OBJECTIVES

primary location of stored histamine

• stored in mast cells

  • rich in tissues prone to injury and in mucous membranes such as airways, mouth, feet, and blood vessels

• also found in gastric mucosa, neurons, and epidermis

common causes for histamine release

• mechanical injury

• morphine

• antibiotics

• radiocontrast media

• polypeptides

• dextran

• venoms

how does histamine effect vascular smooth muscle

vasodilation via H1 receptor activation → nitric oxide production → increased cGMP → smooth muscle relaxation

how does histamine effect capillaries

increased permeability → efflux of plasma proteins and fluid → edema and increased lymph flow

how does histamine effect bronchial smooth muscle

contration via H1 receptor mediated increased intracellular Ca

how does histamine effect gastric mucosa

stimulates gastric acid secretion

how does histamine effect epidermis

wheal and flare response

how does histamine effect CNS neurons

neurotransmitter function (wakefulness, appetite); also excitation in overdose

how does histamine effect peripheral neurons

stimulates pain and itch receptors; modulates appetite/satiety

triple response of lewis

• reddening: few mm around injection site within seconds → due to direct vasodilation from histamine

• flare: red flush extending about 1cm beyond original site → due to axon reflex vasodilation

• wheal: local swelling in 1-2 min → due to increased capillary permeability (edema formation)

type 1 allergic response that H1RA can treat

• allergic rhinitis: nasal discharge, obstruction, sinusitis, otitis media, nasal polyps

• urticaria; pruritic, red, raised skin patches

• angioedema: generalized swelling (skin, lips, oral region); can prevent airway obstruction

• asthma:: limited use; not effective for bronchospasm

• systemic anaphylaxis: helps with urticaria, angioedema, itch, flushing; not effective for hypotension or asthma bronchospasm

MOA of H1RA

• competitive antagonists or inverse agonists at H1 receptors

• first gen agents resemble muscarinic and a-adrenoreceptor blockers in action

effects of H1RA on physiological systems

• capillary permeability: decreased permeability → decreased edema

• vascular smooth muscle: blunt H1 receptor-stimulated vasodilation

• nerve stimulation: suppress histamine-induced pain, itch, and flare responses

contrast 1st vs 2nd generation H1RA: mast cell stabilizing effects and treatment implications

• 1st gen: no mast cell stabilizing effect

• 2nd gen: exhibit mast cell-stabilizing properties → reduce release of mast cell mediators during allergic responses; useful in topical allergic conjunctivitis

contrast distribution of 1st vs 2nd gen H1RA

• 1st gen: readily cross the BBB → higher CNS penetration

• 2nd gen: minimal CNS penetration → nonsedating

• skin: both can persist at high concentrations in skin even after plasma levels decline

explain differences in side effect profiles of 1st vs 2nd generation H1RA

• 1st gen: CNS depression (sedation, impaired alertness), paradoxical excitation (children), anticholingeric effects (dry mouth, blurred vision, constipation, urinary retention); also interact with CNS depressants (opioids, sedatives, alcohol)

• 2nd gen: less CNS penetration → minimal sedation; no muscarinic effects

side effect profile of H1RA

• 1st gen: sedation dizziness, fatigue, paradoxical excitation (children), rare tachydysrhythmias in overdose, allergic skin reactions with topical use, antimuscarinic effects (dry mouth, blurred vision, constipation, urinary retention)

• 2 gen: generally fewer CNS and anticholinergic effects; considered safer

common drug interactions with H1RA and mechanism

• 1st gen

  • additive with antimuscarinics

  • potentiate CNS depressants (opioids, sedatives, alcohol)

• metabolism interactions: drugs that inhibit CYP enzymes (erythromycin, ketoconozole) increases levels; inducers (benzodiazepines) decrease levels

• more significant with 1st gen than 2nd

therapeutic uses of H1RA and common drugs

• allergic rhinitis, urticaria, conjunctivitis: suppress histamine-mediated symptoms

• motion sickness: dimenhydrinate, cyclizine, meclizine, promethazine

• vertigo: dimenhydrinate, meclizine

• sedation: diphenhydramine

• asthma: limited use

• anaphylaxis/angioedema: adjunctive to epinephrine

• contact dermatitis: some benefit, less effective than topical steroids

• common cold: no value

1st gen H1RA agents

• diphenhydramine

• dimenhydrinate

• cyclizine

• meclizine

• promethazine

2nd gen H1RA agents

• cetirizine

• acrivastine

• fexofenadine

• levocetirizine

• epinastine

pathologic features of asthma

lymphocytic and eosinophilic inflammation of bronchial mucosa, remodeling of bronchial wall, thickening of lamina reticularis, hyperplasia of vasculature, smooth muscle, glands, goblet cells

pathophysiologic features of asthma

marked bronchial hyperresponziveness, reversible airway narrowing, mucus hyper secretion

clinical features of asthma

wheezing, cough, shortness of breath, chest tightness

pathologic feature of COPD

predominance of neutrophils, macrophages, Tc1, and Th17 cells; small airway narrowing and fibrosis, destruction of alveolar walls (emphysema)

pathophysiologic features of COPD

progressive airway narrowing, air trapping, hyperinflation, worse on exertion (dynamic hyperinflation)

key mediator in the inflammatory process of asthma

IgE, mast cells, eosinophils, leukotrienes (LTC4, LTD4), histamine, prostaglandins D2, platelet-activating factor (PAF)

key mediators in the inflammatory process of COPD

neutrophils, macrophages, Tc1 cells, Th17 cells

early stage of asthma

triggered by allergen re-exposure → IgE cross linking on mast cells → release of histamine, PGD2, LTC4, PAF → smooth muscle contraction, fall in FEV1

late stage asthma

driven by eosinophils and neutrophils → edema, mucus hyper secretion, smooth muscle contraction, increased reactivity → second fall in FEV1 3-6 hours later

asthma vs COPD

asthma

• intermittent obstruction (reversible with steroids/bronchodilators)

• inflammation mediated by mast cells, eosinophils, IgE

• remodeling, hyper responsiveness

COPD

• progressive, less reversible obstruction

• predominantly neutrophilic/macro/Tc1 inflammation

• alveolar. destruction, mucus hypersecretion, fibrosis

• includes chronic bronchitis and emphysema

target site of B2-agonists

smooth muscle

target site of methylxanthines (theophylline)

smooth muscle

target site of tiotropium/antimuscarinics

smooth muscle (vagal tone)

target site of inhaled corticosteroids (ICS)

inflammatory cells (mast cells, eosinophils, T-lymphocytes)

target site of cromones

mast cells

target site of anti-leukotrienes

leukotriene pathway

target site of anti-IgE (omalizumab)

IgE

target site of anti-IL-5 mAbs

eosinophils

MOA B2-agonists

increased cAMP → bronchodilator; inhibit mediator release, edema, acetylcholine release

MOA methylxanthines (theophylline)

inhibit PDE → increased cAMP; adenosine receptor antagonist

MOA antimuscarinics

block acetylcholine on muscarinic receptors → bronchodilation, decreased mucus secretion

MOA ICS

inhibit cytokines (Th2), reduce eosinophils, decreased vascular bronchodilation, decreased mucus secretion

MOA anti-leukotrienes

block leukotriene synthesis/receptors → reduce bronchoconstriction and mucus

MOA cromones

stabilize mast cells, prevent degranulation

MOA mAbs

block IgE, IL-5, IL-4/13 signaling, reducing eosinophil-driven inflammation

B2-agonists adverse effects

• tremor

• tachycardia

• hypokalemia

• restlessness

• metabolic changes

theophylline adverse effects

• nausea

• vomiting

• headache

• arrhythmias

• seizures at high levels

antimuscarinic adverse effects

• bitter taste

• possible glaucoma with nebulization

• rebound responsiveness if stopped

ICS adverse effects

• oral candidiasis

• hoarsness

• osteoporosis

• cataracts

• slowed childhood growth

anti-leukotrienes adverse effects

• rare hepatotoxicity, rare Churg-Strauss syndrome

cromone adverse effects

generally safe; rarely used today

mAbs adverse effects

• injection site reactions

• rare anaphylaxis

SABA

• albuterol

• onset 15 min

• duration 3-4 hours

• rescue only

• prevents exercise/cold-induced bronchospasm

LABA

• salmeterol, formoterol

• improves asthma control when combined with ICS, not for mono therapy in asthma, safe mono therapy in COPD

ULABA

• indacaterol, vilanterol, olodaterol

• QD dosing

• mainly COPD use (with ICS or LAMA)

quick relievers vs controller

quick relievers

• SABA

• systemic corticosteroids for acute severe cases

controllers

• LABA (with ICS in asthma)

• ICS

• LAMA

• theophylline

• anti-leukotrienes, mAbs

BBW with LABA

must not be used alone in asthma; only in combination with ICS

common adverse effects of B2 agonists

• muscle tremor

• tachycardia

• hypokalemia

• restlessness

• metabolic effects (increased glucose, FFA, lactate)

factors increasing theophylline clearance

• CYP1A2 induction (rifampin, barbiturates, ethanol)

• smoking

• high-protein/low-carb diet

• barbecued meat

• childhood

factors decreasing theophylline clearance

• CYP inhibition (cimetidine, erythromycin, ciprofloxacin, zileuton, zafirlukast)

• CHF

• liver disease

• pneumonia

• viral infection

• old age

adverse effects of theophylline by serum concentration

• <10 mg/L: therapeutic benefit

• 15mg/L: headache, nausea, vomiting, behavioral changes in kids

• High: arrhythmias (PDE3 inhibition, A1 antagonism)

• Very high: seizures (CNS A1 antagonism)

clinical use of antimuscarinics in COPD

• reduce air trapping

• improve exercise tolerance

• superior to B2 agonists in some cases due to vagal tone (only reversible obstruction in COPD)

duration of action of antimuscarinic agents

• Ipratropium: 6–8h

• Aclidinium: 12h

• Tiotropium, umeclidinium: 24h

ICS effect on asthma pathogenesis and control

• inhibit TH2 cytokines

• reduce eosinophils and mast cells

• decrease vascular permeability

• decrease mucus

• inhibit late response to allergen

• improve symptoms, lung function, exacerbation, QoL

indications of monoclonal antibody therapy

• Severe asthma refractory to ICS

• Omalizumab: severe allergic asthma with elevated IgE

• Anti-IL-5 mAbs (reslizumab, mepolizumab, benralizumab): severe eosinophilic asthma (blood eos ≥300/μl)

• Dupilumab (anti-IL4/13): severe asthma with Type 2 biomarkers (eosinophils ≥300/μl or FeNO ≥25 ppb)

physiological control of gastric acid secretions and regulation at the cellular level

• Parietal cells secrete H⁺ into gastric lumen via the H⁺/K⁺-ATPase proton pump.

• Secretion stimulated by:

  • Gastrin (CCK-B receptors)

  • Acetylcholine (ACh) (M3 receptors)

  • Histamine (H2 receptors)

• Histamine → activates adenylyl cyclase → ↑cAMP → activates protein kinases → stimulates proton pump

• Acetylcholine → increases intracellular Ca²⁺ → activates kinases → stimulates proton pump

• Gastrin secreted from G-cells in response to dietary peptides → binds to CCK-B receptors on parietal cells & ECL cells

role of gastrin

secreted by antral G cells; stimulates parietal cells directly and ECL cells → histamine release

role of acetylcholine

released via vagus nerve stimulation; binds M3 receptors on parietal and ECL cells → increased Ca and histamine release

role of histamine

released from ECL cells; binds H2 receptors on parietal cells → increase cAMP → activated proton pump

role of the proton pump

• H⁺/K⁺-ATPase exchanges intracellular H⁺ for luminal K⁺, generating the steepest ion gradient in vertebrates (pH ~7.3 inside vs. ~0.8 in canaliculi)

• Final common pathway for acid secretion regardless of stimulus (gastrin, ACh, histamine)

common acid-related disorders

• Reflux Diseases: GERD, non-erosive & erosive esophagitis, Barrett’s esophagus

• Non-ulcer dyspepsia (NUD)

• Peptic Ulcer Disease: duodenal ulcer, gastric ulcer, NSAID-induced ulcers

drugs that reduce acidity

• H2 receptor antagonists

• proton pump inhibitors

• antacids

mucosal protective agents

• sucralfate

• misopristol

• bismuth compounds

MOA H2RA

• Reversibly compete with histamine for H2 receptors on parietal cells

• Selective for H2; do not affect H1 or H3

• Suppress ~70% of 24h gastric acid secretion

importance of pharmacokinetics of H2RA

• Inhibit 60–70% of acid secretion (esp. nocturnal secretion)

• Effective for healing duodenal ulcers

• Prescription doses maintain >50% inhibition for ~10h

• Given BID; OTC last 6–10h

clinical important drug interactions H2RA

Cimetidine inhibits CYP enzymes:

• CYP1A2: theophylline, amitriptyline

• CYP2C9: phenytoin, S-warfarin, NSAIDs

• CYP2C19: amitriptyline, benzodiazepines

• CYP2D6: opioids, sympathomimetics

• CYP3A4: benzodiazepines, contraceptives, statins, protease inhibitors, macrolides, etc.

MOA proton pump inhibitors

• Prodrugs activated in acidic environment → accumulate in canaliculi of parietal cells

• Covalently bind sulfhydryl groups of cysteines on H⁺/K⁺-ATPase → irreversible inactivation

PPI prodrug activation and bioavailability

• Require acidic environment for activation

• Bioavailability ↓ by ~50% with food

• Should be taken on empty stomach, 1h before meal

PPI pharmacokinetics and duration

• Plasma t½ = 0.5–3h, but effect lasts 24–48h due to irreversible pump inhibition

• Full acid inhibition requires 3–4 days of daily dosing

• Acid secretion resumes 3–4 days after stopping

PPI adverse effects

• Common: nausea, abdominal pain, constipation, diarrhea, flatulence

• Long-term: ↓B12 absorption, ↑hip fracture risk (↓calcium absorption, osteoclast inhibition)

• Possible ↑risk of infection

MOA antacids

• Weak bases react with HCl → salt + water

• Neutralize gastric acid for ~2h post-meal

• Sodium bicarbonate → rapid, causes belching & alkalosis

• Calcium carbonate → slower, can cause hypercalcemia

• Mg(OH)₂ → diarrhea; Al(OH)₃ → constipation; combined to balance effects

common adverse effects of antacids

• NaHCO₃, CaCO₃: belching, metabolic alkalosis, milk-alkali syndrome

• Mg²⁺ salts: diarrhea

• Al³⁺ salts: constipation, toxicity in renal failure

antacid drug interactions

• affect absorption by binding drugs or altering pH

• avoid within 2hrs of tetracyclines, fluoroquinolone, itraconazole, iron

MOA of sucralfate

• take on empty stomach, 1hr before meals

• avoid antacids within 30 min

• separate from other drugs by 2hrs (due to absorption interference)

MOA of misoprostol

• PGE1 analog

• activated EP3 receptors on parietal cells → inhibits acid secretion

• activated EP3 receptors on epithelial cells → stimulates mucus and bicarbonate secretion

counseling points on bismuth compounds

• MOA: coats ulcers/erosion, antimicrobial against H. pylori

• causes harmless black stool and tongue darkening

• use short-term; avoid in renal insufficiency

• high doses may cause salicylate toxicity

• avoid use in children

describe normal water movement in GI tract

• Water makes up 70–85% of stool weight

• Stool water content reflects balance between:

  • Luminal input: ingestion of fluids + secretion of water/electrolytes

  • Output: absorption along the GI tract

• Daily gut challenge = extract water, minerals, nutrients → leave manageable pool of fluid for waste expulsion

• Approximate values:

  • 9 L enters small intestine (2 L ingested, remainder secretions)

  • ~80% absorbed in small intestine

  • 1.5 L enters colon → ~90% absorbed

  • 0.1 L excreted in stool

  • ~95% absorption overall

identify a normal bowel frequency and consistency

• Constipation = decreased frequency, difficulty initiating/passing firm or small stools, or incomplete evacuation

• Debate: 3 times/day vs. 3 times/week can both be considered “normal.”

general principles of non-pharmacological treatment

• First-line:

  • High fiber diet (20–35 g daily)

  • Adequate fluid intake

  • Healthy bowel habits/training

  • Avoid constipating drugs

• If inadequate → supplement with bulk-forming agents or osmotic laxatives

general principles of laxative use

• Stimulant laxatives: lowest effective dose, shortest duration to avoid abuse

• Overuse risks:

  • Excess water/electrolyte loss

  • Secondary aldosteronism if severe volume depletion

  • Excess calcium loss → steatorrhea, protein-losing enteropathy (hypoalbuminemia), osteomalacia

laxation

evacuation of formed stool from rectum

catharsis

evacuation of unformed, watery stool from entire colon

onset of action for softening of feces

• 1-3 days

• bulk-forming (bran, psyllium, methylcellulose, calcium, polycarbophil)

• surfactant/osmotic (decussates, PEG, lactulose/sorbitol/mannitol)

onset of action for soft/semifluid stool

• 6-8 hours

• stimulants (bisacodyl, Senna, cascara)

• mineral oil

onset of action for watery evacuation

• 1-3 hours

• osmotics (magnesium salts, sodium phosphate)

• castor oil

distinguish between effects of fermented vs unfermented fiber

• Fermented fiber:

  • Produces short-chain fatty acids (SCFAs) → prokinetic effect

  • Increases bacterial mass → adds stool volume

• Unfermented fiber:

  • Attracts water → increases stool bulk

• Insoluble, poorly fermentable fibers (e.g., lignin) are most effective for stool bulk/transit

differentiate dietary fibers according to fermentation rates

• Nonpolysaccharides:

  • Lignin – 0% fermented, poor solubility

  • Cellulose – 15% fermented, poor solubility

• Noncellulose polysaccharides:

  • Hemicellulose – 56–87% fermented, good solubility

  • Mucilages/gums – 85–95% fermented, good solubility

  • Pectins – 90–95% fermented, good solubility

MOA of fiber

• Resistant to enzymatic digestion → reaches colon intact

• Traps water/electrolytes → softens stool, increases bulk

• Colonic fermentation → SCFAs (lactate, pyruvate, butyrate) → beneficial to epithelium, increase bacterial mass

fiber supplements used for constipation

• Psyllium husk (Metamucil)

• Methylcellulose (Citrucel)

• Calcium polycarbophil (FiberCon)