Pharmacology
Lecture 13 Pulmonary Drugs “Pharmacologic Therapy of Obstructive Lung Disease”
1) Describe the major categories of drugs used to treat obstructive lung diseases.
Bronchodilators
Beta-adrenergic agonists – activate β2-adrenergic receptors in airway smooth muscle
and produce functional antagonism of bronchoconstriction in airways of all sizes.
Anticholinergics - produce bronchodilation by directly antagonizing the effects of
acetylcholine on the muscarinic receptors in airway smooth muscle.
Theophylline - the mechanism of action remains unclear. Pharmacologic effects
include improved diaphragmatic contraction, smooth muscle relaxation, and increased
mucociliary clearance.
Leukotriene modifiers - prevent the synthesis or action of cysteinyl leukotrienes, by
either blocking at the receptor or blocking the formation of leukotrienes by inhibiting
5-lipooxygenase or the 5-lipooxygenase activating protein.
Anti-inflammatory
Corticosteroids - enter cells, primarily by diffusion, and bind to glucocorticoid
receptors (GRs), which are predominantly localized to the cytoplasm of target cells.
(Cromolyn/Nedocromil) - mechanism is not well understood, these agents prevent the
release of preformed mediators and arachidonic acid metabolites from a number of
cells including mast cells, T-lymphocytes, eosinophils and macrophages.
2) Be able to distinguish the mechanisms of action for beta-adrenergic agonist and
anticholinergic bronchodilators.
Beta-adrenergic agonist - act by activating β2-adrenergic receptors, which activate
adenylyl cyclase, resulting in an increase in cyclic AMP, activation of protein kinase
A, and relaxation of airway smooth muscle through the cyclic AMP/protein kinase A
phosphorylnation cascade.
Anticholinergic bronchodilators - cholinergic control of airway smooth muscle tone
is mediated by nerves that travel in the Vegas. Cholinergic nerves release
acetylcholine, which acts on the muscarinic receptors in the airways to produce
cholinergic effects. Anticholinergics block only bronchoconstriction mediated
through cholinergic nerves, they are not very protective against some stimuli.
Although anticholinergic agents have been shown to be effective in patients with
COPD, β-agonists are more effective in patients with chronic asthma.
3) Identify the major side effects of beta-agonists and understand how they occur.
Tremor and palpitations are the most common side effects, tremor results from
stimulation of beta-2 adrenergic receptors in skeletal muscle, and palpitations occur
primarily from stimulation of beta-2 adrenergic receptors in the peripheral
vasculature, resulting in vasodilation with reflex increase in the force and rate of
cardiac contraction. They may also produce a number of metabolic side effects,
including hypokalemia when given in high doses, this occurs because catecholamines
stimulate potassium uptake by skeletal muscle.
4) Understand the basic pharmacokinetics of theophylline and be able to describe
the major factors that decrease theophylline clearance. Theophylline is well
absorbed from the GI tract. The volume of distribution is relatively constant between
individuals at 0.5 L/kg so that 1 mg/kg will raise the serum level 2 mcg/ml.
Theophylline’s clearance, however, varies markedly between individuals and also
may vary in the same individual over time. Only 10% is eliminated unchanged by the
kidney. The major route of clearance is metabolism by the cytochrome microsomal
enzyme system in the liver, and therefore, several drugs and related conditions that
affect hepatic metabolism may alter its clearance.
Decreased elimination
Congestive heart failure, liver disease, Cor
pulnonale, hypothyroidism, sustained fever, flu
vaccine, high carbohydrate, low-protein diet,
allopurinol (high-dose), Cimetidine, ciprofloxacin,
Erythromycin, methotrexate, propranolol,
Thiabendazole, Verapanil
Increased elimination
Cigarette smoking, charcoaled broiled meats,
hyperthyroidism, low carbohydrate, high protein
diet, carbamazepine, phenobarbital, phenytoin,
rifampin
5) Describe why there are side effects with inhaled atropine but not with inhaled
ipratropium. The therapeutic usefulness of atropine is limited by side effects, due to
its high absorption rate it produces systemic effects such as tachycardia, blurred
vision, dry mouth, and urinary retention due to blockade of muscarinic receptors
outside the lung. Ipratropium is a quaternary ammonium analogue of atropine which
has resolved the problem of side effects with inhaled anticholinergic therapy. This is
because the positive charge on the quaternary ammonium group makes ipratropium
poorly absorbed into the circulation and thus, produces no significant side effects.
6) Be able to describe the mechanism of corticosteroid action at the receptor level.
Corticosteroids enter the cells by diffusion and bind to glucocorticoid receptors (GR)
which are localized to the cytoplasm of target cells. GR exist as part of a larger
heteromeric receptor complex that includes two subunits of heat protein 90 (hsp 90),
which dissociate after the corticosteroid binds, thus activating the GR complex and
allowing it to enter the nucleus. GR forms a Homo dimer and binds to glucocorticoid
response to the elements (GREs), which are DNA sequences located in and around
BG our target genes. This results in transcriptional regulation of specific target genes
producing either induction or repression of gene transcription.
7) Describe the major potential side effects associated with chronic oral
corticosteroid therapy and understand how they can be avoided by use of the
inhaled route for administration.
Organ system
Endocrine
Musculoskeletal
Ophthalmologic
Cardiovascular
Psychiatric
General
Gastrointestinal
Cutaneous
Adverse effects
Adrenal insufficiency, Glucose intolerance
Osteoporosis/compression fractures, myopathy, Osteonecrosis
Cataracts, glaucoma
Hypertension, lipoprotein abnormalities, atherosclerosis
Psychosis, depression, mania
Cushingoid appearance, obesity, hypokalemia, immune
suppression/infection
Pancreatitis, Diverticular rupture
Purpura, atrophy/fragility, hirsutism, delayed wound healing, acne
8) Understand the general approach to therapy (first line drugs) in patients with
asthma and COPD.
Asthma therapy - patients at start treatment at the step most appropriate to the initial
severity of the condition. Establish control; and decreased treatment to do the least
medication necessary to maintain control. All patients receive an inhaled "short
acting" beta-2 agonist to be used as needed for attacks of SOB and wheeze. For acute
exacerbations, a rescue course of oral prednisone may be needed at any time.
Severity class
Step 4 severe
persistent
Step 3 moderate
persistent
Step 2 mild
persistent
Step 1 mild
persistent
Symptoms/Day
Symptoms/Night
Continual
Frequent
Daily
>1 night/week
>2/week but <1 x/day
>2 nights/month
≤ 2 days/week
≤ 2 nights/month
PEF or FEV1
PEF variability
<60%
>30%
>60%-<80%
>30%
≥ 80
20%-30%
≤ 80%
<20%
Daily medications
Preferred treatment:
high-dose ICS plus LADA and, if needed, or
corticosteroid tablets or syrup long-term
Low to medium dose ICS plus LABA
Low dose inhaled corticosteroid
No daily medication needed
COPD - bronchodilators are given either on an as needed basis for relief of persistent
or worsening symptoms, or a regular basis to prevent or reduce symptoms. These
bronchodilators include beta-2 agonists, anticholinergics, and theophylline (less
common). COPD patients are often treated with a combination of beta-2 agonist and
anticholinergic bronchodilators. For acute COPD exacerbations: inhaled beta-2
agonist and inhaled anticholinergic.