PHARMACOLOGY

PHARMA-LC32-DRUGS WITH IMPORTANT ACTIONS ON

SMOOTH MUSCLES PART 2

LECTURE OUTLINE
I. THE EICOSANOIDS: PROSTAGLANDINS, THROMBOXANES,
LEUKOTRIENES, & RELATED COMPOUNDS
A. Products of the Arachidonate Series
B. Inhibition of Eicosanoid Synthesis
C. Clinical Pharmacology of Eicosanoids
II. NITRIC OXIDE
III. DRUGS USED IN ASTHMA
A. Sympathomimetic Agents
B. Beta 2-Selective Drugs
C. Methylxanthine Drugs
D. Antimuscarinic Agents
E. Corticosteroids
F. Leukotriene Pathway Inhibitors
IV. TEST YOURSELF
V. REFERENCES Figure 2. The synthesis of the major arachidonic acid metabolites.
VI. APPENDIX These two (cyclooxygenase and lipoxygenase pathway) are the most
important pathways of arachidonic acid.
I. THE EICOSANOIDS: PROSTAGLANDINS, THROMBOXANES,
LEUKOTRIENES, & RELATED COMPOUNDS Cyclooxygenase Pathway
• Results in the production of different prostaglandins,
Eicosanoids – also known as the “prostanoids”
prostacyclins, and the thromboxane A2
• Includes prostaglandins, leukotrienes, and prostacyclins
Lipooxygenase Pathway
• For leukotrienes and lipoxins

FOCUS ON CYCLOOXYGENASE PATHWAY

Two unique COX isozymes convert AA into prostaglandin
endoperoxides:
1. PGH (Prostaglandin H) synthase-1 (COX-1)
• Expressed constitutively in most cells
• Generates prostanoids for “housekeeping” functions, such as
gastric epithelial cytoprotection
• Produce prostanoids on basal condition
2. PGH synthase-2 (COX-2)
• Readily inducible, its expression levels being dependent on the
stimulus
• Upregulated during inflammation
• Major source of prostanoids

Figure 1. Pathways of arachidonic acid (AA) release and metabolism.

Prostanoids are from the 20-carbon arachidonic acid (arachidonic
acid comes from membrane phospholipids). A chemical stimulus will
stimulate the phospholipase A2 to release arachidonic acid. The
arachidonic acid will have its 4 pathways (1 – can be hydroxylised
into the cyclooxygenase pathway; 2, 3 – hydroxylised enzymatically
via lipoxygenase pathway or P450 pathway; and 4 – non-
enzymatically via the isoeicosanoid pathway). Note the importance
of cyclooxygenase and lipoxygenase pathway.

Figure 3. COX-1 and COX-2 pathways.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• Exert their therapeutic effects through inhibition of the COXs
• Non-Selective COX inhibitors:
o Indomethacin, Sulindac, Meclofenamate and Ibuprofen

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 • Selective COX-2 inhibitors:
o Celecoxib = Diclofenac = Meloxicam = Etodolac <
Valdecoxib << Rofecoxib < Lumiracoxib = Etoricoxib
(increasing COX-2 selectivity, therefore the most
selective would be the Lumiracoxib and Etoricoxib)
• Aspirin
o Acetylates and inhibits both enzymes (COX 1 and 2)
covalently and hence irreversibly
Figure 4. The roles of arachidonic acid metabolites in inflammation.
Vasodilation: PGD2, PGE2, PGF2α , Prostacyclin, Lipoxin A4 & B4
Vasoconstriction: Thromboxane A2, Leukotriene C4, D4 & E4
Bronchodilation: PHD2, PGE2 and prostacyclin
Bronchoconstriction: PGF2α, Thromboxane A2, Leukotriene C4, D4
& E4
Promotes platelet aggregation: Thromboxane A2
Inhibits platelet aggregation: Prostacyclin
Chemoattractant: Leukotriene B4
Inhibits chemotaxis: Lipoxin A4 & B4
Lipooxygenase pathway is important in asthmatic conditions.
Prostaglandins also mediate pain and fever which are the
important systemic manifestation of inflammation.
A. PRODUCTS OF THE ARACHIDONATE SERIES
Alprostadil (PGE1)
• Used for its smooth muscle relaxing effects to maintain the
ductus arteriosus patent in some neonates awaiting cardiac
surgery and in the treatment of impotence
Misoprostol (Cytotec)
• PGE1 derivative
• Cytoprotective prostaglandin used in preventing peptic ulcer
and in combination with Mifepristone (RU-486) for
terminating early pregnancies
Dinoprostone (PGE2) and PGF2α
• Used in obstetrics to induce labor
Latanoprost
• Topically active PGF2α derivatives used in ophthalmology to
reduce intraocular pressure in open-angle glaucoma or ocular
hypertension
Prostacyclin (PGI2)
• Synthesized mainly by the vascular endothelium
• Powerful vasodilator and inhibitor of platelet aggregation
Epoprostenol, Iloprost, Treprostinil
• Treat pulmonary hypertension
B. INHIBITION OF EICOSANOID SYNTHESIS
Corticosteroids
• Block all the known pathways of eicosanoid synthesis
• Inhibit phospholipase A2 activity
o Arachidonic acid production is ceased, eventually, no
production of prostanoids
• In cases of arthritis or asthmatic conditions, which are all
inflammation, steroids are given in order to block eicosanoid
synthesis.
NSAIDs
• Block both prostaglandin and thromboxane formation by
reversibly inhibiting COX activity
• Aspirin: an irreversible COX inhibitor
LOX inhibitors (Zileuton, Zafirlukast, Montelukast, and Pranlukast)
• Mild to moderate asthma
C. CLINICAL PHARMACOLOGY OF EICOSANOIDS
Dinoprostone
• Synthetic preparation of PGE2
• Administered vaginally (vaginal suppository) for oxytocic use
• Induction of labor or softening of the cervix
• 20-mg dinoprostone vaginal suppository repeated at 3- to 5-
hour intervals depending on the response of the uterus
Mifepristone (Antiprogestins) + Misoprostol (oral oxytocic
synthetic analog of PGE1)
• Early legal abortion
• Vaginal route: sepsis
• Cramping pain and diarrhea
Carboprost tromethamine
• Analog of PGF 2α
• Induce second trimester abortions and to control or prevent
postpartum hemorrhage
o 1st choice for postpartum hemorrhage: Oxytocin
o 2nd choice: Methylergonovine (methergine)
o 3rd choice: Carboprost, however, it is contraindicated in:
- Patients with history of asthma because it can lead
to bronchoconstriction
- Patients who are febrile because it will further
elevate the body temperature
• Transient bronchoconstriction and temp elevation
Dysmenorrhea
• Happens due to increase in PGE2 and PGF2α during
menstruation
• NSAIDs inhibit formation of PG
Alprostadil (derivative of PGE1)
• Erectile dysfunction
• Intracavernosal injection: 2.5–25 mcg
• Transurethral suppository: 125 mcg or 250 mcg, up to 1000
mcg
• Prolonged erection and priapism
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Epoprostenol (derivative of PGI2)
• Pulmonary Hypertension
• Lowers peripheral, pulmonary, and coronary vascular
resistance
Iloprost, Treprostinil, Selexipag, Treprostinil
• Prostacyclin analogs with longer half-lives
Patent Ductus Arteriosus
• Transposition of the great arteries, pulmonary atresia,
pulmonary artery stenosis
o Important to maintain the patency of the neonate’s
ductus arteriosus until corrective surgery can be
carried out
• Alprostadil (PGE1): vasodilator and an inhibitor of platelet
aggregation. Alprostadil (or any prostaglandins) is given in
order to make the ductus arteriosus patent before surgical
correction.
Delayed closure of the ductus arteriosus
• Indomethacin: inhibit synthesis of PGE2 and so, close the
ductus
TXA2
• Promotes platelet aggregation
PGI2, PGE2 and PGD2
• Inhibit aggregation
Aspirin:
• NSAIDs can either be COX-1 or COX-2 inhibitors, except for
aspirin which selectively and irreversibly inhibits both the
platelet COX-1 and COX-2, resulting to the inhibition of its
dominant product TXA2
• Cardiovascular events (MI, angina pectoris)
• Inhibit platelet aggregation
o Patients who complain for chest pain or chest heaviness,
and on ECG there is MI, aspirin (4 tablets) can be given
to be chewed by the patient → inhibit platelet
aggregation and relieve angina pectoris
“Cytoprotection”
• Remarkable protective effect of the E prostaglandins against
peptic ulcers
• Enprostil, Misoprostol
Latanoprost, Bimatoprost, Travoprost
• PGF 2α derivative used for glaucoma
• Drops into the conjunctival sac once or twice daily
Bimatoprost
• Treatment of eyelash hypertrichosis
II. NITRIC OXIDE
Not the same with:
• Nitrous Oxide (N2O) which is a volatile anesthetic
• Nitrogen Dioxide (NO2) which is a toxic pulmonary irritant gas
Mechanism of Action:
• Activates soluble guanylyl cyclase to elevate cGMP levels in
vascular smooth muscle
Effects:
• Vasodilation
• Relaxes other smooth muscle
• Inhalation of NO leads to:
o Increased blood flow to parts of the lung exposed to NO
- Nitric oxide can be given in cases of constricted
blood vessels due to deposition of lipid material or
platelet aggregates (VASODILATORY EFFECT)
o Decreased pulmonary vascular resistance
NITRIC OXIDE DONORS
1. ORGANIC NITRATES
A. Nitroglycerin
• Dilates veins and coronary arteries
• Metabolized to NO by mitochondrial aldehyde reductase,
an enzyme enriched in venous smooth muscle, accounting
for the potent venodilating activity
• Antianginal effects (venous dilation decreases cardiac
preload and coronary artery dilation)
B. Isosorbide dinitrate (Isordil)
• Sublingual, given if the patient is having a myocardial
infarction
Both are used for anginal conditions
➢ Decrease the cardiac preload and
➢ Dilate the coronary arteries
2. ORGANIC NITRITES
Amyl nitrite
• Antianginal inhalant
• Arterial vasodilators
• Euphoric effects
• + Sildenafil = can cause lethal hypotension
o Given commonly for elderly patients with erectile
dysfunction/impotence. But note if there is a history
of MI or angina, wherein sildefanil is contraindicated.
- Elderlies who took sildenafil for sexual
intercourse will have heart attack.
3. Sodium Nitroprusside
• Dilates arterioles and venules
• For rapid pressure reduction in arterial hypertension
4. NO Gas Inhalation
• Reduced pulmonary artery pressure and improved perfusion
of ventilated areas of the lung
• Pulmonary hypertension, acute hypoxemia, and
cardiopulmonary resuscitation
III. DRUGS USED IN ASTHMA
FOCUS ON LIPOOXYGENASE PATHWAY
PATHOGENESIS OF ASTHMA
• Mediated by immune globulin (IgE)
• Produced in response to exposure to foreign proteins (house
dust mite, cockroach, animal danders, molds and pollens)
• IgE binds to high affinity receptors (FCεR-1) on mast cells in
the airway mucosa
• Re-exposure to the allergen triggers the release of mediators
stored in the mast cells’ granules and the synthesis and release
of other mediators
Early asthmatic response
• Histamine, tryptase, leukotrienes C4 and D4 and prostaglandin
D2 released cause the smooth muscle contraction and
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 vascular leakage responsible for the acute • More pronounced adverse effects and is thus rarely
bronchoconstriction prescribed
Late asthmatic response Terbutaline
• Sustained phase of bronchoconstriction • Subcutaneous injection (0.25 mg)
• Influx of inflammatory cells into the bronchial mucosa and • Sometimes used to inhibit the uterine contractions associated
with an increase in bronchial reactivity with premature labor
• Due to cytokines characteristically produced by T2 Long-acting β2-selective agonists (LABA)
lymphocytes, especially interleukins (IL) 5, 9, and 13 • 12-hour durations of action (high lipid solubility)
• Cytokines • Salmeterol and Formoterol
o Attract and activate eosinophils • No anti-inflammatory action
o Stimulate IgE production by B lymphocytes • Not be used as monotherapy for asthma
o Stimulate mucus production by bronchial epithelial cells • Used for nebulization
• Corticosteroid therapy: inhibition of the production of Ultra-long-acting β agonists
proinflammatory cytokines in the airways • IIndacaterol, Olodaterol, Vilanterol, and Bambuterol
o E.g., Hydrocortisone, Prednisone in order to inhibit the
TOXICITIES OF BETA 2-SELECTIVE DRUGS
inflammatory cytokines in the airways
o Blocks the arachidonic acid pathways • Decreased arterial oxygen tension (PaO2):
o Tx: supplemental oxygen
A. SYMPATHOMIMETIC AGENTS • Cardiac arrhythmias
Adrenoceptor Agonists • Tachyphylaxis
• Mainstays in the treatment of asthma
C. METHYLXANTHINE DRUGS
• Binding to β-adrenergic receptors: stimulates adenylyl cyclase
and increases the formation of intracellular Camp • Theophylline (tea), Theobromine (cocoa) and Caffeine
o Relaxes airway smooth muscle and inhibits release of (coffee)
bronchoconstricting mediators from mast cells MOA:
• Inhibit microvascular leakage and increase mucociliary 1. High concentration: inhibit phosphodiesterase enzyme,
transport, improving the airways thereby increasing concentrations of intracellular cAMP
• AE: tachycardia, skeletal muscle tremor, decreases in serum ▪ Cyclic AMP:
potassium levels ➢ Stimulation of cardiac function
o Chronic use leads to constipation ➢ Relaxation of smooth muscle
• Isoproterenol, Terbutaline, Metaproterenol, Albuterol ➢ Reduction in the immune and inflammatory activity of
(salbutamol) specific cells
Epinephrine 2. Inhibition of cell surface receptors for adenosine
3. Enhancement of histone deacetylation
• Injected subcutaneously (0.4 mL of 1:1000 solution) or
• Inhaled as a microaerosol from a pressurized canister (320 PHARMACODYNAMICS
mcg per puff) – patients with asthma can be nebulized using • Mild cortical arousal with increased alertness and deferral of
epinephrine + saline solution fatigue (caffeine)
• Maximal bronchodilation is achieved within 15 min after • Positive chronotropic and inotropic effects → tachycardia
inhalation and lasts 60–90 min • Arrhythmias
• Stimulates α, β1, β2 receptors: tachycardia, arrhythmias, and • Decrease blood viscosity (pentoxifylline)
worsening of angina pectoris • Stimulate secretion of gastric acid and digestive enzymes
Isoproterenol • Weak diuretics (theophylline)
• Nonselective β1 and β2 bronchodilator • Improve the ventilatory response to hypoxia and to diminish
• When inhaled: 80–120 mcg isoproterenol causes maximal dyspnea
bronchodilation within 5 minutes and has a 60- to 90-min D. ANTIMUSCARINIC AGENTS
duration of action
MOA
• AE: Tachycardia, cardiac arrhythmias
• Competitively inhibit the action of acetylcholine at muscarinic
B. BETA 2-SELECTIVE DRUGS receptors
ANTICHOLINERGIC AGENTS
Albuterol, Terbutaline, Metaproterenol and Pirbuterol
Atropine:
• Metered-dose inhalers
• Bronchodilator
Albuterol and Terbutaline
• Potent competitive inhibitor of acetylcholine at postganglionic
• Available in oral form muscarinic receptors
• AE: skeletal muscle tremor, nervousness, and occasional • Can cross the blood-brain barrier
weakness o Sedation as side effect
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Ipratropium 3. Inflammation is a complex tissue reaction that includes the
• Potent atropine analog/derivative release of cytokines, leukotrienes, prostaglandins, and peptides.
• When nebulized, the effect will be profound tachycardia (HR Prostaglandins involved in inflammatory processes are typically
can reach up to 120 bpm) because of their anticholinergic produced from arachidonic acid by which of the following
activity. enzymes?
a. Cyclooxygenase-1
E. CORTICOSTEROIDS b. Cyclooxygenase-2
MOA c. Glutathione-S-transferase
• Inhibition of production of inflammatory cytokines d. Lipoxygenase
o Inhibits phospholipase A2 enzyme to stop arachidonic e. Phospholipase A2
acid production 4. Which of the following is a recognized effect of nitric oxide (NO)?
• Do not relax airway smooth muscle directly, but reduce a. Arrhythmia
bronchial hyperreactivity and reduce the frequency of asthma b. Bronchoconstriction
exacerbations c. Constipation
• Contraction of engorged vessels in the bronchial mucus d. Inhibition of acute graft rejection
• Potentiation of the effects of β-receptor agonists e. Pulmonary vasodilation
• Inhibition of the infiltration of asthmatic airways by 5. Oral medications are popular for the treatment of asthma in
lymphocytes, eosinophils, and mast cells children because young children may have difficulty with the
proper use of aerosol inhalers. Which of the following is an
Prednisone: 30–60 mg/day per orem
orally active inhibitor of leukotriene receptors?
Methylprednisolone: 0.5–1 mg/kg every 6–12 hours IV
a. Albuterol
Hydrocortisone
b. Aminophylline
Inhalational treatment: c. Ipratropium
• Beclomethasone, Budesonide, Ciclesonide, Flunisolide, d. Montelukast
Fluticasone, Mometasone and Triamcinolone e. Zileuton
• Included in puff Diskus for bronchial asthma maintenance
V. REFERENCES
F. LEUKOTRIENE PATHWAY INHIBITORS
Leal, J. (2023). Drugs with important actions on smooth muscles
• Inhibition of 5-lipoxygenase, thereby preventing leukotriene [PPT].
synthesis Katzung, B. (2018). Basic and clinical pharmacology (14th ed.).
o Zileuton McGraw Hill Education.
• Inhibition of the binding of LTD4 to its receptor on target
ANSWERS: 1D 2D 3B 4E 5D
tissues thereby preventing its action
o Zafirlukast and Montelukast

IV. TEST YOURSELF

1. You have been treating a 50-year-old woman with moderately
severe arthritis with nonsteroidal anti-inflammatory drugs for 6
months. She now complains of heartburn and indigestion. You
give her a prescription for a drug to be taken along with the anti-
inflammatory agent, but 2 days later she calls the office
complaining that your last prescription has caused severe
diarrhea. Which of the following is most likely to be associated
with increased gastrointestinal motility and diarrhea?
a. Aspirin
b. Corticosteroids
c. Leukotriene LTB4
d. Misoprostol
e. Zileuton
2. A 57-year-old man has severe pulmonary hypertension and right
ventricular hypertrophy. Which of the following agents causes
vasodilation and may be useful in pulmonary hypertension?
a. Angiotensin II
b. Ergotamine
c. Prostaglandin PGF2α
d. Prostacyclin
e. Thromboxane
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VI. APPENDIX

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