SMOOTH MUSCLE

Vasoactive agents

When a heart is ischemic there are two ways to fix it: either increase oxygen delivery or decrease oxygen
demand.
 Calcium channel blockers - decrease oxygen demand by reducing heartbeat and afterload by
arteriolar dilation
 Dilation of coronary  increase oxygen delivery
 Beta blockers  decrease oxygen demand
 Acute txt  vasodilator that can immediately reduce immediately the demand of oxygen:
o Nitroglycerine  antianginal treatment. Organic nitrates are metabolized in vessels and
release nitric oxide.  reduce cardiac work
 NO activate guanylyl cyclase  increase in cGMP in vascular smooth muscle
cells
 Increase cGMP  decrease intracellular calcium and decrease activity myosin
light chain kinase  leading to myosin light chain dephosphorylation 
prevents its interaction with actin.
 Nitrates cause then venous dilation and increase in venous capacitance  veins
are more sensitivity and large arteries but capillaries/arterioles are only minimal
dilated
 Decrease ventricular preload, venous return and filling of the heart and
decreases the wall stress.
 Decrease pulmonary pressure and CO
 Nitrates treat chronic stable angina  reduces left ventricular and diastolic
volume  less load  decrease oxygen myocardial requirements
 Rapidly metabolized organic  bioavailability is low  use sublingual
administration of nitroglycerine avoid first pass metabolism (for acute symptom
relief) not suitable for long term
 Oral nitrate preparations have a longer duration  prophylaxis  isosorbide
mononitrate/dinitrate

o Isosorbide mononitrate/dinitrate
 Require larger dosing due to first pass metabolism
 Prinzmetal angina – vasospastic angina  reversed by nitrate therapy and
calcium channels as it prevents coronary vasospasm
 Unstable angina, STEMI and Non STEMI  acute coronary syndrome  nitrate
therapy but no show in mortality effect
 Avoided if Right Sided MI  reduce right ventricular preload  give IV fluids to
improve preload
 IV nitroglycerine can be used in emergency hypertension + acute treatment for
pulmonary edema
 SIDE EFFECTS:
 Can cause hypotension  activates baroreceptors that cause reflex
tachycardia and increase in cardiac contractility
 Orthostatic hypotension
 Combination with beta blocker and calcium channel blockers 
reduces reflex sympathetic response  decreases side effects
 Nitrates cause throbbing headaches and cutaneous flushing
 Nitrates can lead to methemoglobinemia
 Avoid tolerance to the vasodilators effect with daily nitrate free
intervals, if not done this may lead to tachyphylaxis due to decreased
metabolism of the drug by endothelium.
  Monday disease in occupational disease
 Patients on PDE-5 inhibitors (sildenafil) for erectile dysfunction should
avoid nitrate therapy for 24h (give you a severe hypotension)
 Avoid in hypertrophic obstructive cardiomyopathy  dynamic left
ventricular outflow obstruction that worsens in case of reduced
ventricular volume by decreased preload.

Migraines – aura of variable duration that involves severe throbbing unilateral headaches, nausea, visual
scotomas, vomiting and speech abnormalities that can last a few hours-few days. Common migraine is
without aura.
Trigeminal nerve afferents that innervate intracranial arteries in meninges  release vasoactive peptides
(CGRP, substance P and neurokinin A) onto meningeal vessels  neurogenic inflammation 
vasodilation and protein extravasation  pain due to perivascular edema

 Triptans + sumatriptan  first line in acute treatment  agonists of 5HT1b and 5HT1d receptors
found on meningeal vessels, trigeminal nerve and brain stem.
 Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Zolmitriptan

o Activation of the receptors on the vessels  induce vasoconstriction of cerebral and

meningeal vessels which decreases inflammation and decreases the stretch on pain
receptors
o Activation of the receptors on the trigeminal nerve  prevent release of vasoactive
peptides which decreases vasodilation
o Activation of the receptors on brain stem  inhibiting pain pathways
o SIDE EFFECTS:
 Tingling, dizziness and muscle weakness
 Chest pain or discomfort due to coronary vasospasm – contraindicated in angina
(Prinzmetal angina) or coronary heart disease
o Triptans combined with inhaled oxygen are an acute treatment for cluster headache
o Triptan and NSAIDS  acute treatment for migraine
o Ergotamine  for acute migraine  5HT receptor agonist with alpha adrenoreceptors.
Vasoconstrictors, blocks trigeminal nerve transmission.
 SIDE EFFECTS: Uterus contraction – contraindicated during pregnancy  fetus
damage
o Prophylaxis:
 Calcium channel blockers (cyproheptadine  5HT agonist + CCB)
 Beta blockers (Propanolol)
 Valproic acid (antiepileptic)
 Topiramate (antiepileptic)
 Tricyclic antidepressants (amitryptaline)
 Methylsergide  5HT agonist
 Pizotifen  5HT agonist and histamine agonist

Prostaglandin, analogs prostacyclin, analogs bosentan, sildenafil

 COX 1 and COX 2 produce prostanoids (prostaglandins)
 Alprostadil (PGE1)  erectile dysfunction therapy
o Vasodilator  potent smooth muscle relax effects
o Maintains ductus arteriosus open  Coarctation of the aorta
o NSAIDS (indomethacin)  closes ductus arteriosus – not recommended in the third
trimester of pregnancy  can cause premature closure
 Misoprostol (PGE1)
 o Promotes protective mucus secretion by gastric mucosa  low doses can inhibit gastric
secretion
o Prevention of NSAIDS induced peptic ulcers  give PPI or PGE1 agonists
o Potent oxytocic action  facilitate labor or terminate pregnancy by promoting uterus
muscle contraction  pregnancy category X drug
o Cause diarrhea and abdomen discomfort
 Dinoprostone (PGE2)
o Stimulates contraction and ripens the cervix to facilitate labor or terminate pregnancy
 Carboprost (PGF2a)
o Promotes uterine contraction and control postpartum hemorrhage or abortion
 Latanoprost and Travoprost (PGF2a)
o Stable long acting that can be used in management of glaucoma  increasing aqueous
humor outflow
o SIDE EFFECT: Increase iris pigmentation

Pulmonary hypertension treatment:

 Prostacyclin agonists
 Endothelium receptor antagonists
 Phosphodiesterase inhibitors

Direct vasodilatory effects on pulmonary vasculature  decrease pulmonary hypertension

Idiopathic  manifests as dyspnea and exercise intolerance in women 20-40.
Heart failure, COPD and Thromboembolic disease  Pulmonary Hypertension

Treatment:
 Prostacyclin agonists  vasodilation due to COX 2 in the vessel endothelium
o Ilioprost and epoprostenol
o Epoprostenol  IV is first line improve symptoms, survival and prevent lung transplant
o SIDE EFFECT: flushing, headache and hypotension
 Phosphodiesterase inhibitors (PDE-5)  increase intracellular cGMP by inhibiting its
degradation by PDE
o Sildenafil and tadalafil
o Increase cGMP  dephosphorylation of MLC preventing its interaction with actin
o Erectile dysfunction and PHT
 Endothelin inhibitors  block effect of endothelin potent vasoconstrictor that also stimulates
endothelium proliferation.
o Bosentan  Vasodilation  treatment of pulmonary hypertension
o SIDE EFFECTS: Fatal hepatoxicity – monthly liver tests

SIDE EFFECT: Precipitate severe hypotension

ASTHMA

Asthma is characterized by acute bouts of shortness of breath chest tightness, wheezing and coughing.
Asthma involves both a wide spread reversible spasm of bronchoairways and also an eosinophilic
inflammation of bronchomucosa.
Treatment with both bronchodilator (beta 2 agonists) and anti-inflammatory therapy (inhaled steroid)

Beta 2 selective agonists, Leukotriene inhibitors, muscarinic antagonist, methylxanthines, chromones

and sulfate, alpha proteinase inhibitor (prolastin, aralast) omalizumab
Long term treatment  increase doses until patient achieves control.

Allergic asthma  IgE mediated  histamine, leukotrienes, prostaglandins  vasoconstriction and

bronchoconstriction.
Selective beta 2 relaxes smooth muscle  albuterol
 Albuterol, pirbuterol (SABA)
 Terbutaline  smooth muscle relaxation – treats preterm labor and also acute
bronchoconstriction (LABA)
 Available as metered dose inhalers for acute symptom relief  short acting (SABA) maximum
bronchodilation in 15 minutes and persistent for 3-4 hours.

Mild asthma  occurs in exercise, allergen or after a URI  specially at night

If not treated, chronic airway constriction is accompanied by remodeling and thickening. of the bronchial
wall as well as hyperplasia of pulmonary vasculature, smooth muscle, secretory gland and goblet cells 
irreversible

Persistent asthma  inhaled corticosteroids (beclomethasone, budesonide, fluticasone)  added as

daily maintenance therapy for persistent symptoms.
 SIDE EFFECTS: moon facies in Cushing’s disease
They don’t relax smooth muscle directly but rather they inhibit the inflammatory mediators and mast
cells blocking inflammation and cellular infiltration associated with asthma.
Daily  reduce bronchial hyperreactivity and reduce frequency of exacerbation.
Inhalation avoids the systemic effects  oropharyngeal candidiasis  Treated with tropical clopiprazole
and gargle water and spit after therapy.

Side effects of beat adrenergic include skeletal muscle tremors and vasoconstriction and hypertension.
 Tachyphylaxis, a blunting in the response to adrenergic agonists on repeated use, can be
countered by switching to a different agonist or by adding a methylxanthine or corticosteroid to
the regimen.

Leukotrienes result of action of 5 LOX converts Arachidonic acid into leukotrienes (LTB4, C4, D4 and E4)
and prostanoid synthesis (thromboxane, prostacyclin and inflammatory prostaglandins)
AA  COX or LOX
 LTB4 is a chemoattractant for inflammatory cells (neutrophils)
 LTC4, D4 and E4 potent bronchoconstrictor and increase vascular permeability and mucus
production #1 is LTC4
 Montelukast and Zafirlukast  LTD4 antagonist  bronchodilation for mild persistent asthma
therapy but less effect on hyperreactivity and dilation of administrations than steroids  take
orally
 Zileuton  direct LOX inhibitor is an alternative therapy for mild persistent asthma  risk of
hepatoxicity

NSAIDS (aspirin induced asthma)  Inhibiting COX shifts AA metabolism to LOX pathway

Salmeterol and formoterol  LABA (if still persistent) – moderate or severe persistent asthma. Achieve
their long duration due to high lipid solubility  bronchodilator effects can last up to 12 hours. Daily
controller + corticosteroids
 Increased dose of inhaled corticosteroids treats persistent asthma.

Alternative therapy  Methylxanthine (theophylline)  increase intracellular cGMP by inhibiting its

breakdown by phosphodiesterases and increase cAMP  aids in SM relaxation  most effective
bronchodilator  orally
  Some studies suggest that it is a adenosine receptor antagonist  adenosine causes
bronchoconstriction and promotes release of histamine in response to IgE stimulation
o SIDE EFFECT: nervousness, tremor, positive inotropic and chronotropic and death.
Metabolized by CYP450 in the liver.
o Cerebral vasoconstriction

Mast cell degranulation is important in the pathogenesis of asthma  antigen binding to IgE on mast
cells causes degranulation and release of inflammatory mediators (histamine).
 Omalizumab  monoclonal antibody directed against IgE, preventing mast cell sensitization 
evidence of allergic sensitization tested by skin test + blood test with elevated IgE
 Chromolyn sodium  inhibits mast cell degranulation (prevent release of histamine)  used in
prophylaxis for allergic asthma or exercise asthma but replaced by leukotrienes and steroids

Emergency situation to treat acute severe asthma exacerbation:

 Albuterol  inhaled short-short acting beta 2 agonists
 Systemic corticosteroids IV administered or orally
 Nebulized ipratropium bromide (anticholinergic)  bronchodilation through smooth muscle
relaxation
 Subcutaneous or intramuscular epinephrine  children with severe exacerbation. Potent alpha
and beta agonist.

Muscarinic antagonist
 Ipratropium and tiotropium used via inhalation cause bronchodilation in acute asthma, especially
in COPD patients, and they may be safer than β agonists are in patients with cardiovascular
disease.
 They are the drugs of choice in bronchospasm caused by β blockers.
 There are minor atropine-like effects.

Prolastin  treats emphysema as it inhibits elastase.

Antihistamines - H1 receptors antagonists

Histamine sequestered inside the granules of mast cells.

H2 histamine receptors is coupled to Gs protein  increase in cAMP  located on gastric principle cells
 mediates gastric acid secretion

H1 histamine are located in vasoendothelium, bronchoairways and brain. It’s coupled to the Gq protein
(mediates allergic inflammation)

 Increases nasal and bronchial mucus production (H1 receptor activation)

 Increases vascular receptor permeability (H1 receptor agonist)  ) pain, pruritus, urticaria and
hives.
 Constriction of bronchial smooth muscle (H1 receptor activation)
 H1 receptor blocker (antihistamine) treats allergy

Histamine functions as a neurotransmitter in the brain  H1 receptor regulates sleep and arousal and
cardiovascular regulation.  side effects of drugs that block histamine in sleep

1st generation H1 Blockers (Diphenhydramine, Chlorpheniramine, Dimenhydrinate, Hydroxyzine,

Meclizine, Promethazine)
Histamine mediates type-1 allergic reaction hives, allergic rhinitis or hay fever (H1 receptor blockers are
1st line therapy)
1st generation H1 blockers treat vestibular nausea or motion sickness (lipophilic  enter CNS  act on
vestibular system and brainstem)
 Side effects:
o 1st generation H1 blockers cause drowsiness (lipophilic  cross BBB  central effects)
#1 Diphenhydramine  treat insomnia
o 1st generation H1 blockers antagonize peripheral and central muscarinic receptors
(pupillary dilation, dry mouth, urinary retention, constipation, exacerbation of glaucoma,
and delirium)  adrenergic properties
o 1st generation H1 blockers treat extrapyramidal side effects caused by antipsychotics to
treat acute dystonia due to antimuscarinic effects re-establish dopaminergic cholinergic
balance  #1 Diphenhydramine
o 1st generation H1 blockers stimulate appetite and weight gain (anti-serotonergic effects
– in CNS
o 1st generation H1 blockers antagonize alpha-1 receptors  dizziness and hypotension
o 1st gen H1 blockers cause cognitive impairment in the elderly and delirium  central
antihistamine and antimuscarinic effects

2nd generation H1 blockers (Fexofenadine, Cetirizine, Loratadine)

 2nd generation H1 blockers are less lipophilic  do not cross BBB  less sedating (also less
antimuscarinic, ant serotonergic or anti alpha adrenergic properties
 Use this drugs for the treatment of allergic rhinitis or chronic urticaria with minimal side effects.