Pulmonary pharmacology Flashcards
Histamine storage
- Mast cell granules –> as ionic complex with heparin SO4
- Basophils –> as ionic complex with chondroiton monoSO4
- GI –> amine precursor uptake decarboxylase cells = enterochromaffin like (ECLs) cells
- PNS neurons –> in some autonomic interneuons = small intensely fluorescent (SIF) cells
- magnocellular nuclei of the hypothalamic mammillary region
Pools of histamine storage
- Slowly turning over pool = mast cells +basophiles –> storage in large granules, several weeks for replenishment
- Rapidly turning over pool = gastric ECL cells and CNS neurons –> production and release depends on physiological stimuli
Allergeic symptomatology –> relates to tissue histamine content and mast cell distribution
- tissue content of histamine
- lung –> receptor = H1
- symptoms –> asthma - nasal epithelia –> receptor = H1
- symptoms –> sinus inflammation + hay fever - skin/face –> receptor = H1
- symptoms –> dermatitis, eczema, hiver, allergic conjunctivitus - stomach/duodenum –> receptor = H2
- symptoms –> “non-allergic”
Stimuli for histamine release
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
Actions of histamine
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)
Histamine receptor subtypes
- H1 –> smooth muscle, vascular endothelium, brain
- Gq –> increased IP3, DAG + Ca –> activation of NFKB - H2 –> gastric parietal cells, cardiac muscle, mast cells, brain
- Gs –> increased cAMP - H3 –> CNS and some peripheral nerves
- Gi/o –> decreased cAMP - H4 –> hematopoietic cells, gastric mucosa
- Gi/o –> decreased cAMP + increased intracellular Ca
Characteristics of H1 antihistaminic drugs
- 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
Pharmacodynamics of H1 receptor antagonists
- first generation
- second generation
First generation
- sedating (early»_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
Ues of H1 antagonists
Effective in…
- allergic disorders –> conjunctivitis, hay fever, pruritis, rhinitis
- mild sleep disorders
- motion sickness
Limited to ineffective in…
- anaphylactic reactions
- asthma
- chronic sinusitis
Side effects of H1 antagonists
- 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
H2, H3, H4 anti-histamines
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
Summary of histamine
- 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
Leukotrienes
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
Effects of cysLTs on airway
- bronchoconstriction
- airway hyperresponsiveness
- plasma exudation
- mucous secretion
- eosinophilic recruitment
Kinetics of histamine and cysLTs on airway conductance
- 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
LT synthesis
- 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
LT receptors
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
Glucocorticoids
Phospholipase inhibitors –> prevent AA production
Zileuton
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
Zafirlukast + montelukast
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
LT summary
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
Treatment of asthma
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
Treatment of COPD
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
Anticholinergics
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
Beta adrenergic agonists
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
Classes of B2 agonists
- short acting (3-4) hours –> rapid onset (15-30 min) = albuterol, levalbuterol, metaproterenol, terbutaline
- long acting (>12 hrs) –> formoterol, salmeterol, arformoterol
- Combination –> inhaler with long acting beta agonist and a corticosteroid
Cellular mechanisms of B2 agonists
Smooth muscle relaxation produced by
- decreased intracellular calcium
- increased calcium-activated K conductance
- decreased myosin light chain phosphorylation
Adverse effects
- 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
Methylxanthines
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
Mechanisms of methylxanthines
- 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
Adverse effects of methylxanthines
- 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
Glucocorticoids
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)
Adverse effects of glucocorticoids
- osteoporosis
- skin breakdown
- muscle wasting
- cataracts/glaucoma
- hyperglycemia
- hypertension
- retardation of growth in kids
Cromolyn Na
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
Omalizumab
Monospecific anti-IgE antibody
- administered s.c. every 2-4 weeks
- major side effect = anaphylactic response
- very expensive
Antihistamines in treatment of asthma
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
