‫المملكة العربية السعودية‬

Kingdom of Saudi Arabia

Ministry of Education ‫وزارة التعليم‬
University of Hail ‫جامـعـة حـائل‬
Master of Science in Nursing ‫كلية التمريض‬

THE EICOSANOIDS: PROSTAGLANDINS, THROMBOXANES,

LEUKOTRIENES, & RELATED COMPOUNDS& NITRIC OXIDE AND
DRUGS FOR ASTHMA

Prepared by :
Amal Abdullah Al-harbi
master student in uoh –emergency
nursing

Supervisor:
Dr / Bahia Galal
Associate Professor-Medical –
surgical nursing
 OUTLINES

The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes,-1

& Related Compounds Chapter 18: Basic & Clinical

Pharmacology

:Basic & clinica pharmacology 2- nitric oxide Chapter 19

Drugs used in Asthma Chapter 20:Basic & clinica pharmacology-3

Chapter 18

The Eicosanoids: Prostaglandins, Thromboxanes,-1

Leukotrienes, & Related Compounds
 THE EICOSANOIDS
• The eicosanoids are oxygenation products of poly-unsaturated 20-
carbon fatty acids. They are found amply in the animal kingdom
and are also found in a variety of plants.
• They are highly potent and display an extraordinarily wide spectrum
of important biologic activities. Thus, their specific receptors,
• receptor ligands, and enzyme inhibitors are therapeutic targets for
a growing list of conditions .
 Basic Terms
• Cyclooxygenase (Cox) is an enzyme that catalyzes the conversion of
arachidonic acid to prostaglandins.
• Leukotrienes: They are inflammatory chemicals the body releases
after coming in contact with an allergen or allergy trigger.
• Lipoxygenase: LOX exists in a broad range of organisms, including
prokaryotes, fungi, plants (mosses and flowering plants), and
animals from the basal placozoan Trichoplax to primates.
 Arachidonic Acid & other Polyunsaturated Precursors
• Arachidonic acid (AA) is the most abundant of the eicosanoid precursors, it is a 20-carbon
(C20) fatty acid that contains four double bonds (designated C20:4–6).
• The first double bond in AA occurs at 6 carbons from the methyl end, defining AA as an
omega-6 fatty acid.
 Classes of Eicosanoids

• Prostaglandins,
• Thromboxanes,
• Leukotrienes
 Synthesis of Eicosanoids

Eicosanoids are synthesized by stereo- and regio-specific peroxidation of

arachidonic acid by three enzyme families namely lipoxygenases,

cyclooxygenases, and cytochrome P450 Lipid droplets and signaling lipids

 BASIC PHARMACOLOGY OF EICOSANOIDS
• The eicosanoids act mainly in an autocrine and a paracrine fashion, ie,
close to the site of their synthesis, and not as circulating hormones.
• These ligands bind to receptors on the cell surface, with pharmacologic
specificity determined by
• receptor density and type on different cells.
 Effects Of Prostaglandins & Thromboxanes
• The prostaglandins and thromboxanes have major effects on smooth muscle

in the vasculature, airways, and gastrointestinal and reproductive tracts.

• Many of the eicosanoids’ contractile effects on smooth muscle can be
inhibited by lowering extracellular calcium or by using calcium channel-
blocking drugs.
 Effects of Prostaglandins & Thromboxanes on Vascular
smooth muscles
• TXA2 is a smooth muscle cell mitogen and is the only eicosanoid that has
convincingly been shown to have this effect.
• The mitogenic effect is potentiated by exposure of smooth muscle cells to
testosterone, which up-regulates smooth muscle cell TP expression.
• Vasodilator prostaglandins, especially PGI2 and PGE2, promote vasodilation by
increasing cAMP( cyclic adenosine monophosphate) and decreasing smooth muscle
intracellular calcium.
• In the microcirculation, PGE2 is a vasodilator produced by endothelial cells.
• PGI2 inhibits proliferation of smooth muscle cells, an action that may be particularly
relevant in pulmonary hypertension.
 Effects of Prostaglandins & Thromboxanes
Gastrointestinal tract
• Most of the prostaglandins and thromboxanes activate gastrointestinal

smooth muscle.

• Longitudinal muscle is contracted by PGE2 (via EP3) and PGF2α (via FP),

whereas circular muscle is contracted strongly by PGF2α and weakly by

PGI2.

• Administration of either PGE2 or PGF2α results in colicky cramps.

• The leukotrienes also have powerful contractile effects.

Effects Of Prostaglandins & Thromboxanes On Airways
• Studies about DP1 and DP2 receptor suggest an important role of this
prostanoid in asthma.
• The cysteinyl leukotrienes act principally on smooth muscle in peripheral
airways and are a thousand times more potent than histamine, both in vitro
and in vivo.
• They also stimulate bronchial mucus secretion and cause mucosal edema.
• Bronchospasm occurs in about 10% of people taking NSAIDs, possibly
because of a shift in arachidonate metabolism from COX metabolism to
leukotriene formation.
Effects Of Prostaglandins & Thromboxanes on Platelets

• Platelet aggregation is markedly affected by eicosanoids.

• PGI2 is a potent inhibitor of platelet aggregation.
• Dysfunctional genetic variants in the human prostacyclin receptor as well as drug
inhibition of COX-2 lead to increased platelet activation and aggregation.
• This has recently been demonstrated to have major implications regarding adverse
cardiovascular events,
• TXA2 is a powerful inducer of platelet aggregation. TXA2 additionally amplifies the
effects of other, more potent, platelet agonists such as thrombin.
EFFECTS OF PROSTAGLANDINS & THROMBOXANES
ON KIDNEY
• The major renal eicosanoid products are PGE2 and PGI2, followed by PGF2α and
TXA2.
• The kidney also synthesizes several hydroxy-eicosatetraenoic acids, leukotrienes,
cytochrome P450 products, and epoxides.
• Prostaglandins play important roles in maintaining blood pressure and regulating
renal function, particularly in marginally functioning kidneys and volume-
contracted states.
• PGE2 and PGI2 maintain renal blood flow and glomerular filtration rate through
their local vasodilating effects.
• These prostaglandins also modulate systemic blood pressure through regulation of
water and sodium excretion.
effects of prostaglandins & thromboxane On reproductive
Organs
Female reproductive organs:
• Studies demonstrate a role for PGE2 and PGF2α in early reproductive processes such as
ovulation, luteolysis, and fertilization.
• Uterine muscle is contracted by PGF2α, TXA2, and low concentrations of PGE2; PGI2
and high concentrations of PGE2 cause relaxation.
• PGF2α, together with oxytocin, is essential for the onset of parturition.
• PGI2 also assists in promoting uterine smooth muscle cell maturation.
Male reproductive organs:
• The major source of prostaglandins is the seminal vesicle; the prostate, despite the name
“prostaglandin,” and the testes synthesize only small amounts.
• Thromboxane and leukotrienes have not been found in seminal fluid.
• Men with a low seminal fluid concentration of prostaglandins are relatively infertile.
Effects of Prostaglandins & Thromboxanes on central and
Peripheral Nervous Systems
Fever:
• PGE2 increases body temperature, predominantly via EP3,
• Exogenous PGF2α and PGI2 induce fever, whereas PGD2 and TXA2 do not.
• Endogenous pyrogens release interleukin-1, which in turn promotes the synthesis and
release of PGE2. This synthesis is blocked by aspirin, other antipyretic NSAIDs, and
acetaminophen.
Sleep:
• When infused into the cerebral ventricles, PGD2 induces natural sleep via activation of
DP1 receptors and secondary release of adenosine.
• PGE2 infusion into the posterior hypothalamus causes wakefulness.
• PGE2 contribute to so-called central sensitization, an increase in excitability of spinal
dorsal horn neurons, that augments pain intensity, widens the area of pain perception.
Effects Of Prostaglandins & Thromboxanes On Cancer
• There has been considerable interest in the role of prostaglandins in the development of
malignancies.
• Pharmacologic inhibition of COX-2 restrains tumor formation in models of colon, breast,
lung, and other cancers.
• Chronic low-dose aspirin does not have a substantial impact on cancer incidence;
however, it is associated with reduced cancer death.
• Polymorphisms in COX-2 have been associated with increased risk of some cancers.
• COX-2 expression is associated with markers of tumor progression in breast cancer.
• In mouse mammary tissue, COX-2 is oncogenic whereas NSAID use is associated with a
reduced risk of breast cancer in women, especially for hormone receptor-positive tumors.
• Data from animal models and epidemiologic studies in humans are consistent with a role
for COX-1 as well as COX-2 in the production of oncogenic prostanoids.
.
 Effects Of Lipoxygenase & Cytochrome p450-Derived
Metabolites

• Lipoxygenases generate compounds that can regulate specific cellular

responses that are important in inflammation and immunity.
• Cytochrome P450-derived metabolites affect nephron transport functions
either directly or via metabolism to active compounds.
• The biologic functions of the various forms of hydroxy- and
hydroperoxyeicosaenoic acids are largely unknown, but their
pharmacologic potency is impressive.
Effects Of Lipoxygenase & Cytochrome On Blood Cells and
Inflammation

• LTB4 is a potent chemo-attractant for T lymphocytes, neutrophils, eosinophils, and

monocytes.
• Cysteinyl leukotrienes contribute to inflammation by increasing endothelial
permeability, thus promoting migration of inflammatory cells to the site of
inflammation.
• The leukotrienes have been strongly implicated in the pathogenesis of inflammation,
especially in chronic diseases such as asthma and inflammatory bowel disease.
• Lipoxins have diverse effects on leukocytes, including activation of monocytes and
macrophages and inhibition of neutrophil, eosinophil, and lymphocyte activation.
 Effects of Lipoxygenase & Cytochrome On Heart and Smooth
Muscle
1. Cardiovascular:
• It play a role in myointimal proliferation that occurs after vascular injury such as that caused
by angioplasty.
• LTB4 may cause vasoconstriction as well as smooth muscle cell migration and proliferation,
possibly contributing to atherosclerosis and injury-induced neointimal proliferation.
• LTC4 and LTD4 reduce myocardial contractility and coronary blood flow, leading to
depression of cardiac output.
2. Gastrointestinal:
• Human colonic epithelial cells synthesize LTB4, a chemo-attractant for neutrophils.
• The colonic mucosa of patients with inflammatory bowel disease contains substantially
increased amounts of LTB4.
3. Airways:
• The cysteinyl leukotrienes, particularly LTC4 and LTD4, are potent broncho-constrictors and
cause increased micro- vascular permeability, plasma exudation, and mucus secretion in the
airways.
• LTC4-specific receptors have not been found in human lung tissue, whereas both high- and
low-affinity LTD4 receptors are present.
EFFECTS OF LIPOXYGENASE & CYTOCHROME
ON KIDNEY
• There is substantial evidence for a role of the epoxygenase products in
regulating renal function.
• Both 20-HETE and the EETs are generated in renal tissue.
• 20-HETE has been implicated in the pathogenesis of hypertension.
• In contrast, studies support an antihypertensive effect of the EETs.
• EETs increase renal blood flow and may protect against inflammatory
renal damage by limiting glomerular macrophage infiltration.
 Pharmacology Of Eicosanoids
• Enzyme inhibitors and receptor antagonists have been developed to
interfere with the effects of the eicosanoids.
• The discovery of COX-2 as a major source of inflammatory prostanoids led
to the development of selective COX-2 inhibitors to preserve the
gastrointestinal and renal functions directed through COX-1, thereby
reducing toxicity.
Eicosanoids Role in Abortion
• Prostaglandins may terminate pregnancy at any stage by promoting uterine
contractions.
• The drugs are used for first- and second-trimester abortion and for priming
or ripening the cervix before abortion.
• Dinoprostone, a synthetic preparation of PGE2, is administered vaginally for
inducing abortion in the second trimester of pregnancy.
• Dinoprostone is metabolized in local tissues and on the first pass through the
lungs (about 95%). The metabolites are mainly excreted in the urine. The
plasma half-life is 2.5–5 minutes.
• For abortion, the recommended dosage is a 20-mg dinoprostone repeated at 3-
to 5-hour intervals, depending on the response of the uterus. The mean time to
abortion is 17 hours, but in more than 25% of cases, the abortion is
incomplete and requires additional intervention.
 Eicosanoids Effect on Cardiovascular System
• PGI2 has been used to treat pulmonary hypertension arising from primary
lung disease and that arising from heart or systemic diseases.
• Prostacyclin has been used successfully to treat porto-pulmonary
hypertension, which arises secondary to liver disease.
• The first commercial preparation of PGI2 approved for treatment of
pulmonary hypertension (epoprostenol) improves symptoms, prolongs
survival, and delays or prevents the need for lung or lung-heart
transplantation.
• Side effects include headache, hypotension, nausea, and diarrhea
 Eicosanoids Effect On Respiratory System
• PGE2 promotes coughing, whereas PGF2α and TXA2 are both strong
bronchoconstrictors.
• leukotriene-receptor inhibitors (eg, zafirlukast, montelukast) are effective in
asthma.
• A lipoxygenase inhibitor (zileuton) has also been used in asthma but is not as
popular as the receptor inhibitors.
• Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit
eicosanoid synthesis and thus limit the amounts of eicosanoid mediator
available for release.
• Cromolyn appears to inhibit the release of eicosanoids and other mediators such
as histamine and platelet-activating factor from mast cells.
 Eicosanoids Effect On Gastrointestinal System
• Prostaglandins have a protective effect against peptic ulcers.
• PGE compounds protect against peptic ulcers produced by either steroids or NSAIDs.
• Misoprostol, a synthetic analog of PGE1 protects against NSAID-induced peptic ulcers
at low doses.
• Misoprostol inhibits gastric acid secretion at higher doses.
• Misoprostol is also a pregnancy category X drug.
• Misoprostol use is low, probably because of its adverse effects including abdominal
discomfort and occasional diarrhea.
• Dose-dependent bone pain and hyperostosis have been described in patients with liver
disease who were given long-term PGE treatment.
 SUMMARY
• There are multiple subfamilies of eicosanoids, including the
prostaglandins, thromboxanes, leukotrienes and lipoxins.
• Eicosanoids function in diverse physiological systems and pathological
processes such as: inhibiting inflammation, allergy, fever and other
immune responses; regulating the abortion of pregnancy and normal
childbirth; contributing to the perception of pain; regulating cell growth;
controlling blood pressure,
• Prostacyclin have been shown to be effective in the treatment of pulmonary
hypertension. Multiple formulations are now available including intravenous,
inhalational, and more recently, oral.
CHAPTER 19
NITRIC OXIDE
 AN OVERVIEW

Nitric oxide (NO) is a gaseous molecule that diffuses across cell membranes and
regulates a wide range of physiologic and pathophysiologic processes including
cardiovascular, inflammatory, and neuronal functions.
OXIDES OF NITROGEN

Name Structure Known Function

Nitric oxide (NO) •N=O Vasodilator, platelet inhibitor, immune regulator,
neurotransmitter,
Peroxynitrite (NO −) −O=N−O−O Oxidant and nitrating agent
Nitroxyl anion (NO−) N−=O Can form from nonspecific donation of an electron from
metals to NO
Exhibits NO-like effects, possibly by first being oxidized to
NO

Nitrous oxide (N O) N−=N+=O Anesthetic

Dinitrogen trioxide (N O=N−N+=O Auto-oxidation product of NO that can nitrosylate protein

O)   thiols
−O

Nitrite (NO −) −O=N=O Stable oxidation product of NO

Slowly metabolized to nitrosothiols, and decomposes to NO
at acidic pH

Nitrate (NO −) −O=N+−O Stable oxidation product of NO

−O 
 Mechanism in Body
There are three major targets of Nitric Oxide:
1. Metalloproteins:
• Nitric Oxide interacts with metals, especially iron in hemoglobin.
• Nitric Oxide also has cytotoxic effects, especially when it is produced at high levels, eg, in activated
macrophages.
2. Thiols—
• Nitric Oxide reacts with thiols to form nitrosothiols. In proteins, the thiol moiety is found in the
amino acid cysteine.
3. Tyrosine Nitration:
• The immune system cells produce large amounts of Nitric Oxide.
• Nitric Oxide undergoes both oxidative and reductive reactions.
• Nitric Oxide reacts very efficiently with superoxide to form peroxynitrite (ONOO–), a highly reactive
oxidant that leads to DNA damage.
 Pharmacologic Characteristics Of Nitric Oxide

• Nitric Oxide can be used therapeutically. Inhalation of Nitric Oxide results in reduced
pulmonary artery pressure and improved perfusion of ventilated areas of the lung.
• Inhaled Nitric Oxide is used for pulmonary hypertension, acute hypoxemia, and
cardiopulmonary resuscitation, and improvements in pulmonary function.
• Nitric Oxide enzyme inhibitors have efficacy in diseases such as inflammatory conditions,
sepsis, and neurodegenerative diseases.
• Nitric Oxide (NO) donors are used clinically to elicit smooth muscle relaxation.
• Sodium Nitroprusside is used for rapid pressure reduction in arterial hypertension.
Vascular Effects Of Nitric Oxide
• Nitric Oxide (NO) has a significant effect on vascular smooth muscle tone and blood
pressure.
• Nitric Oxide diffuses to vascular smooth muscle, leading to vaso-relaxation.
• NO may have an additional inhibitory effect on blood coagulation.
• NO also protects against atherogenesis.
• NO reduces the ability of monocytes and leukocytes to adhere to endothelial
cells, which is an early step in the development of atheromatous plaques.
 Role of Nitric Oxide in Inflammation and Infection

• Nitric Oxide also appears to play an important protective role in the body via
immune cell function.
• Nitric Oxide (NO) stimulates the synthesis of inflammatory prostaglandins by
activating cyclooxygenase isoenzyme 2 (COX-2).
• Through its effects on COX-2, its direct vasodilatory effects, and other
mechanisms, NO generated during inflammation contributes to the erythema,
vascular permeability, and subsequent edema associated with acute inflammation.
 ROLE OF NITRIC OXIDE IN CENTRAL NERVOUS SYSTEM
• Nitric Oxide (NO) has an important role in the central nervous system as a
neurotransmitter.
• Unlike classic transmitters such as glutamate or dopamine, Nitric Oxide is not stored, but
rather is synthesized and immediately diffuses to neighboring cells.
Role of Nitric Oxide in peripheral Nervous system
• Penile erection is thought to be caused by the release of Nitric Oxide from NANC(non-
adrenergic non-cholinergic) neurons;
• Nitric Oxide promotes relaxation of the smooth muscle in the initiating factor in penile
erection—and inhibitors of NOS have been shown to prevent erection caused by pelvic
nerve stimulation in the rat.
• An established approach in treating erectile dysfunction is to enhance the effect of Nitric
Oxide signaling by inhibiting the breakdown of cGMP.
Role of Nitric Oxide In Respiratory Disorders
• Nitric Oxide inhalation dilates pulmonary vessels, resulting in decreased pulmonary
vascular resistance and reduced pulmonary artery pressure.
• Inhaled Nitric Oxide also improves oxygenation by reducing mismatch of ventilation and
perfusion in the lung.
• Inhalation of NO results in dilation of pulmonary vessels in areas of the lung with better
ventilation, thereby redistributing pulmonary blood flow away from poorly ventilated
areas.
SUMMARY
Subclass, Drug Mechanism of Effects  Clinical  Pharmacokinetics,
Action Applications Toxicity, Interactions
NITRIC OXIDE NO activates Vasodilator • Hypoxic Inhaled gas
)NO( soluble relaxes other • respiratory Toxicity
guanylyl cyclase smooth muscle failure and Methemoglobinemia
to elevate inhalation of NO • pulmonary
cGMP levels in leads to increased hypertension
vascular blood flow to
smooth muscle parts of the lung
exposed to NO
and decreased
pulmonary
vascular
resistance
CHAPTER 20:
DRUGS USED IN ASTHMA
 INTRODUCTION
• A consistent increase in the prevalence of asthma over the past 60 years has made it an
extraordinarily common disease.
• The global estimate of the number of affected individuals is 300 million.
• In the United States alone, 17.7 million adults (7.4% of the population) and 6.3 million
children (8.6% of the population) have asthma.
• Considering the disease’s prevalence, the annual mortality in the USA is low—
around 3500 deaths—but many of these deaths are considered preventable, and the
number has not changed much despite improvements in treatment.
 Pharmacology Of Agents used in the
Treatment Of Asthma

• The drugs most used for asthma management are adrenoceptor

agonists or sympathomimetic agents, and inhaled corticosteroids.
• Adrenoceptor agonists are instrumental in the treatment of
asthma.
 EPINEPHRINE
• Epinephrine is used to treat wheezing and shortness of breath that commonly
occur with asthma. Controlling these symptoms can decrease time lost from work
or school. Epinephrine belongs to a class of drugs known as bronchodilators.
• Epinephrine is an effective bronchodilator when injected subcutaneously or
inhaled. Maximal bronchodilation is achieved within 15 minutes after inhalation
and lasts 60–90 minutes.
• Its current use is for treatment of the acute vasodilation and bronchospasm of
anaphylaxis.
 EPHEDRINE
• Ephedrine is used for temporary relief of shortness of breath, chest tightness, and
wheezing due to bronchial asthma.
• Ephedrine is a decongestant and bronchodilator. It works by reducing swelling
and constricting blood vessels in the nasal passages and widening the lung airways,
allowing patient to breathe more easily.
• Compared with epinephrine, ephedrine has a longer duration, oral activity, more
central effects, and much lower potency.
• The most important side effect hypertension
 ISOPROTERENOL
• Isoproterenol is a potent bronchodilator.
• 80–120 mcg of isoproterenol causes maximal bronchodilation within 5 minutes and
has a 60- to 90-minute duration of action.
• An increase in asthma mortality in the United Kingdom in the mid-1960s was
attributed to cardiac arrhythmias resulting from the use of high doses of inhaled
isoproterenol.
 BETA2-SELECTIVE DRUGS
• β2-selective adrenoceptor drugs, particularly albuterol, are the most widely used
medications for the treatment of acute asthma.
• These drugs differ structurally from epinephrine in having a larger substitution on
the amino group and in the position of the hydroxyl groups on the aromatic ring.
• They are effective after inhaled or oral administration and have a longer duration
of action than epinephrine or isoproterenol.
VARIANTS OF BETA2 DRUGS
BETA2
• Albuterol, terbutaline, metaproterenol, and pirbuterol are available as inhalers for
asthma.
• They are administered by inhalation, these agents cause bronchodilation within
within 15 minutes of administration and persists for 3–4 hours.
• Albuterol and terbutaline are also available in oral form. One tablet, two or three
times daily is the usual regimen;
• the principal adverse effects are skeletal muscle tremor, nervousness, and
occasional weakness.
 Methylxanthine Drugs
• The three important methylxanthines are theophylline, theobromine, and
caffeine.
• Their major source is beverages (tea, cocoa, and coffee, respectively).
• The use of theophylline has almost ceased with demonstration of the
greater efficacy of inhaled adrenoceptor agonists for acute asthma and of
inhaled anti-inflammatory agents for chronic asthma.
• Also, theophylline is toxic, it causes (nausea, vomiting, trembling).
• Despite these disadvantages of theophylline, it is still used in some
countries because of its low cost.
 Pharmacodynamics Of Methylxanthine Drugs
• The methylxanthines have effects on the central nervous system, kidney,
and cardiac and skeletal muscle as well as smooth muscle.
• Of the three agents, theophylline is most selective in its smooth muscle
effects, whereas caffeine has the most marked central nervous system
effects.
• All methylxanthines, particularly caffeine, cause increased alertness and
deferral of fatigue. The caffeine contained in beverages, approximately
100 mg in a cup of coffee, cause nervousness and insomnia in individuals
and slight bronchodilation in patients with asthma.
 Anti-Muscarinic Drugs
• Antimuscarinic agents are effective bronchodilators
• Ipratropium is a potent bronchodilator.
• Ipratropium appears to be as effective as albuterol in patients with COPD(chronic
obstructive pulmonary disease )
• Longer-acting antimuscarinic agents, includes tiotropium, umeclidinium and
aclidinium.
• Daily inhalation of tiotropium has been shown not only to improve functional
capacity of patients with COPD, but also to reduce the frequency of exacerbations
of their condition.
CORTICOSTEROIDS
• Corticosteroids have long been used in the treatment of asthma and work by inhibition
of production of inflammatory cytokines.
• They do not relax airway smooth muscle directly but reduce bronchial hyperactivity
and reduce the frequency of asthma exacerbations if taken regularly.
• Their effect on airway obstruction is due to the inhibition of the infiltration of
asthmatic airways by lymphocytes, eosinophils, and mast cells.
• The remarkable benefits of systemic glucocorticoid treatment for patients with severe
asthma have been noted since the 1950s.
• They have toxic effect, especially when given repeatedly, as is necessary for a chronic
disease like asthma.
CROMOLYN & NEDOCROMIL
• Cromolyn sodium and nedocromil sodium were once widely used for asthma
management, especially in children, but have now been replaced by other
therapies.
• These drugs are thought to act by inhibiting mast cell and, as such, have no direct
bronchodilator action.
• When taken regularly
• these agents reduce symptomatic severity and the need for bronchodilator
medications, particularly in young patients with allergic asthma.
• These drugs are poorly absorbed into the systemic circulation and have little
toxicity, but are not as potent as some newly discovered drugs.
LEUKOTRIENE PATHWAY INHIBITORS
• The involvement of leukotrienes in many inflammatory diseases and in
anaphylaxis prompted the development of drugs that block their synthesis or
interaction with their receptors.
• zileuton, zafirlukast and montelukast, have been shown to improve asthma
control and to reduce the frequency of asthma exacerbations in clinical trials.
• They are not as effective as even low-dose ICS( inhaled corticosteroid) therapy in
inducing and maintaining asthma control, but are preferred by many patients,
especially by the parents of asthmatic children, because of often exaggerated
concerns over the toxicities of corticosteroids.
• They have the additional advantage of being effective when taken orally, which is
an easier route of administration than aerosol inhalation in young children.
MONOCLONAL ANTIBODIES FOR USE IN ASTHMA
MONOCLONAL ANTIBODIES USED IN ASTHMA TO DECREASE THE
IMUNOGLOBULINS AND CTYOKINED INVOLVED IN STHMNA

Antibody Name Isotype Target

Omalizumab Humanized IgG1 IgE
Mepolizumab Humanized IgG1 IL-5
Benralizumab Humanized IgG1 IL-5 receptor
Reslizumab Humanized IgG4 IL-5
Lebrikizumab Humanized IgG4 IL-13 (IL-4 receptor- binding epitope)
GSK679586 Humanized IgG1 IL-13 receptors α1, α2

Tralokinumab Humanized IgG4 IL-13 receptors α1, α2

Dupilumab Humanized IgG4 IL-4 receptor

Pharmacology Of Drugs used in The Treatment Of Asthma: Bronchodilators
 Bronchodilators, such as inhaled albuterol, are rapidly effective, safe, and inexpensive.
 Patients with only occasional symptoms of asthma require no more than an inhaled
bronchodilator taken on an as-needed basis.
 If symptoms require this therapy more than twice a week, if nocturnal symptoms
occur more than twice a month, additional treatment is needed.
 All patients with asthma should be instructed in a simple action plan for severe,
frightening attacks: to take up to four puffs of albuterol every 20 minutes over 1 hour.
 If no improvement is noted after the first four puffs, additional treatments should be
taken while on the way to an emergency department or other higher level of care.
 Pharmacology of Drugs used in The Treatment of Asthma: Muscarinic Antagonists

• Inhaled muscarinic antagonists occupy a limited place in the treatment of asthma.

• They are used largely as alternative therapies for patients intolerant of β-adrenoceptor agonists.
• The airway effects of antimuscarinic drugs given in full doses have been shown to be affective
only in reducing hospitalization rates in patients with severe airflow obstruction.
• The long-acting antimuscarinic agents tiotropium and aclidinium have not yet earned a place in
the treatment for asthma, although the addition of tiotropium to an ICS has been shown to be
effective.
• As a treatment for COPD, these agents improve functional capacity, and reduce the frequency of
exacerbations.
 Pharmacology of Drugs used in The Reatment of Asthma:
Corticosteroids
• If asthmatic symptoms occur frequently, or if significant airflow obstruction persists despite
bronchodilator therapy, inhaled corticosteroids should be started.
• For patients with severe symptoms or severe airflow obstruction, initial treatment with a
high dose of an ICS is appropriate.
• Once clinical improvement is noted, usually after 4–6 weeks, the dose of treatment should
be stepped down.
• An issue for ICS treatment is patient adherence. Only a minority of patients take
corticosteroids regularly. This may be a function of a general “steroid phobia” fostered by
emphasis on the hazards of long-term oral corticosteroid therapy and by ignorance of the
difference between glucocorticoids and anabolic steroids,
Pharmacology of Drugs used in the Treatment of Asthma: Leukotriene
Antagonists; Cromolyn & Nedocromil

• Although cromolyn and nedocromil are not as effective as a low dose of an ICS, both avoid
the issue of “steroid phobia” described above and are commonly used in the treatment of
children.
• The leukotriene receptor antagonist montelukast is the most widely prescribed of these
treatments, especially by primary care providers.
• This drug, taken orally, is easy to administer and is rarely associated with troublesome
adverse effects.
• leukotriene is widely used for treating children in the USA, particularly those who have
concurrent symptomatic allergic rhinitis.
 SUMMARY
• Albuterol: its mechanism of action is through Selective β2 agonist, it causes efficacious
bronchodilation.
• Salmeterol : mechanism of action through Selective β2 agonist, it causes efficacious
bronchodilation.
• Epinephrine: its mechanism of action is through nonselective α and β agonist, it causes
Bronchodilation plus effects on cardiovascular and other organ systems.
• Isoproterenol: its mechanism of action is through β1 and β2 agonist, , it causes
Bronchodilation plus powerful cardiovascular effects.
• CORTICOSTEROIDS (Fluticasone) its mechanism of action is through altering gene
expression, it reduces mediators of inflammation.
• Cromolyn, nedocromi: its mechanism of action is through altering function of delayed
chloride channels and inhibiting inflammatory cell activation
 REFRENCES
Chapter 18: Basic & Clinica Pharmacology -1
:Basic & clinica pharmacology 2 - Chapter 19
Chapter 20:Basic & clinica pharmacology - 3
Thank you