen

• NOT an acute rescue drug

⭐ Albuterol = acute relief
⭐ Salmeterol = maintenance

Terbutaline

β₂ agonist → bronchodilation + uterine relaxation.

⚠️ Do not consider prolonged/oral terbutaline routine therapy for preterm labor because of important cardiovascular safety risks.

EPINEPHRINE ⭐⭐⭐ Receptors

α₁ + α₂ + β₁ + β₂

Effects

α₁ → vasoconstriction, ↑ BP, ↓ mucosal edema
β₁ → ↑ HR + contractility
β₂ → bronchodilation

Anaphylaxis Drug of choice

IM EPINEPHRINE

Preferred site:
Mid-anterolateral thigh

Typical adult dose:
0.3–0.5 mg IM of 1 mg/mL epinephrine

Can be repeated according to clinical response/emergency protocol.

⭐ Anaphylaxis → IM epinephrine FIRST

Antihistamines are adjuncts, not substitutes.

EPINEPHRINE + LOCAL ANESTHETIC ⭐⭐⭐

Vasoconstriction causes:

↓ Local blood flow
→ ↓ systemic LA absorption
→ ↑ anesthesia duration/effectiveness
→ ↓ peak systemic LA concentration
→ ↑ hemostasis

Dental maximum

Healthy adult: 0.2 mg

Significant cardiovascular disease/cardiac caution: commonly 0.04 mg

1:100,000 epinephrine

= 0.01 mg/mL

1.8-mL cartridge ≈ 0.018 mg

Therefore:

0.04 mg ≈ 2 cartridges

⭐ Cardiac dose ≈ 2 cartridges of 1:100,000 epi

Stable cardiovascular disease is not an automatic contraindication to epinephrine; use the lowest effective dose, aspirate and inject slowly, and avoid intravascular injection.

Excess epinephrine

• Palpitations

• Tachycardia

• Tremor

• Anxiety

• Hypertension

• Arrhythmias

Immediate pounding heart + tremor after LA injection → suspect rapid systemic epinephrine exposure/intravascular injection.

NOREPINEPHRINE

α₁ + α₂ + β₁

Minimal β₂ activity.

→ Strong vasoconstriction
→ ↑ SVR and BP

Major use:

• Septic/distributive shock

Memory:
NE = vessels > heart >> lungs

ISOPROTERENOL

β₁ + β₂

β₁ → ↑ HR/contractility
β₂ → vasodilation + bronchodilation

Clinical use is limited, including selected bradyarrhythmias/heart block.

AMPHETAMINES

Mechanism:

↑ release of NE + dopamine
+
↓ their reuptake

Effects:

• ↑ Alertness/attention

• ↓ Appetite

• ↑ HR/BP

Adverse effects:

• Insomnia

• Weight loss

• Tachycardia

• Hypertension

• Anxiety

• Dry mouth

• Misuse/dependence risk

ADHD DRUGS Adderall

Mixed amphetamine salts

Dextroamphetamine

Uses:

• ADHD

• Narcolepsy

Methylphenidate

NOT an amphetamine

Blocks dopamine + norepinephrine reuptake

Uses:

• ADHD

• Narcolepsy

Dexmethylphenidate

Active d-enantiomer of methylphenidate

Concerta

Extended-release methylphenidate

Atomoxetine

Non-stimulant selective norepinephrine reuptake inhibitor

⚠️ Boxed warning: suicidal ideation risk in children/adolescents.

PHENTERMINE

Sympathomimetic anorectic

Used short-term as an adjunct for selected patients with obesity.

Adverse effects:

• Insomnia

• Tachycardia

• ↑ BP

• Dry mouth

⭐ RAPID REVISION

α₁ → Phenylephrine → vasoconstriction

α₂ → Clonidine → ↓ sympathetic outflow

β₁ → Dobutamine → ↑ contractility

β₂ → Albuterol → bronchodilation

Epinephrine → α₁ + α₂ + β₁ + β₂

Norepinephrine → α₁ + α₂ + β₁

Isoproterenol → β₁ + β₂

Anaphylaxis → IM epinephrine

Acute bronchospasm → Albuterol

Salmeterol → maintenance, NOT rescue

Epi + LA → ↓ absorption + ↑ duration + hemostasis

Cardiac epi limit → 0.04 mg ≈ 2 cartridges of 1:100,000

Clonidine withdrawal → rebound hypertension

β₂ agonists → tremor + tachycardia + hypokalemia

Amphetamine → ↑ release of NE + DA

Methylphenidate → blocks NE/DA reuptake

Atomoxetine → selective NE reuptake inhibitor; non-stimulant

Theophylline/aminophylline → methylxanthines, NOT adrenergic agonists

In an average adult male:

ICF = ⅔ of TBW
ECF = ⅓ of TBW

➟ Higher in infants/children (~70–75%)
➟ Higher in males than females on average
➟ Lower in elderly individuals
➟ Body fat and body water are inversely related

Reason: Adipose tissue contains relatively little water.

Indicator-dilution principle

Volume = Amount of indicator introduced ÷ Final concentration

⭐ Inulin is the classic reference marker for ECF volume because it distributes throughout ECF but does not enter cells.

➟ Mg²⁺ is an important intracellular cation
➟ It is the major intracellular divalent cation

⭐ Remember:

ECF → Na⁺ outside
ICF → K⁺ inside

Movement of substances:

High concentration → Low concentration

➟ Does not require ATP
➟ Does not require a carrier
➟ Does not show saturation kinetics

Rate of diffusion is proportional to:

Surface area × concentration gradient × diffusion coefficient

and inversely proportional to:

Membrane thickness

Passive transport using a carrier/channel protein.

➟ Moves down the electrochemical gradient
➟ No ATP required
➟ Shows specificity and saturation

Glucose is transported by GLUT transporters.

Insulin-responsive glucose transporter

Found mainly in:

➟ Skeletal muscle
➟ Cardiac muscle
➟ Adipose tissue

Insulin → GLUT4 translocation to cell membrane → ↑ glucose uptake.

Insulin resistance or inadequate insulin action can cause persistent hyperglycemia.

Poorly controlled diabetes is associated with:

➟ Increased risk/severity of periodontitis
➟ Delayed wound healing
➟ Increased susceptibility to infection

Water moves primarily by osmosis, often through aquaporin (AQP) channels.

Classically associated with:

Anti-AQP4 IgG antibodies

Aquaporin-5 is expressed in salivary gland acinar cells and helps water movement during saliva formation.

Clinical laboratories generally use serum osmolality.

mOsm/kg ≈ 2[Na⁺] + Glucose/18 + BUN/2.8

where glucose and BUN are in mg/dL.

Equivalent:

2[Na⁺] + 0.056 × glucose + 0.36 × BUN

Normal serum osmolality ≈ 275–295 mOsm/kg

Osmolal gap = Measured osmolality − Calculated osmolality

An increased gap may occur with substances such as:

➟ Methanol
➟ Ethylene glycol
➟ Isopropanol

Classic example of primary active transport.

For every ATP hydrolyzed:

3 Na⁺ OUT : 2 K⁺ IN

Therefore, it is electrogenic.

➟ Maintains low intracellular Na⁺
➟ Maintains high intracellular K⁺
➟ Helps maintain resting membrane potential
➟ Drives many forms of secondary active transport
➟ Helps regulate cell volume

Na⁺/K⁺-ATPase contains:

➟ α subunit → catalytic/ion-binding functions
➟ β subunit → glycoprotein important for membrane expression and stability

Activity may be increased by:

➟ Thyroid hormone
➟ Aldosterone
➟ Insulin

Renal dopamine can reduce tubular Na⁺ reabsorption partly by inhibiting Na⁺/K⁺-ATPase activity.

Na⁺/K⁺-ATPase in salivary gland cells helps establish ion gradients necessary for electrolyte and fluid secretion.

Primary saliva produced by acinar cells is modified by salivary ducts before entering the oral cavity.

Fusion of intracellular vesicles with the plasma membrane → release of their contents.

SNARE proteins mediate vesicle docking and membrane fusion.

⭐ Neurotransmitter release from nerve terminals is Ca²⁺ dependent regulated exocytosis.

Clostridium botulinum toxin

➟ Cleaves specific SNARE proteins
➟ Prevents acetylcholine release at cholinergic nerve terminals
➟ Produces flaccid paralysis

Botulinum toxin may be used clinically for selected cases of:

➟ Sialorrhea
➟ Oromandibular dystonia
➟ Certain temporomandibular/masticatory muscle disorders

Its effect results from reduced acetylcholine release.

Tetanospasmin

➟ Produced by Clostridium tetani
➟ Cleaves SNARE-associated proteins
➟ Prevents release of inhibitory neurotransmitters:

GABA + glycine

→ Loss of inhibition of motor neurons
→ Spastic paralysis

Uptake of extracellular material into the cell through membrane vesicles.

Important mechanisms include:

➟ Uses clathrin-coated pits
➟ Important for receptor-mediated endocytosis

➟ Uses caveolin

Cubilin is a receptor involved in receptor-mediated uptake, particularly in tissues such as the proximal renal tubule; it should not be considered one of the principal vesicle-coat proteins like clathrin or caveolin.

Weak acids and weak bases cross lipid membranes more readily in their uncharged form.

NH₃ diffuses into the renal tubular lumen.

NH₃ + H⁺ → NH₄⁺

NH₄⁺ is charged and becomes trapped in the tubular fluid, facilitating acid excretion.

Local anesthetics are weak bases.

B + H⁺ ⇌ BH⁺

➟ Uncharged base (B) crosses the nerve membrane
➟ Charged form (BH⁺) binds the intracellular voltage-gated Na⁺ channel

In acidic infected tissue:

↓ pH → more drug becomes ionized (BH⁺)
→ less uncharged drug crosses the nerve membrane
→ reduced anesthetic effectiveness

⭐ Extremely important physiology/pharmacology concept for INBDE.

DLCO = Diffusing capacity of the lung for carbon monoxide

Carbon monoxide is used because it binds avidly to hemoglobin, keeping pulmonary capillary CO partial pressure extremely low.

Therefore:

DLCO assesses gas transfer across the alveolar-capillary membrane.

DLCO may be reduced in:

➟ Emphysema
➟ Pulmonary fibrosis
➟ Anemia

1. Local anesthetic + infection:
Acidic tissue → more ionized LA → poor membrane penetration → reduced anesthesia.

2. Salivary secretion:
AQP5 facilitates water movement in salivary acinar cells.

3. Diabetes:
GLUT4 is insulin responsive in skeletal/cardiac muscle and adipose tissue; poor glycemic control is strongly relevant to periodontal disease and wound healing.

4. Botulinum toxin:
Cleaves SNARE proteins → inhibits ACh release; selected dental/orofacial applications include sialorrhea and some muscle hyperactivity disorders.

5. Na⁺/K⁺-ATPase:
3 Na⁺ out / 2 K⁺ in; establishes ionic gradients fundamental to nerve, muscle and salivary gland physiology.