Respiratory and Gastrointestinal Drugs respiratory-system.jpg


Ensuring that oxygen is available at all time is the most essential job of the respiratory sysytem. If for even a few minute it's job is rendered, the living cells of our bodies will become compromised in wich death may occur.

Drugs may be used to treat diseases that render the oxygen supply. Drugs may work by direct and indirect effects on the respiratory system. The drugs used must be able to stimulate respiration, improve ventilation, provide relief from respiratory infections or obstruction of the airway.

Oxygen is essential in most emergency situations that may occur in the dental office, except for hyperventalation.

Patients with chronic obsructive lung disease may require long-term low flow oxygen therapy. This is the use of oxygen made available for home and out of home use on a regular basis. Patients who require LTOT will usually require 1 to 3 L/minute for at least 15 hous a day.

The oxygen tanks will always be green for safety reasons.

Doxapram is a drug that can be used in an emergency situation such as drug-indiced coma, overdose of inhalation anesthetics, shock, hypoxemia, increased intracranial pressure and acute or chronic lung disease. It is used as a CNS stimulant (analeptic). Doxapram must only be used in small doses because it could cause tonic-clonic convulsions and should only be given once.


I.) Relief of Cough
Two types of cough:
- productive- leads to removal of sputum from the lungs
- dry cough- no removal of sputum

Treatment of cough mainly consists of treating the underlying cause. A productive cough should not be suppressed except in special circumstances (eg, when it exhausts the patient or prevents rest and sleep) and generally not until the cause has been identified. Suppressing a productive cough is less advisable because sputum needs to be cleared. Cough remedies are categorized as antitussives and expectorants.
Antitussives: Either centrally or peripherally acting. Centrally acting antitussives inhibit or suppress the cough reflex by depressing the medullary cough center or associated higher centers. The most commonly used drugs in this group are dextromethorphan and codeine.
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Dextromethorphan, a congener of the narcotic analgesic levorphanol, has no significant analgesic or sedative properties, does not depress respiration in usual doses, and is nonaddictive. No evidence of tolerance has been found during long-term use. Extremely high doses may depress respiration.
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Codeine, which has antitussive, analgesic, and slight sedative effects, is especially useful in relieving painful cough. It also exerts a drying action on the respiratory mucosa that may be useful (e.g., in bronchorrhea) or deleterious (e.g., when bronchial secretions are already viscous). At doses used for cough suppression, codeine has minimal respiratory depressant effects. Nausea, vomiting, constipation, tolerance to antitussive as well as analgesic effects, and physical dependence can occur, but potential for abuse is low.

Other centrally acting antitussives include chlophedianol, levopropoxyphene, and noscapine in the nonnarcotic group and hydrocodone, hydromorphone, methadone, and morphine in the narcotic group.
Peripherally acting antitussives may act on either the afferent or the efferent side of the cough reflex. On the afferent side, an antitussive may reduce the input of stimuli by acting as a mild analgesic or anesthetic on the respiratory mucosa, by modifying the output and viscosity of the respiratory tract fluid, or by relaxing the smooth muscle of the bronchi in the presence of bronchospasm. On the efferent side, an antitussive may make secretions easier to cough up by increasing the efficiency of the cough mechanism. Peripherally acting agents are grouped as demulcents, local anesthetics, and humidifying aerosols and steam inhalations.
Demulcents are useful for coughs originating above the larynx. They form a protective coating over the irritated pharyngeal mucosa. They are usually given as syrups or lozenges and include acacia, licorice, glycerin, honey, and wild cherry syrups.

Local anesthetics (e.g., lidocaine, benzocaine, hexylcaine hydrochloride, and tetracaine) are used to inhibit the cough reflex under special circumstances (e.g., before bronchoscopy or bronchography). Benzonatate, a congener of tetracaine, is a local anesthetic; its antitussive effect may be due to a combination of local anesthesia, depression of pulmonary stretch receptors, and nonspecific central depression.
Humidifying aerosols and steam inhalations exert an antitussive effect by acting as a demulcent and by decreasing the viscosity of bronchial secretions. Inhaling water as an aerosol or as steam, with or without medicaments (sodium chloride, compound benzoin tincture, eucalyptol), is the most common method of humidification. The efficacy of added medicaments has not been clearly proved.

Expectorants: These drugs help expel bronchial secretions from the respiratory tract by decreasing their viscosity, thus facilitating removal, and by increasing the amount of respiratory tract fluid, thus exerting a demulcent action on the mucosal lining. Most expectorants increase secretions through reflex irritation of the bronchial mucosa. Some, like the iodides, also act directly on the bronchial secretory cells and are excreted into the respiratory tract.
The use of expectorants is highly controversial. No objective experimental data show that any of the available expectorants decreases sputum viscosity or eases expectoration. Data may be lacking partly because of inadequate technology for obtaining such evidence. Thus, the use and choice of expectorants are often based on tradition and the widespread clinical impression that they are effective in some circumstances.
Adequate hydration is the single most important measure that can be taken to encourage expectoration. If it is unsuccessful, using an expectorant in addition may produce the desired result.
-Iodides are used to liquefy tenacious bronchial secretions (e.g., in late stages of bronchitis, bronchiectasis, and asthma). A saturated solution of potassium iodide is the least expensive, most commonly used preparation. Their usefulness is limited by low patient acceptance because they have an unpleasant taste and because side effects (e.g., acneiform skin eruptions, coryza, erythema of face and chest, painful swelling of the salivary glands) are common. The side effects are reversible and subside when the drug is stopped. Iodinated glycerol is better tolerated than potassium iodide solution but is probably less effective. Prolonged use of iodides or iodinated glycerol can lead to hypothyroidism.
-Guaifenesin is the most commonly used expectorant in OTC cough remedies. It has no serious adverse effects, but there is no clear evidence of its efficacy.

Many other traditional expectorants (e.g., ammonium chloride, terpin hydrate, creosote, squill) are found in numerous OTC cough remedies. Their efficacy is doubtful, particularly in the dosages of most preparations.
Less commonly used drugs: Mucolytics (e.g., acetylcysteine) have free sulfhydryl groups that open mucoprotein disulfide bonds, reducing the viscosity of mucus. As a rule, their usefulness is restricted to a few special instances such as liquefying thick, tenacious, mucopurulent secretions (e.g., in chronic bronchitis and cystic fibrosis). Acetylcysteine is given as a 10 to 20% solution by nebulization or instillation. In some patients, mucolytics may aggravate airway obstruction by causing bronchospasm. If this occurs, these patients may inhale a nebulized sympathomimetic bronchodilator or take a formulation containing acetylcysteine (10%) and isoproterenol (0.05%) before taking the mucolytic.
Proteolytic enzymes (e.g., pancreatic dornase) are useful only when grossly purulent sputum is a major problem. They seem to offer no advantage over mucolytics. Local irritation of the buccal and pharyngeal mucosa and allergic reactions commonly follow repeated doses. Dornase alfa, the new highly purified recombinant human deoxyribonuclease I (rhDNase), seems likely to become important in the treatment of cystic fibrosis, although its place has not been defined.


II.) Decongestants

These agents are all a-adrenergic agonists. They exert their action by vasoconstriction of nasal blood vessels, reducing the volume of the nasal mucosa and opening up the airways. They can either be used topically for short-term relief or systemically for prolonged relief.
Short-acting (topical) decongestants: Delivered as nasal sprays, these agents have the benefit of avoiding deleterious side-effects of systemic introduction of a-agonists. The most commonly used short-acting agonist decongestant is phenylephrine. Repeated topical use of these compounds can lead to down-regulation of the receptors, and subsequent rebound hyperemia in the nasal blood vessels.
Long-acting systemic decongestants: Used for prolonged duration of action, with an increased potential for systemic side-effects. Psuedoephedrine is the most commonly used long-acting a-agonist decongestant. Other agents such as ephedrine and phenylpropanolamine were formerly used, but they have been withdrawn from the OTC market.


III.) Treatment of Asthma
Pathophysiology of Asthma

-
clinically characterized by recurrent, episodic bouts of coughing, wheezing, and shortness of breath.
-quantitated by a reduction in FEV1
-physiologically characterized by increased responsiveness of trachea and bronchi to various stimuli and by widespread narrowing that changes either spontaneously or in response to therapy.
-pathologically characterized by contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration.


Pathogenesis of Asthma

-essentially a hyper-responsiveness to a number of substances that results in a reduction in the respiratory system’s ability to provide sufficient airflow .
-mediated by IgE antibodies bound to mast cells in airway mucosa
-re-exposure to antigen (pollen, fur, etc.), antigen-antibody reaction triggers the release of mediators stored in mast cell granules and synthesis and release of other mediators.
-early mediators include: histamine
tryptase and other neutral proteases
leukotrienes (LTC4, LTD4)
prostaglandins
-result of mediators is airway smooth muscle contraction and vascular leakage
-late mediators include: GM-CSF interleukins (IL4, IL5)
-late mediators attract and activate eosinophiles and stimulate IgE production

-released mediators also activate neural pathways that can result in the release of compounds such as ACh at smooth muscle by vagal efferents resulting in contraction:


Therapeutic Approach to Asthma
-asthmatic bronchospasm results from a combination of a release of mediators and an exaggerated response to their effects
-from the various steps involved in the process, there are several points of attack:
-prevent mast cell degranulation
-reducing bronchial responsiveness
-relax airway smooth muscle
-all three approaches are in current use.


Cromolyn & Nedocromil

-act by inhibiting mast cell degranulation, presumably by inhibiting delayed chloride channels, which are involved in the process of mast cell activation
-effective only when used prophylactically
-cannot reverse bronchospasm or alter bronchial tone
-poorly absorbed from the gut, so delivered topically by inhalation of a microfine powder or aerosolized solution.
-can also be used as a nasal spray to reduce symptoms of allergic rhinitis
-very few side effects, presumably due in part to the localized application of the drugs


Methylxanthines such as theophylline
-act by reducing the breakdown of cAMP through the inhibition of phosphodiesterases
-cAMP has bronchodilator activity through increasing the rate in inactivation of MLCK, an important component in smooth muscle contraction:
-agents that elevate [cAMP] will lead to bronchodilation
-methylxanthines are taken orally, and this can lead to a number of side-effects due to increases in [cAMP] in a number of other systems:

CNS; nervousness and tremor
Cardiovascular: positive chronotropic and inotropic effects
GI: stimulate secretion of gastric acid and digestive enzymes
Renal: diuretic activity

-need to measure plasma levels of these compounds in order ensure that levels remain in the therapeutic range (5-20 mg/L for theophylline); toxicity is most common at levels>20 mg/L
-no longer used as a first-line therapy.


Sympathomimetic Agents
-b adrenergic receptor agonists, especially b2-selective
-work by elevating [cAMP] levels to promote bronchodilation.
-b2-selective agonists do not have the chronotropic or inotropic effects of non-selective or b1-selective agonists.
-nonselective agents such as epinephrine, ephedrine, and isoproterenol are no longer or rarely used due to potential side effects
-b2-selective agonists are generally delivered either via metered-dose inhalers or nebulizer. In either case, localized application results in relatively few side-effects.
-commonly used agents include
albuterol (Ventolin)
metoproterenol (Alupent)
terbutaline (Brethine)
pirbuterol (Maxair)
salmeterol (Servent)
-generally used when bronchocontriction occurs, and bronchodilation effect lasts for 3-4 hours
-salmeterol is a long-acting b2 agonist (12 hours or more). Thought to get its long-acting effect through the high lipid solubility of the compound, creating a “slow-release” depot within the airways.


Muscarinic Antagonists

-inhibit effects of vagal-released acetylcholine at muscarinic receptors in the airways
-atropine is the classic muscarinic antagonist, but is not used due to systemic adverse effects
-ipratopium bromide can be delivered via inhaler and is poorly absorbed, resulting in few systemic effects.
-takes up to 45 minutes to exert its effects, but effects can last for hours
- rarely used in asthma; common in COPD (see below)


Corticosteroids

-have anti-inflammatory action, so reduce the responsiveness of airways.
-do not reverse bronchospasm
-thought to work mainly via inhibition of the production of cytokines
-can be delivered either orally or inhaled
-oral corticosteroids such as prednisone are usually only used in cases where urgent treatment is needed due to the problems with systemic actions of these agents such as adrenal suppression
-treatment with oral corticosteroids is usually for a fixed period only 7-10 days

-dosages are usually reduced over the period of treatment to avoid rebound phenomena associated with drop in steroid levels.
-inhaled steroids avoid these systemic effects, allowing them to be used in chronic/prophylactic treatment
-agents include:

beclomethasone (Beclovent, Vanceril)
triamcinolone (Azmacort)
fluticasone (Flovent)

-most common side effect is occurrence of oropharyngeal candidiasis due to significant deposition of the steroid on the oropharynx.

Leukotriene Pathway Inhibitors

-leukotrienes (in particular LTC4 and LTD4) are involved in the inflammatory response, so blocking their production or action can be a useful form of treatment
-leukotrienes are synthesized from arachidonic acid via 5-lipoxygenase, and bind to receptors on target tissues
-blocking production with 5-lipoxygenase inhibitors has been shown to be effective in both blocking response to antigen challenge. Currently used orally-active compounds include zileuton (Zyflo)
-blocking actions of LTD4 at its receptor also reduces inflammatory response. Currently used orally active compounds include zafirlukast (Accolate).


So, Which Ones Are Actually Used?
-in patients with mild asthma and occasional symptoms, inhaled b agonists on an “as needed” basis
-in cases with more chronic attacks (several a week or more) additional treatment such as using either an inhaled corticosteroid or cromolyn on a prophylactic basis is merited
-in more severe cases, inhaled corticosteroids is the treatment of choice, with b agonists used as needed. In many cases, the b agonist used is the long-acting salmeterol, which can also be used prophylactically
-oral corticosteroids are used in cases of severe, prolonged attacks that are not controlled by the above methods in order to get things back under control


IV.) Treatment of COPD

- characterized by persistent, partially or nonreversible airflow limitation, dyspnea, cough and expectoration. Cigarette smoking is the most important risk factor.
-manifests as one of three pathological entities:

a.) chronic bronchitis
b.) chronic obstructive bronchitis
c.) emphysema


- NO DRUG TREATMENT CAN AFFECT THE NATURAL HISTORY OF COPD. TREATMENT IS DESIGNED TOWARD CORRECTION OF SYMPTOMS, MAINTENANCE OF LUNG FUNCTION, AND IMPROVEMENT OF QUALITY OF LIFE
- Since obstruction to airflow is the most typical characteristic of COPD, bronchodilators are drugs of first choice.
- in mild forms, a short-acting b2 agonist such as albuterol followed by the muscarinic antagonist ipratropium are used on as “as needed” basis or before exercise.
- for more severe cases, short-acting
b2 agonists with ipratropium are prescribed on a regular basis (3-4 times per day)

- theophylilline is used when b
agonists and ipratropium are ineffective; however, due to systemic effects of theophylline its use is declining.
-the efficacy of corticosteroids in the treatment of COPD is still under debate, but recent evidence suggests that inhaled corticosteroids, either alone or in combination with salmeterol, can result in a significant increase in FEV1 in COPD patients. Chronic use of oral or systemic corticosteroids should be avoided.
-leukotriene synthesis inhibitors or leukotriene receptor antagonists have not been adequately tested in COPD patients, so their use cannot be recommended at present
.


Gastrointestinal

Peptic ulcers: stomach or duodenal mucosal lesion
-Duodenal or Gastric
-Cause: Bacterium helicobactor pylori
-Ulcer development: caused by an imbalance between gastric acid, pepsin and protective factors (mucosal defenses)
Drug Therapy:
-Patients with documented duodental ulcers are treated for H. pylori
-many drugs, usually in combination, are used in management and eradication of H. Pylori infections. Drugs include:
-bismuth compounds
-amoxicillin
-tetracycline
-clarithromycin
-metronidazole
-omeprazole
-H2 antagonist
Mechanism of action:
-cytoprotective effects
-compounds bind to the ulcer base, stimulating mucous and prostaglandin production
-antibacterial effect: inibition of proteolytic, lipolytic, and urease activities
-In monotherapy: bismuth comounds eradicate H. pylori in about 20% of patients
- Bismuth compounds with antibiotics eradicate H. pylori in up to 95% of patients
-Most succesful protocal: triple therapy: bismuth compounds, metronidazole, amoxicillin or tetracycline.


Adverse Reactions of the gastrointestinal system to drugs:
Opioid Anaglesics: May produce constipation, nausea, and vomiting.
Asprin containing anagesic: Associated with gastirc distress, decal blood loss, and ulceration.
Anti-inflmatory agents: Share the ulcerogenic action of asprin.
Sedative-hypnotic chloral hydrate may be prscribed by dentist: Produces gastric irritation.
Antibiotic agents: Gastrointestinal distress.
Erythromycin, Tetracycline, clindamycin, and extended spectrum penicllins: nausea, diarrhea, entercolitis, and pseudomembranous coltis.



Respiratory drugs


Drug Name
Mechanism of Action
Adverse Effects
Zafirlukast (Accolate)
Leukotriene receptor antagonist-prevent the synthesis of leukotrienes which produce bronchoconstriction and increase mucous secretion.
This drug may cause...
  • gastric irritation
  • nausea, vomiting, diarrhea
  • abdominal pain
  • dizziness
  • headache
  • abnormal liver functions
Albuterol (Proventil, Ventolin)
Salmeterol (Serevent)

Beta2-adrenergic agonist-stimulate beta receptors in the lungs and produce bronchodilation.
This drug may cause...
  • nervousness
  • tachycardia
  • insominia
  • diarrhea
  • fatigue
  • lightheadedness
  • bronchitis
  • epistaxis
  • rash
  • muscle cramps
  • angioedema
Ipratropium (Atrovent IH)
Anticholinergic-inhibits acetylcholine from binding to muscarinic receptors resulting in decreased secretions and bronchodilation.
This drug may cause...
  • nervousness
  • tachycardia
  • xerostomia
  • GI distress/nausea
  • fatigue
  • headache
  • bronchitis/URI
  • epistaxis
  • hypersensitivity reactions to soybean or peanut
Triamcinolone (Azmacort IH)
Fluticasone (Flovent)

Corticosteroid-reduces inflammation and inhibits the release of inflammatory products
This drug may cause
  • cough
  • hoarseness
  • flushing
  • dizziness
  • oral candidiasis
  • xerostomia
  • taste alterations
  • adrenal suppression
  • poor wound healing
  • immunosuppression
Cromolyn (Intal)
Mast cell degranulation inhibitor-prevents the release of histamine, leukotrienes and other substances from sensitized mast cells.
This drug may cause...
  • URI
  • nausea
  • dizziness
  • drowsiness
  • cough
  • rash
  • swollen parotid glands
  • epistaxis
  • taste alterations
  • burning mouth/throat
  • increased sputum
  • dry throat
Theophylline (Theo-Dur, Slo-Bid)
(Methyl)Xanthines-blocks action of adenosine, inhibits cyclic nucleotide phosphodiesterase and prostaglandins to produce bronchodilation.
This drug may cause...
  • nausea, vomiting, diarrhea
  • headache
  • tachycardia
  • insomnia
  • trembling
  • nervousness
  • bitter taste
  • xerotomia




Gastrointestinal drugs


GI Drugs
Mechanism of Action
Adverse Effects
Nizatidine (Axid)
Cimetidine
Famotidine (Pepcid)
Ranitidine (Zantac)

Histamine2-receptor antagonists block basal and gastric acid secretions.
This drug may cause...
  • slurred speech
  • nausea, vomiting, diarrhea
  • delusions, confusion
  • constipation
  • headache
  • reversible hepatitis
  • impotence
  • reduction in sperm counts
  • xerostomia, taste alteration
  • granulocytopenia
  • thrombocytopenia
  • neutropenia
Lansoprazole (Prevacid)
Omeprazole (Prilosec)

Proton Pump Inhibitors block gastric acid secretion by inhibiting the H/K ATPase enzyme system at the surface of the parietal cells in the stomach.
This drug may cause...
  • headache
  • abdominal pain
  • nausea, vomiting
  • constipation
  • anxiety
  • confustion
  • rash
  • candidiasis
  • increased cough
  • epistaxis
  • xerostomia
Misoprostol (Cytotec)
Prostaglandin - increases gastric mucus production and inhibits gastric acid secretion
This drug may cause...
  • GI distress/nausea
  • abdominal pain
  • menstrual disorders
Sucralfate (Carafate)
Combines with proteins in the intestinal tract to form a complex that binds to ulcer site in the duodeum.
This drug may cause...
  • constipation
  • xerostomia
  • nausea. vomiting
  • dizziness
  • rash
  • angioedema
Metoclopramide (Reglan)
Stimulates motility of upper GI tract and increases peristalsis of duodeum. Accelerates emptying of GI.
  • restlessness
  • fatigue
  • nausea, diarrhea
  • constipation
  • drowsiness
  • headache
  • rash
  • xerostomia
  • tachycardia









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Gastrointestinal Drugs and mechanism Web site:

http://cpharm.vetmed.vt.edu/vm8784/GI/gi.htm