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Lectures > Pulmonary pharmacology > Flashcards

Pulmonary pharmacology Flashcards

1
Q

Histamine storage

A
  1. Mast cell granules –> as ionic complex with heparin SO4
  2. Basophils –> as ionic complex with chondroiton monoSO4
  3. GI –> amine precursor uptake decarboxylase cells = enterochromaffin like (ECLs) cells
  4. PNS neurons –> in some autonomic interneuons = small intensely fluorescent (SIF) cells
  5. magnocellular nuclei of the hypothalamic mammillary region
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2
Q

Pools of histamine storage

A
  1. Slowly turning over pool = mast cells +basophiles –> storage in large granules, several weeks for replenishment
  2. Rapidly turning over pool = gastric ECL cells and CNS neurons –> production and release depends on physiological stimuli
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3
Q

Allergeic symptomatology –> relates to tissue histamine content and mast cell distribution
- tissue content of histamine

A
  1. lung –> receptor = H1
    - symptoms –> asthma
  2. nasal epithelia –> receptor = H1
    - symptoms –> sinus inflammation + hay fever
  3. skin/face –> receptor = H1
    - symptoms –> dermatitis, eczema, hiver, allergic conjunctivitus
  4. stomach/duodenum –> receptor = H2
    - symptoms –> “non-allergic”
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4
Q

Stimuli for histamine release

A

Multiple triggers cause a rise in mast cell and basophil intracellular calcium –> leads to histamine release

  • cold, radiation, venom stings, bacterial toxins
  • antigen-antibody IgE mediated reactions
  • some charged drugs –> morphine, codeine, tubocurarine + substance P

Histamine releasers –> polybasic substances that cause histamine release

  • compound 48/80 –> a useful research tool to study histamine release
  • substance P
  • polymyxin B
  • mastoparan
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5
Q

Actions of histamine

A

Range from itch to anaphylactic shock

  • depolarization of primary sensory nerves –> itch
  • small vessel dilation trapping large amounts of blood –> increased capillary permeability –> plasma escapes from circulation –> shock

Major actions of histamine:

  • lungs = bronchoconstriction –> asthma like symptoms (H1)
  • VSM = post capillary venule dilation, terminal arteriole dilation, venoconstriction (H1)
  • Vascular endothelial cells = contraction and separation of endothelial cells –> edema, wheal response (H1)
  • nerves = sensitization of afferent nerve terminals –> itchiness + pain (H1)
  • heart = minor increase in heart rate and contractility (H2)
  • stomach = increased gastric acid secretion –> peptic ulcer disease + heartburn (H2)
  • CNS = neurotransmitter –> circadian rhythms, wakefullness (H3)
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6
Q

Histamine receptor subtypes

A
  1. H1 –> smooth muscle, vascular endothelium, brain
    - Gq –> increased IP3, DAG + Ca –> activation of NFKB
  2. H2 –> gastric parietal cells, cardiac muscle, mast cells, brain
    - Gs –> increased cAMP
  3. H3 –> CNS and some peripheral nerves
    - Gi/o –> decreased cAMP
  4. H4 –> hematopoietic cells, gastric mucosa
    - Gi/o –> decreased cAMP + increased intracellular Ca
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7
Q

Characteristics of H1 antihistaminic drugs

A
  • 6 chemical classes
  • all are inverse agonists
  • many possess common structure
  • similarity in structure to cholinergic agonists and local anesthetics confers shared effects
  • dissimilar in structure to histamine
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8
Q

Pharmacodynamics of H1 receptor antagonists

  • first generation
  • second generation
A

First generation

  • sedating (early&raquo_space;> late)
  • anticholinergic
  • anti-emetic/antimotion sickness
  • short half lives

Second generation

  • generally lack CNS effects
  • longer half lives
  • minimal anti-muscarinic + anti-adrenergic effects
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9
Q

Ues of H1 antagonists

A

Effective in…

  • allergic disorders –> conjunctivitis, hay fever, pruritis, rhinitis
  • mild sleep disorders
  • motion sickness

Limited to ineffective in…

  • anaphylactic reactions
  • asthma
  • chronic sinusitis
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10
Q

Side effects of H1 antagonists

A
  • most frequent = CNS depressant effects –> dizziness, fatigue, sedation (additive with other CNS depressants such as alcohol)
  • next most frequent = GI –> loss of appetite, nausea, vommitting, epigastric distress, constipation, diarrhea
  • anti-muscarinic effects –> dryness, blurred vision, constipation, urinary retention (1st generation)
  • cardiotoxic effects –> prolongs Qt interval leading to ventricular arrhythmias (early 2nd generation)
  • drug allergy –> after oral but more commonly after topical application
  • teratogenic effects
  • acute poisoning –> similar to atropine poisoning due to CNS excitation = hallucinations, ataxia, convulsions, fixed dilated pupils with flushed face, sinus tachycardia
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11
Q

H2, H3, H4 anti-histamines

A

H2 antagonist –> inhibits gastric acid secretion

  • differs in structure from H1 antagonist
  • acts as competitive antagonist of histamine binding

H3 antagonist –> acts at pre-synaptic autoreceptors on histaminergic neurons to increase neuronal firing; also act presynaptically as heteroreceptors in CNS and PNS

  • promotes wakefulness and improves cognitive function
  • regulates ach release in PNS
  • none clinically available

H4 receptors –> expressed on cells with inflammatory or immune function = HA mediated eosinophil chemotaxis, also may have a role in pruritis and neuropathic pain
- no H4 antagonists have been tested in clinical trials

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12
Q

Summary of histamine

A
  • basic amine store in mast cells and basophils
  • multiple receptors –> H1 and H2 are most important
  • actions include…
    1. bronchoconstriction
    2. vasodilation
    3. increases vascular permeability
    4. cardiostimulatory
    5. stimulates GI acid secretion
    6. serves as a CNS neurotransmitter
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13
Q

Leukotrienes

A

Locally acting lipid mediators
- arachidonic metabolites synthesized in response to a host of stimuli that elicit inflammatory and immune responses and contribute significantly to inflammation and immunity

Airways LTs = cysteinyl LTs –> LTC4, LTD4 + LTE4
- cysLTs bind to cysLT1 + LT2 receptors

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14
Q

Effects of cysLTs on airway

A
  • bronchoconstriction
  • airway hyperresponsiveness
  • plasma exudation
  • mucous secretion
  • eosinophilic recruitment
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15
Q

Kinetics of histamine and cysLTs on airway conductance

A
  • histamine produces an immediate but transient decrease in human airway conuctance –> blocked by H1 antagonists
  • cysLTs actions and slower and longer last –> blocked by cysLT1 + cysLT2 antagonists
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16
Q

LT synthesis

A
  • first step in LT synthesis = release of arachidonic acid from membrane phospholipids by PLA2
  • 5 lipooxygenase acts on AA to produce LTs
  • COX acts on AA to produce PGs
17
Q

LT receptors

A

Gq –> activation increases PLC + ca

  • LTB4 –> binds to BLT1 + BLT2 receptors
  • cysLTs = LTC4, LTD4 + LTE4 –> bind to cysLT1 + cysLT2 receptors
  • airway smooth muscle has cysLT1 receptors
18
Q

Glucocorticoids

A

Phospholipase inhibitors –> prevent AA production

19
Q

Zileuton

A

LT synthesis blocker

  • inhibits 5-lipooxygenase pathway
  • effective in asthma, inflammatory bowel disease and rheumatoid arthritis
  • effective in cold, drug and allergen induced asthma

Potential problems with…

  • breast feeding, pregnancy or planning to become pregnant
  • hepatic disease (rare)
  • interaction with other meds
  • regular alcohol consumption
20
Q

Zafirlukast + montelukast

A

cysLT1 receptor antagonists
- results in a 2x increased in FEV1 in asthmatics

Side effects

  • abdominal pain
  • dizziness
  • headache
  • rhinitis
  • sore throat
  • rare cases of hepatic dysfunction
21
Q

LT summary

A

5-lipooxygenase –> converts AA to LTs

  • LTA4 –> converted to cysLTs –> bronchospastic
  • LTB4 –> chemotactic
  • play role in many inflammatory conditions including asthma

Zafirlukast + montelukast = block cysLT1 receptor

Zileuton = 5-LOX inhibitor

Less broadly effective than B2 agonist because they antagonist only one of several bronchoconstrictor mediators

22
Q

Treatment of asthma

A

Bronchodilators

  • beta 2 adrenergic agonists
  • anticholinergic agents
  • methylxanthines (theophylline)

Anti inflammatory agents

  • glucocorticoids –> 1st line of preventative treatment
  • LT pathway modifying agents –> receptor antagonists and LT synthesis inhibitors
  • anti IgE therapy
  • cromolyn sodium + nedocromil sodium
  • antihistaminic agents –> limited used, not really used
23
Q

Treatment of COPD

A

Bronchospasm

  • beta 2 agonists –> first line intervention
  • anticholinergics –> may/may not be used initially
  • xanthine derivatives –> second line intervention
  • combinations of beta agonists, anticholinergics and theophylline are used
  • cysLTs play little or no role
  • glucocorticoids are much less beneficial for COPD than for asthma –> they are appropriate for severe cases or acute exacerbations of COPD
24
Q

Anticholinergics

A

Block cholinergic receptors (M3) to reduce Ach mediated bronchoconstriction and mucus secretion

  • used for bronchodilation and decongestion
  • generally inhaled
  • used mainly to treat COPD

Side effects

  • dry mouth
  • constipation
  • urinary retention
  • tachycardia
  • blurred vision
  • confusion

Not FDA approved for asthma, but used as a rescue therapy in subset of asthma patients who can not tolerate beta agonists or where sympathomimetics are containdicated due to heart disease or tachyarrhythmia

25
Q

Beta adrenergic agonists

A

Stimulate B2 receptors = increase cAMP –> activates pka –> adds inhibitory phosphate to contractive proteins
- non-selective (alpha and beta receptors) or selective (beta only)

Mode of administration

  • inhalation –> decreased adverse effects, but decreased distal airway drug effects in bronchospasm
  • oral/subQ –> increase adverse effects, but increase drug effects at distal airway

Additional effects

  • prevent mediator release from mast cells via B2 receptors
  • prevent microvascular leak
  • increase mucous secretion from submucosal glands and ion transport across airway epithelium
  • reduced neurotransmission in airway cholinergic nreves via presynaptic B2 receptors
26
Q

Classes of B2 agonists

A
  1. short acting (3-4) hours –> rapid onset (15-30 min) = albuterol, levalbuterol, metaproterenol, terbutaline
  2. long acting (>12 hrs) –> formoterol, salmeterol, arformoterol
  3. Combination –> inhaler with long acting beta agonist and a corticosteroid
27
Q

Cellular mechanisms of B2 agonists

A

Smooth muscle relaxation produced by

  • decreased intracellular calcium
  • increased calcium-activated K conductance
  • decreased myosin light chain phosphorylation
28
Q

Adverse effects

A
  • cardiac irregularities
  • increased airway hyper-responsiveness = increased risk of bronchoconstrictive attacks
  • –> secondary to prolonged/excessive use
  • –> secondary to stimulation of B1 receptors
  • skeletal muscle tremor
  • nervousness, restlessness, tremor –> secondary to stimulation of CNS adrenergic receptors
29
Q

Methylxanthines

A

Theophylline + aminophylline
- mainly used to treat COPD, occasionally asthma

Actions

  • bronchodilates
  • increase respiratory muscle strength
  • accelerates mucocilliary transport
  • decrease pulmonary artery pressure
  • limits release of inflammatory mediators from mast cells, lymphocytes and eosinophils
30
Q

Mechanisms of methylxanthines

A
  • inhibits phosphodiesterase enzyme (PDE) = increased cAMP –> causes smooth muscle relaxation/bronchodilation
  • inhibition of PDE in inflammatory cells –> anti-inflammatory effects
  • adenosine receptor antagonist –> adenosine is a bronchoconstrictor
  • inhibits intracellular calcium release
  • typically oral administration
31
Q

Adverse effects of methylxanthines

A
  • highly toxic –> narrow therapeutic index
  • –> monitor plasma levels, significant inter-individual variation in metabolism and drug-drug interactions
  • supra-therapeutic doses –> nausea, confusion, irritability, restlessness
  • higher doses can be life threatening –> seizures + cardiac arrhythmias
32
Q

Glucocorticoids

A

Inhaled corticosteroids = triamcinolone, prednisolone, beclomethasone

Inhibits inflammatory response

  • inhibits production/migration of inflammatory mediators
  • disrupts eicosanoid biosynthesis
  • increases transcription of anti-inflammatory proteins (IL-10+IL-12)
  • decreases transcription of pro-inflammatory proteins (IL-4 induces B cell IgE production; IL-5 recruits eosinophils)

Administered via injection, inhalation or orally (fewer advedrse effects with inhalation)

33
Q

Adverse effects of glucocorticoids

A
  • osteoporosis
  • skin breakdown
  • muscle wasting
  • cataracts/glaucoma
  • hyperglycemia
  • hypertension
  • retardation of growth in kids
34
Q

Cromolyn Na

A

Prophylactic rx for upper respiratory tract –> decreases airway responsiveness of upper respiratory tract

  • inhibits release of inflammatory mediators from pulmonary mast cells = “mast cell stabilizing agent”, but many other inflammatory cells are “stabilized”
  • administered via MDI, nebulizer or nasal spray

Adverse effects
- irritation of nasal and upper respiratory passages

35
Q

Omalizumab

A

Monospecific anti-IgE antibody

  • administered s.c. every 2-4 weeks
  • major side effect = anaphylactic response
  • very expensive
36
Q

Antihistamines in treatment of asthma

A

Little evidence H1 receptor antagonists provide useful clinical benefit

  • newer H1 have some beneficial effects but this may be unrelated to H1 receptor antagonist
  • not recommended in routine management of asthma

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