Pulmonary pharmacology Flashcards
(36 cards)
1
Q
Histamine storage
A
- 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
2
Q
Pools of histamine storage
A
- 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
3
Q
Allergeic symptomatology –> relates to tissue histamine content and mast cell distribution
- tissue content of histamine
A
- 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”
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
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)
6
Q
Histamine receptor subtypes
A
- 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
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
8
Q
Pharmacodynamics of H1 receptor antagonists
- first generation
- second generation
A
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
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
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
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
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
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
14
Q
Effects of cysLTs on airway
A
- bronchoconstriction
- airway hyperresponsiveness
- plasma exudation
- mucous secretion
- eosinophilic recruitment
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
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
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
26
Classes of B2 agonists
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
Cellular mechanisms of B2 agonists
Smooth muscle relaxation produced by
- decreased intracellular calcium
- increased calcium-activated K conductance
- decreased myosin light chain phosphorylation
28
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
29
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
30
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
31
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
32
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)
33
Adverse effects of glucocorticoids
- osteoporosis
- skin breakdown
- muscle wasting
- cataracts/glaucoma
- hyperglycemia
- hypertension
- retardation of growth in kids
34
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
35
Omalizumab
Monospecific anti-IgE antibody
- administered s.c. every 2-4 weeks
- major side effect = anaphylactic response
- very expensive
36
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
