Transcript Respiratory drugs - Suny-perfusion

Respiratory drugs
I. Bronchodilators
• Bronchodilators are indicated for the
treatment of asthma (both acute and
chronic) and COPD (emphysema and
bronchitis).
• There are 3 major categories of
bronchodilators: beta adrenergics,
anticholinergics, and xanthines
A. Beta adrenergic bronchodilators
1. adrenergic receptors
• In the late 1940’s, two types of adrenergic
receptors were identified and were
classified as α and β, based on their
different responses to various adrenergic
drugs.
• These receptors were eventually further
differentiated into subtypes: α1, α2, β1, β2,
and β3.
• Alpha receptors are primarily found in
vascular smooth muscle.
• Stimulation of α1 receptors leads to
excitation/contraction/vasoconstriction,
whereas stimulation of α2 receptors leads
to relaxation/vasodilation.
• Beta receptors are found in fat cells and in
both cardiac and smooth muscle.
• The predominant type in cardiac muscle
are β1 receptors.
• β2 receptors are found in both cardiac and
smooth muscle (bronchial, skeletal, and
vascular).
• β3 receptors are found in fat cells.
• Similar to alpha receptors, stimulation of
β1 receptors causes
excitation/contraction/vasoconstriction
• and stimulation of β2 receptors causes
relaxation/vasodilation.
2. beta adrenergic agents
• The beta adrenergic bronchodilators are
classified chemically as catecholamines
(or derivatives of catecholamines).
• The basic catecholamine structure
consists of a benzene ring with 2 OH
groups. Attached to the benzene ring is a
secondary amine side chain.
• The composition of the side chain is
related to the type of receptor the drug has
a preference for:
• the LARGER the side chain, the MORE
SPECIFIC is the receptor interraction.
• Epinephrine has a small methyl group (the
CH3) attached to the amine nitrogen. It
activates equally, both α and β receptors.
• Isoproterenol has a larger isopropyl group
attached to the amine nitrogen, and
stimulates β receptors, but not α to any
significant degree.
• Many bronchodilators have an even larger
group (t-butyl or bigger) attached to the
amine nitrogen. These drugs are specific
for β2 receptors.
• Catecholamines are rapidly inactivated by
the enzyme catechol-O-methyltransferase
(COMT), found throughout the body.
• This enzyme forms an ether linkage
through its attachment of a methyl group
to the OH group on C-3 of benzene.
• This inactivation limits the duration of
action of catecholamine drugs to a few
hours.
• To counteract this, pharmaceutical
companies have formulated drugs which
have a CH2—OH group (albuterol,
pirbuterol, salmeterol);
• or an amide group (formoterol,
arformoterol) at this site rather than an OH
group.
• This has effectively doubled or quadrupled
the duration of the drug.
• Catecholamines are not normally
administered orally because they undergo
Phase II biotransformations in the GI tract
(attachment of a sulfate or glucuronate at
C-4) which inactivates them.
3. Bronchodilator mechanism of action
• Although some adrenergic bronchodilators
can stimulate α and β1 receptors, the
majority of these agents have selective β2
actions.
• Attachment to a β2 receptor leads to
activation of a G protein on the
cytoplasmic side of the membrane.
• The G protein stimulates the enzyme
adenylate cyclase to increase the
synthesis of the secondary messenger
cAMP.
• An increase in cAMP results in an
increase in the inactivation of a myosin
kinase, causing smooth muscle relaxation.
• Beta adrenergic bronchodilators are
indicated for the relaxation of airway
smooth muscle in treating asthma and
COPD.
• They are the most widely used and are
believed to be the most effective agents
for short term relief of asthma.
• Long term control is generally most
effectively achieved with an inhaled
corticosteroid.
4. Very short acting agents
• Very short acting agents have an onset on
between 1-5 minutes and a duration of
less than 3 hours.
• a. epinephrine (Adrenalin CI, Epinephrine
Mist, AsthmaHaler Mist, AsthmaNefrin, Epi
Pen)
• onset: minutes
• duration: 1-3 hours
• Epinephrine stimulates both α and β
receptors, and therefore has a number of
effects.
• It is a powerful bronchodilator that also
causes elevation of blood pressure,
tachycardia, headache, and insomnia.
• It has been administered by inhalation
using a metered dose inhaler, MDI
(Primatene Mist) or small volume
nebulizer, SVN.
• The FDA has determined that traditional
MDI’s which use a CFC propellant cannot
be sold in the U.S. after December 2008
(according to the Montreal Protocol, which
attempts to limit CFC’s in the atmosphere).
• Wyeth, which produces Primatene Mist
has not released a version with the
required hydrofluoralkane, HFA propellant
as of January 2009.
• Epinephrine is also available in a premeasured form (EpiPen) for intramuscular
injections, and targeted for individuals
susceptible to anaphylactic reactions
b. isoproterenol (Isuprel)
• Isoproterenol has both β1 and β2 actions and is
only available today parenterally, to treat
patients in shock or who experience
bronchospasm during anesthesia. It is no longer
manufactured for use in a SVN.
c. isoetharine
• Isoetharine is a β2 specific agent with a
very rapid onset (about 1 minute)
generally administered by SVN.
5. Short acting agents
• Short acting agents have an onset of
between 1-15 minutes and a duration of
up to 8 hours.
• Technically, they are not catecholamines,
but are derivatives of catecholamine that
are not as susceptible to deactivation by
COMT.
a. metaproterenol (Alupent)
• This is administered via SVN or orally as it
is not susceptible to inactivation in the GI
tract.
b. albuterol (Teva’s Proair HFA; Schering
Plough’s Proventil HFA; and
GlaxoSmithKline’s Ventolin HFA)
• These are all newly formulated
bronchodilators. Albuterol is also available
via SVN and in an oral formulation.
c. levalbuterol (Xopenex, Xopenex HFA)
• Levalbuterol is available as a SVN solution
or in a MDI.
d. pirbuterol (Maxair Autohaler)
• is administerd via MDI. The manufacturer
does not yet have an available HFA
associated brand, and has been granted
additional time to reformulate an HFA
version.
6. Long acting agents
• Long acting agents have an onset of 15-20
minutes and a duration of up to 12 hours.
• Each of the drugs in this category are
characterized by their larger, more
nonpolar side chains.
• This is significant in that it allows the drug
to actually diffuse into the phospholipid
bilayer of the membrane and anchor the
drug to the membrane.
• This leads to a continuous activation of the
receptor and is the basis for the longer
duration of action of drugs in this class.
• These long acting agents are not “rescue”
drugs.
• A shorter acting agent should also be
prescribed for asthmatic patients who
need additional bronchodilator therapy.
• It is suggested that a long acting agent be
introduced in the treatment of asthma
once it is established that symptoms are
not being controlled by regular low doses
of inhaled corticosteroids.
• Using both an inhaled corticosteroid and a
long acting β2 agonist often results in a
decrease of asthma symptoms.
a. salmeterol (Serevent)
• This is available via dry powdered inhaler,
DPI.
b. formoterol fumurate (Foradil Aerolizer,
Perforomist)
• Foradil Aerolizer is administered via DPI.
Perforomist, administered via SVN
solution was approved by the FDA in
2007.
c. Advair Diskus
• Advair Diskus is a combination of
salmeterol and the corticosteroid
fluticasone.
• Patients on Advair have demonstrated
better asthma control compared to those
taking either drug separately.
d. arformoterol (Brovana)
• This medication, available via SVN
solution has been approved by the FDA
for maintenance of COPD.
7. Adverse effects of beta adrenergics
• The adverse effects of beta adrenergic
bronchodilators include:
• dizziness,
• headache,
• insomnia,
• increases in blood pressure,
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nausea,
nervousness,
tachycardia,
developed tolerance to bronchodilator
effect,
• and the asthma paradox (an increase in
death or near death situations).
B. Anticholinergic bronchodilators
1. muscarinic receptors
• The lung is innervated not only by sympathetic nerve
fibers (the blood vessels and glands of the lungs), but
also by parasympathetic nerve fibers (the mucous
glands and smooth muscle).
• The parasympathetic branch includes the
vagus nerves, which release acetylcholine
and therefore are labeled cholinergic.
• The receptors which bind acetylcholine are
termed muscarinic receptors.
• The binding of acetylcholine to muscarinic
receptors of submucosal glands stimulates
secretion.
• The binding to muscarinic receptors
located on smooth muscle of the airway
causes bronchoconstriction.
• There are 5 subtypes of muscarinic
receptors all linked to various G proteins,
with a couple of different effects.
• Binding may activate a G protein which in
turn activates phospholipase C.
• This initiates a cascade which ultimately
leads to intracellular Ca2+ increase and
either smooth muscle contraction or
release of secretions from glands.
• Or, binding activates a G protein which
inhibits adenylate cyclase and therefore
inhibits the secondary messenger, cAMP.
• (Remember cAMP is necessary for
smooth muscle relaxation as well as
decreases in intracellular Ca2+).
• By blocking muscarinic receptors,
anticholinergic agents cause
bronchodilation as well as inhibition of
secretion release from mucous glands.
• The discovery of this class of drugs arose
from the use of the leaves of Datura
stramonium in India for treating asthma.
These leaves contain atropine, a potent
inhibitor of acetylcholine.
2. anticholinergic agents
a. ipratropium bromide (Atrovent, Atrovent
HFA)
• This agent is administered via SVN or
MDI. It is indicated for the treatment of
COPD (maintenance prevention of airflow
obstruction).
• Its onset of action is about 15 minutes and
its duration is about 4-6 hours, about the
same as the short acting beta adrenergics.
• However, it peaks more slowly (1-2 hours)
compared to the beta adrenergics (5
minutes- 1 hour).
b. combination ipratropium bromide and
albuterol
• Combivent, via MDI with CFC propellant
should still be available. Combivent is
anticipated to have an HFA product in
2010 or 2011.
• DuoNeb, via SVN)
c. tiotropium bromide (Spiriva)
• This agent was approved in 2005. Its long
duration of action (24 hours) allows for
once daily dosing. It is administered via
DPI.
3. Adverse effects of anticholinergics
• The adverse effects associated with
anticholinergic bronchodilators include:
• Mydriasis (pupil dilation) and cycloplegia
(the lens remains “flattened” and does not
thicken).
• These 2 effects can reduce drainage of
the aqueous humor, leading to increased
pressure in patients with glaucoma.
• Drying effects (dry mouth, lack of tears,
trouble urinating, constipation)
• Increased heart rate.
C. Xanthine bronchodilators
1. mechanism of action
• The mechanism by which xanthines cause
bronchodilation is not conclusively known.
• It had been proposed that xanthines
function by inhibiting phosphodiesterase.
• Phosphodiesterase normally degrades
cAMP.
• By preventing this, cAMP concentrations
are increased and, as with the beta
adrenergics, increases in cAMP lead to
relaxation of bronchial smooth muscle.
• Researchers are not positive, however,
that this is the actual or only mechanism at
play. An alternative theory suggests that
the xanthines block adenosine.
• Adenosine is a naturally occurring
compound that binds to and stimulates
alpha receptors.
• By blocking these alpha receptors, the
xanthines can prevent the smooth muscle
contraction that is normally mediated by α1
stimulation.
• The xanthines are now generally reserved
for those asthmatic and COPD patients
whose symptoms remain poorly controlled
despite receiving regular treatment with
low dose inhaled corticosteroids and a
bronchodilator (β2 adrenergic or
anticholinergic).
• The very low cost of the xanthines is a
consideration for economically
disadvantaged patients or those in
countries where health care resources are
limited.
2. xanthine agents
a. theophylline
• (Asmalix, Bronkodyl, Elixophyllin, QuibronT, Respbid, Sustaire, Theobid, Theodur,
Theostat, Theovent, Uniphyl)
• This is available via immediate release
and timed release capsules and tablets,
syrup, elixir, and injection.
b. aminophylline (Phyllocontin, Truphylline)
• This is a salt of theophylline which
releases free theophylline after
administration. It is available as anhydrous
aminophylline (86% theophylline) or
aminophylline dihydrate (79%
theophylline)
c. oxtriphylline
• This is also a salt which releases 64%
theophylline.
3. Adverse effects of xanthines
• The most frequently reported adverse
effects associated with xanthines are:
• anxiety,
• nausea,
• tachycardia,
• and vomiting.
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Other adverse effects include
angina,
anorexia,
arrhythmias,
headache,
insomnia
and seizures.
II. Mast cell stabilizers
• Mast cell stabilizers are also known as
cromones. They are indicated as
prophylactic therapy in the management of
mild asthma.
• They inhibit inflammation by preventing
degranulation of mast cells, which blocks
the release of the chemical mediators of
inflammation.
• Their mechanism of action is not
completely understood, but is believed to
involve stopping Ca2+ influx into mast
cells.
• Ca2+ is necessary for release of granules
containing mediators of inflammation
(histamine, SRS-A) from the mast cell.
• Mast cell stabilizers are not as effective as
inhaled corticosteroids, but their inclusion
along with a standard dose of an inhaled
corticosteroid appears to improve asthma
control.
• Generally, younger patients are more
likely to respond favorably to this
treatment regimen.
• Daily use of a mast cell stabilizer also has
reduced the need for bronchodilator
rescue in some clinical trials.
1. cromolyn sodium (Intal)
• This is available via SVN, MDI (HFA)
• It is also found in a nasal spray
(Nasalcrom) for the prophylactic treatment
of seasonal and nonseasonal allergic
rhinitis.
• In terms of effectiveness, cromolyn sodium
is comparable to theophylline, yet fewer
side effects are reported with its use.
• When therapy is first initiated, nasal
congestion may be experienced by some
patients.
• Sneezing, cough, nasal itching, or burning
have also been reported.
2. nedocromil sodium (Tilade CFC- free)
• Available in a MDI (HFA)
• 3. Adverse effects of mast cell
stabilizers:
• throat irritation, cough, dry mouth,
wheezing
III. Corticosteroids
A. Corticosteroids administered by
inhalation
• Corticosteroids administered by inhalation
are indicated for the long-term control of
asthma.
• They may decrease the need for systemic
corticosteroids.
• Inhalation corticosteroids are being
recommended by many physicians as the
first-line maintenance therapy for adults
with daily or frequent asthma symptoms.
• At present there are seven FDA approved
inhaled corticosteroids available, and
others are in development:
• 1. beclomethasone (QVAR)
• 2. budesonide (Pulmicort)
• 3. flunisolide (AeroBid)
• 4. fluticasone (Flovent)
• 5. triamcinolone (Azmacort)
• 6. mometasone (Asmanex Twisthaler)
• 7. ciclesonide (Alveso)
• The goal of all inhaled corticosteroids is to:
• produce long-lasting therapeutic effects at
the site of action
• minimize systemic side effects
• Local adverse effects include hoarseness,
cough, and oral candidiasis or thrush.
B. Corticosteroids administered
intranasally
• Nasal-spray corticosteroids are considered
the most effective drugs for treating severe
allergic rhinitis.
• They suppress important stress and other
hormones in the HPA (hypothalamicpituitary-adrenal) axis.
• The suppression of these hormones
blocks the inflammatory response that
triggers an allergic attack. Nasal-spray
corticosteroids include:
• 1. triamcinolone (Nasacort)
• 2. mometasone furoate (Nasonex)
• 3. fluticasone (Flonase)
• 4. beclomethasone (Beconase,
Vancenase)
• 5. flunisolide (Nasalide)
• 6. budesonide (Rhinocort)
• 7. ciclesonide (Omnaris)
• Side effects of nasal steroids may include:
• Dryness, burning, stinging in the nasal
passage
• Sneezing
• Headaches and nosebleed (uncommon)
C. Corticosteroids administered
systemically: asthma
• Corticosteroids may be administered
systemically (PO, rectally, IM, IV) in the
treatment of asthma.
• Systemic corticosteroids help control
inflammation in the airways of the lungs in
asthma.
• They are used to:
• achieve relief of some asthma symptoms
during a moderate or severe asthma
attack (they are not rescue drugs, though)
• Get control of symptoms when starting
long-term treatment of asthma after an
initial diagnosis.
• Corticosteroids may make the episode
shorter and prevent early recurrence of
episodes.
• Oral medications are generally used for 5
to 7 days and then stopped.
• People with severe persistent asthma may
need to take corticosteroids by mouth daily
or every other day to control their
symptoms.
• Corticosteroids administered in the
treatment of asthma include:
• 1. dexamethasone (Cortastat, Decadrol,
Decadron, Dexasone, Primethasone)
• 2. methylprednisolone (depMedalone,
DepoMedrol, Depoject, Depopred,
Duralone, Medralone, Medrol)
• 3. prednisolone (Articulose, Cotolone,
Delta-Cortef, Hydeltrasol, Key-Pred, NorPred, Orapred, Pediapred, Prednisol,
Prelone)
• 4. prednisone (Cordrol, Deltasone, Liquid
Pred, Orasone, Prednicot, Sterapred)
•
• 5. triamcinolone (Amcort, Clinacort,
Triamolone, Triamonide, Trilone)
Adverse effects of systemic
corticosteroids
• If systemic steroids have been prescribed
for one month or less, the following side
effects may arise:
• increased appetite
• Weight gain
• Sleep disturbance
• Almost everyone on systemic steroids for
more than a month suffers from some
adverse effects. These may include any of
the following:
• Osteoporosis, particularly in smokers,
postmenopausal women, the elderly,
those who are underweight or immobile,
and patients with diabetes or lung
problems.
• Precipitation or aggravation of diabetes
mellitus
• Increase in circulating triglycerides
• A redistribution of body fat onto the face
• back of neck or upper back
• or the trunk
• Salt retention: leg swelling, raised blood
pressure, weight increase and heart
failure.
• Psychological effects including insomnia,
mood changes, increased energy,
excitement, delirium or depression.
• Skin problems such as thinning and acne
IV. Antihistamines
A. histamine
• When a sensitized individual comes into
contact with antigen, mast cells and
basophils release histamine.
• The intensity of allergic symptoms is
proportional to the amount of histamine
released.
• Histamine dilates small blood vessels and
capillaries which produces a transient
decrease in blood pressure.
• This can result in hypotension and
circulatory collapse with large histamine
concentrations.
• Dilation of cerebral blood vessels
stimulates pain receptors causing
throbbing headache (histaminic
cephalgia).
• Histamine also causes fluids to leak out of
capillaries, causing congestion in nasal
mucous membranes and edema and/or
hives in the skin.
• Histamine also irritates sensory nerve
endings, resulting in itching and pain.
• Histamine produces contraction of the
smooth muscle of the bronchioles by
stimulating H1 receptors, leading to
breathing difficulties.
B. H1 receptor antagonists
• These drugs are used to relieve acute
reactions in which histamine has already
been released.
• They are usually administered orally as
they are well absorbed from the GI tract.
Antihistamines are classified as 1st or 2nd
generation.
C. 1st generation antihistamines
• 1st generation antihistamines are
characterized by nonselective interaction
with both peripheral and central histamine
receptors.
• They cause dryness and sedation along
with relief of allergy symptoms.
• In addition, they depress sensory nerve
activity, thus relieving itching and pain. 1st
generation antihistamines include:
1. brompheniramine (Dimetapp Allergy):
• 12-24 mg every 12 hours
2. chloropheniramine (Chlor-Trimeton):
• 2-4 mg every 4-6 hr; available OTC
3. clemastine (Tavist):
• 1.34-2.68 mg BID, available OTC
4. diphenhydramine (Benadryl)
• 25-50 mg every 4-6 hr, sedative dose 50
mg at bedtime, available OTC
5. promethazine (Phenergan):
• 12.5 mg QID, sedative dose 25-50 mg at
bedtime
6. triprolidine pseudoephedrine (Actifed):
• 2.5 mg triprolidine, 60 mg
pseudoephedrine; every 4-8 hours up to 4
doses/day
D. 2nd generation antihistamines
• 2nd generation antihistamines are more
selective for peripheral H1 receptors and
therefore, are not sedating or drying.
• They have equal antiallergic activity to 1st
generation drugs. 2nd generation
antihistamines include:
1. cetirizine (Zyrtec):
• 5 or 10 mg, once a day; available OTC
• If theophylline and Zyrtec are both
prescribed, the dose of theophylline will
probably need to be reduced.
• Zyrtec can be administered with either
erythromycin or ketaconazole, and does
not lead to an increased risk of heart
irregularities that is seen when these
drugs are taken with some of the other
2nd generation antihistamines.
• Zyrtec does cause sleepiness in about
14% of patients.
2. fexofenadine (Allegra):
• 60 mg bid, or 180 mg once daily, also
OTC
• Clinical studies indicate that coadministration with either erythromycin or
ketoconazole enhances Allegra
absorption, which increases the
bioavailability of Allegra.
•
• Aluminum/magnesium antacids may
decrease Allegra absorption, therefore
decreasing its effectiveness.
3. loratadine (Claritin):
• 10 mg/day, also OTC
4. azelastine (Astelin)
• Available, by prescription as a nasal spray
for treatment of allergic rhinitis.
5. desloratadine (Clarinex)
• 5 mg once daily