Drug Treatment for Pulmonary Disorders

Introduction

• The Pulmonary System- includes the lungs and the muscles of breathing, such as the diaphragm, which pump air into and out of the lungs. The purpose of the lungs is to get enough oxygen into the body and to get rid of carbon dioxide that is a waste product of the body.

• Pulmonary Circulation- carries the blood to and from the lungs. In the heart, the blood flows from the right atrium into the right ventricle; the tricuspid valve prevents backflow from ventricles to atria. The right ventricle contracts to force blood into the lungs through the pulmonary arteries. In the lungs oxygen is picked up and carbon dioxide eliminated, and the oxygenated blood returns to the heart via the pulmonary veins, thus completing the circuit. In pulmonary circulation, the arteries carry oxygen-poor blood, and the veins bear oxygen-rich blood.

Read more: circulatory system: Pulmonary Circulation | Infoplease.com http://www.infoplease.com/encyclopedia/science/circulatory-system-pulmonary-circulation.html#ixzz3Eu6nnDAH

Bronchial Asthma

• Asthma is considered to be a chronic inflammatory disorder of the airways that produces acute bronchoconstriction and shortness of breath. The bronchi become hyper reactive as a result of an inflammatory process involving a variety of stimulants including allergens, environmental chemicals, exercise, cold air, aspirin-type drugs, and viruses.

• Asthma associated with a specific allergen is labeled as extrinsic type disease and is probably the most common form. In allergic asthma T helper cells are predominantly activated, and they release cytokines, forcing the production and release of immunoglobulin E (IgE) from B cells.

• Asthma not associated with a known allergy is considered intrinsic asthma. Two other categories of asthma are:

1. Exercise- induced asthma (EIA)- when conducted in cold dry air, produces bronchoconstriction in some patients. This wheeze regularly occurs within just a few minutes of exercise.

2. Asthma associated with chronic obstructive pulmonary disease (COPD)- preventive treatment with β2 inhalers usually works well for this type of asthma.

Inhalation Delivery Devices

• Delivery of drugs to the lungs allows the medication to interact directly with the diseased tissue. This mode of administration reduces the risk of adverse effects, specifically systemic reactions, and allows for the reduction of dose compared with oral administration.

• Most of the inhaled drugs are administered through a pressurized metered- dose inhaler. This is an aerosol delivery system that uses a chlorofluorocarbon propellant to spray drug into the respiratory tract.

• These metered-dose inhalers are convenient and inexpensive but requires some coordination and practice for effective use. Correct use of the device requires activation and a simultaneous inhalation.

• The device containing this canister of drug is warmed to room temperature and then shaken well. The mouth piece is held approximately 1 inch from the mouth unless a sprayer is used. The pt. performs a normal exhalation and then presses down on the canister while breathing in slowly for 2 to 5 seconds. The pt. should hold his/her breath for at least 10 seconds if possible to allow the medicine to enter the lungs. If 2 puffs is prescribed, the pt. should wait 5 minutes between inhalations. It may be difficult for children and elderly to maneuver the device and coordinate the inhalation.

Drug Treatment for Asthma

• The drugs used to treat asthma can be divided into two categories: 1. Short- term relievers- are those drugs that can be used during acute asthma attacks. For this

reason they are also referred to as recue inhalers. They include β2-agnoists, anticholinergic, and some sympathomimetic.

2. Long- term controllers- those that are used to prevent attacks from occurring and include steroids, leukotriene modifiers, theophylline, and cromolyn.

Short-term Relievers

• β2 Adrenoceptor Agonists- are the most commonly prescribed drugs for the treatment of asthma. These agents are available in metered-dose inhalers and nebulizers, as well as in tablet and injectable forms. They produce relaxation of the airway smooth muscles, resulting in bronchodialation, inhibits inflammatory mediators release from mast cells, and enhance mucociliary clearance.

• Two categories of β2- agonists are actually used in the treatment of asthma:

1. Short-acting agents- action is rapid, often within 5 to 10 minutes. Maximum effect usually occurs within 30 minutes, and duration of action is 4 to 6 hours. Examples of the short-acting agents includes, salbutamol, albuterol, and terbutaline.

2. Long-acting agents- salmeterol and formoterol are long-acting agents that produces bronchoilations for 12 to 15 hours. These drugs contain a long lipophilic side chain on the molecule that binds to the membrane near the receptor, slowing wash out of the drug. These long-acting agents are not appropriate for acute asthmatic episodes because of their delayed action, but they may be used to prevent nocturnal asthmatic attacks and provide protection for unanticipated or prolonged physical activity.

Short-term Relievers

• Side effects of β2- agonists include tremor, tachycardia, hypokalemia, and hyperglycemia. Increased mortality has been reported with the overuse of β2 inhalers, but this was most likely due to worsening disease rather than actual use of the drug. Less selective adrenergic agonists, such as epinephrine or isoproterenol, are most likely to produce side effects than β2- selective agents, particularly cardiac arrhythmias and rebound bronchospasm.

• Anticholinergic Agents- the muscarinic receptor antagonists cause bronchodilations by blocking the actions of acetylcholine on airway smooth muscle. These drugs do not prevent all types of bronchospasm but are effective against asthma produced by irritant stimuli. These drugs also decrease mucus secretion, which is why they are effective for COPD than asthma.

• The anticholinergic agents that may be used in asthma treatment include inhaled ipratropium, tiotropium, and oxitropium. These synthetic compounds are permanently charged, preventing significant systemic absorption after inhalation, thus minimizing side effects. When inhaled, they produce maximum bronchodialation in 30 minutes with duration up to 5 hours.

• In general, dry mouth and pharyngeal irritation are the major side effects.

Long-term Controllers

• Corticosteroids – regular use of an inhaled corticosteroid can reduce bronchial inflammation and hyper responsiveness in pt. with persistent asthma. Steroids block the release of arachidonic acid from airway epithelial cells, which in turn blocks production of prostaglandins and leukotriene's.

• Inhaled steroids- have been the drug of choice for reducing the number of asthmatic attacks in pt. who have moderate persistent and for those who require β2 inhalers more than once a day. Regular use of an inhaled steroid is associated with a reduced number of deaths from asthma. Examples of inhaled steroids include beclomethasone, budesonide, and fluticasone.

• Oral or parenteral corticosteroid- are the most effective treatments for acute exacerbations of asthma that do not respond well to β2- agonists. Even when pt. respond to short-term relievers, they may still receive a 10 day course of oral steroids to help decrease symptoms and prevent relapse. Long-term daily use of oral steroids produces severe side effects including hyperglycemia, weight gain, increase BP, osteoporosis, cataracts, increase susceptibility to infections, etc.

Long-term controllers

• Leukotriene Antagonists and Leukotriene Receptor Blockers- blocks the actions of leukotriene, decreasing the migration of eosinophil, production of mucus, and the bronchoconstriction. They are the first new class of antiasthmatic agents in 30 years. Montelukast and zafirlukast are leukotriene receptor antagonists, and zileuton inhibits synthesis of leukotriene. These drugs have been slightly less effective than the long-acting β- agonists and inhaled steroids, but the addition of these agents permits a reaction in corticosteroid dose. The side effect may include complaints of gastrointestinal upset and headaches

• Cromolyn and Nedocromil- inhibits mast cell degranulation. When stimulated, mast cells release granules containing histamine, leukotriene, and prostaglandins- all of which produce an inflammatory mediatory response. These drugs block release of these inflammatory mediators and thus decrease airway hyper responsiveness, but they have no bronchodilating activity. They are used only for prophylaxis. They have few side effects with the exception of their bitter taste, but they are less effective than inhaled corticosteroids.

• Theophylline- is a methylxanthine, a substance found in coffee, tea, and chocolate. It was developed as a result of the observation that consuming great amounts of caffeine-containing beverages reduced the incidence of asthma. It acts as the phosphodiesterase inhibitor, which in turns increases intracellular cyclic adenosine monophosphate, resulting in relaxation of smooth muscle. It also has some anti-inflammatory properties. Side effects include, nausea, vomiting, headache, insomnia, nervousness, tachycardia, and hypertension.

Acute Severe Asthma(Status Asthmaticus)

• This is a life-threatening illness requiring rapid and aggressive treatment. It may occur because the airway become refractory to the β2- agonists, particularly when administered frequently with 36 to 38 hours to regain control over he airways. In addition, the mucus plugs that develop begins to reach the distal airways.

• Immediate treatment involves administering humidified oxygen by mask plus intravenous (IV) fluids for hydration to help liquefy the mucus. Additional treatment includes oral or IV steroids, followed by a β2- agonists administered with a nebulizer. Monitoring the pt. response to treatment includes measurement of peak expiratory flow rate, oxygen saturation, and blood gases every 15 to 30 minutes.

Other Drugs Useful In Respiratory Disorders

Coughs, nasal congestions, and thick mucus are symptoms of respiratory disorders. For each of these indications, specific symptoms reduction drugs are available.

Antitussives

• These drugs are used to treat recurrent or persistent cough. Nonspecific cough, not resulting from asthma or as a side effect of ACE inhibitors, may be triggered by mechanical or chemical stimulations of the upper respiratory tract. This stimulus is relayed to the to the cough center in the medulla and then to the respiratory muscles. The efferent pathways for cough involves the phrenic nerve and abrupt contractions of the intercostal muscles. Peripheral cough receptors are sensitive to local anesthetics, and topical application of lidocaine is used to inhibit cough during bronchoscopy.

• Drugs that suppress cough act by decreasing activity of the afferent nerves or decreasing the sensitivity of the cough center. Menthol vapor inhalation is effective in reducing sensitivity of the peripheral cough receptors. Inhalations of the menthol vapors or sucking lozenges containing menthol will decrease the need to cough.

Rhinitis and Rhinorrhea

• Rhinitis : Is an acute or chronic inflammation of the nasal mucosa, • Rhinorrhea : is the production of watery nasal secretions.• Both conditions are results from a viral infection of the nasal mucosa or an

IgE-type allergy.• Blood flow and vascular permeability to the mucosa are increased, resulting

in fluid build in the nasal passages and difficulty breathing.

• Nasal Spray: the major ingredients are Sympatholytic drugs that vasoconstrict the blood vessels. • Major Side effects : are vasoconstriction and elevated blood pressure. • Other Side effects : they can also aggravate hyperthyroidism, diabetes, glaucoma, and

benign prostatic hyperplasia. This is particularly true with the oral mixtures that contain phenylephrine. Patients will develop tolerance to the topical agents, if is used repeatedly, but will not usually develop tolerance to the oral decongestants.

Other treatments for Rhinitis and Rhinorrhea• Autocoids such as histamine are released as a result of immunological

reaction. • Antihistamines and the local administration of glucocorticosteroids are useful

in controlling disease associated with these reactions.• Histamine acts on the nasal mucosa, largely on H1 receptors.• The antihistamines or H1 receptor blockers reduce nasal congestion, mucosal

irritation, and cough by reducing secretions.

• The first generation H1 antagonists, diphenhydramine and chlorpheniramine, were effective except that they interfered with learning and motor performance and posed a safety hazard because of the excessive somnolence they caused. • The newer antihistamines do not cross the BBB and therefore produce less

sedation than their older counterparts. Example, loratadine, cetirizine, and fexofenadine.• The glucocorticosteroids that are applied topically to the nasal mucosa include

triamcinolone, beclomethasone, fluticasone, and OTC cromolyn- all of which are sprayed directly into the nostrils.

• Leukotriene receptor antagonist montelukast has also been approved for the treatment of seasonal allergic rhinitis in adults and children since it decrease symptoms more than placebo.

Mucolytics• Respiratory mucus consists of water and glycoproteins that are cross-linked by

disulphide bonds. • Normally only about 100 mL of fluid is produced in the respiratory tract per day,

and most of this is swallowed.

• In disease states, more mucus is produced, and it tends to be more viscous. • The purpose of mucolytics is to liquefy mucus so that it can be cleared from the

airway with a cough.• Carbocysteine and mecysteine open disulphide bonds and reduce the viscosity

of mucus and can be given orally ot by inhalation and are particularly useful in cystic fibrosis (CF).• Water inhalation and use of a humidifier or vaporizer are also considered

mucolytic treatments because hydration can lower viscosity.

• Dornase alfa is a phosphorylated glycosylated recombinant human deoxyribonuclease that hydrolyzes DNA and is effective for airway clearance in CF. Copious amounts of neutrophil-derived DNA accumulates as a result of degenerating neutrophils. Recombinant human deoxyribonuclease 1 also breaks down DNA to reduce the viscosity of sputum. • The most common adverse reactions associated with the treatment are upper

airway irritations, including pharyngitis and laryngitis.

Respiratory Stimulants• Drugs that are used to stimulate the respiratory system are called analeptics.• They are central nervous system stimulants with very low therapeutic indexes. • Doxapram increases both the rate and depth of respiration and acts on the

medullary respiratory center. • Nasal intermittent positive pressure ventilation has largely replaced its use.

However it may still be used for post operative respiratory depression and opiate overdose.• Aminophylline may also be used as a respiratory stimulant when given slowly

by IV infusion.

Oxygen Therapy• Oxygen therapy should be initiated whenever there is moderate or new-onset

hypoxia, PAO2<50 mm Hg. Patients with chronic hypoxia may be able to maintain adequate oxygenation with a PAO2 less than this by compensations such as increasing red blood cell mass. • However, concentrations of oxygen may still be indicated, particularly when

PaCO2 is increased, which is usually COPD. The stimulus to breathe is elevated CO2 but this can be diminished in patients with chronically high CO2 and replaced instead by a drive connected to a low oxygen.

• Elevating the oxygen level therefore might remove the stimulus to breathe. • High concentration oxygen therapy is indicated when both O2 and CO2 levels

are low, as might be seen in a patient with a pulmonary embolism, pneumonia, or myocardial infarction and early in an acute severe asthma attack. Long-term continuous oxygen therapy is given to patients with severe hypoxia and corpulmonale caused by COPD.

Chronic Obstructive Pulmonary Disease• Clinical signs and symptoms include excessive production of sputum with mucus pluggin, cough, increased respiratory rate, hypoventilation, hypercapnia, and hypoxia. Anatomical changes that occur include glandular hypertrophy, goblet cell metaplasia, and inflammation and fibrosis of the airways (smaller airways greater than larger airways), leading to a narrowing of the lumen and obstructive flow. Many of these changes are irreversible, which is what separates this illness from asthma. Drugs are used to improve functional abilities and to turn around the reversible component of the disease.

• The therapeutic approach to COPD needs to be flexible enough to keep up with the progression of the disease. • The American Thoracic Society recommends spirometry measurements to help

determine the presence and severity of COPD. • During the early, largely asymptomatic phase, the therapeutic goal is to slow the

lost of lung function. An important step in this process is, of course, the cessation of cigarette smoking.

• Traditionally, patients have used a combination of short-acting ß₂-agonists and anticholinergic drugs . Combination therapy appears to be slightly better than monotherapy with short-acting ß₂-agonists in reducing exacerbations but is not superior to monotherapy with ipratropium. Salbutamol and ipratropium given four times a day is the most common combination eg inhaler.• The anticholinergic compounds reduce neurogenic control of mucus, which is

probably why monotherapy with ipratropium is efficacious. • The longer-acting agents, the ß₂-agonists formoterol and salmeterol, and the

anticholinergic agent tiotropium have recently been introduced as treatment for COPD.

• Combining a longer-acting ß₂-agonists with ipratropium is more effective than combining a short-acting agent with ipratropium. In this case the patients will carry around 2 inhalers.• Inhaled corticosteroids with and without long-acting ß₂-agonists are also used in

the treatment of COPD.• Other treatments of COPD include antibiotics since there is the pressence of

copious amount of sputum which provides fertile ground for bacterial growth; and mucolytic agents such as N-acetylcysteine which reduce the viscosity of the mucus.• As COPD progresses, oxygen therapy becomes necessary to relieve hypoxemia

and prolong survival.

Cystic Fibrosis• CF is a multisystem disease in which there is a defect in a gene on chromosome

7 that encodes a chloride channel common to epithelial cells (CFTR, cystic fibrosis transmembrane conductance regulator). Failure to develop this channel affects epithelial cells lining the airways, intestines, biliary and pancreatic ducts, vas deferens, and sweat ducts. The result is that fluid secretion is diminished and what is secreted becomes more viscous, leading to plugging of ducts. There is also an up-regulation of sodium channels, particularly in the airways, leading to reabsorption of sodium. Proinflammatory pathways are also up-regulated in the airways, and bacterial killing is diminished.

• Failure of the pancreas to produce digestive enzymes leads to the inability to absorb fats and protein. Specifically, the fat-soluble vitamins A, D, E, and K cannot be absorbed. The deficiency of vitamin K may lead to bleeding. Supplementation with water-miscible forms of these vitamins is necessary. Drugs that inhibit acid secretion may also be administered to enhance survival of the pancreatic enzymes. • In the lungs, due to mucus plugging and impaired mucociliary clerance, mucus

produced in the glands have difficulty getting out and this leads to hypertrophy of the gland. Several drugs to help correct these defective ion channels are under study. An aerosolized form is available for patients with CF. Benzamil is a related drug that has a longer effect on the sodium channel.• Because thinning of secretions and keeping the airways open are major

treatment goals in CF, mucolytic agents and combination with PT is used.

Therapeutic concerns with drugs for respiratory disorders• Patients with respiratory illnesses will commonly receive drugs from any of the

following categories: steroids, ß₂-agonists, and anticholinergic agents. The therapeutic concerns are largely related to their side effects:• Tachycardia• Hypertension• Urinary retention• Dry mouth, which produce swallowing difficulty• Thrush• Oral candidiasis• Bruising• Osteoporosis• Hyperglycemia• Atrophy of skin and muscles• Tremor • Hypokalemia

Drugs for Gastrointestinal Tract

Disorders.

Physiological Control of Digestion.

• Control of digestion is a multisystem effort involving neuronal and hormonal regulation.• Input from all of these systems coordinates the three phases of

digestion.

Neuronal Control• The gastrointestinal (GI) tract is a long hollow tube surrounded by strong

smooth muscles that propels food from one end to the other.• It has five layers.An inner mucosal layer,a submucosal layer,circular

smooth muscle ,longitudinal smooth muscle and an outer serosal layer(peritoneum).• Two interconnected neural plexuses which together is known as the

enteric nervous system provide neural input for smooth muscle contraction.

• Both the enteric and myenteric plexuses receive preganglionlic input from the parasympathetic fibers of the vagus nerve where most of the fibers are cholinergic.• The neurons secrete acetylcholine and norepinephrine but also serotonin

,purines,nitric oxide and several peptides.

Hormonal Control • Gastrin primary function is to stimulate gastric acid secretion from

parietal cells,which aid in digestion of food.• Gastrin also increases pepsinogen which becomes pepsin when exposed

to acid.• Growth of the mucosa of the stomach and small and large intestine is

facilitated by gastrin.• Secretin is released and activated when chyme enters the intestine with

a PH less than 3.0.

• Secretin stimulates the pancreas to secrete a bicarbonate containing solution.• Cholecystokinin stimulates contraction of the gallbladder to release its

bicarbonate contents into the small intestine also stimulates the secretion of pancreatic enzymes.• Two other important enzymes are the gastric inhibitory peptide and

motilin.• Gastric inhibitory peptide is released in response to glucose and fats.It

turns off gastric acid secretion in the stomach as the chyme passes into the intestine.• Motilin stimulates intestinal motility.

Phases of Digestion• There are three main phases of digestion ,the first of which begins even

before the food enters the mouth .This is the cephalic phase.• At the sight or smell of food acid is released in the stomach.• The next phase is called the gastric phase.It begins when food comes into

contact with the antrum.• The third phase begins when the chyme enters the duodenum and is

referred to as the intestinal phase.• During this phase the proteolytic enzyme activity in the stomach

decreases and acid secretion lessens.

Acid-Related Disease and Its Treatment• Because the parietal cell secretes acid,it has become the target of many drugs for the treatment of acid related disorders.

• The three receptors ,Ach,histamine and gastrin are contained with the wall of the parietal cell.

• When histamine occupies the receptor,it results in cyclic adenosine triphosphate converting into adenosine monophosphate providing energy for the acid pump.

• When either Ach or gastrin occupies the receptor,the signal to initiate the production of acid is the calcium ion.• The proton pump is located in parietal cell and can be blocked by

histamine blockers, anticholinergic agents and drugs called proton pump inhibitors.• The pump transports chloride into the stomach with potassium.• The potassium is exchanged for hydrogen from the cell from the K/H –

ATPase Pump.• The acid is obtained from the combination of carbon dioxide and water

to yield carbonic acid which disassociates into hydrogen ions and bicarbonate ion.• The enyzme that catalyzes the binding of carbon dioxide and water is

carbonic anhydrase.

Disease related to excess acid production.• Gastroesophageal reflux disease occurs when there is an upwards movement of

gastric contents into the esophagus.• This results from the lower sphincter relaxation. It results from gastric dimension

after a large meal or delayed gastric emptying and may increase in frequency when alcohol or fatty food is consumed.• Regular reflux produces a mucosal injury to the esophagus, resulting in

hyperemia,inflammation and heartburn.• Other symptoms include belching and pain in the retrosternal or epigastric are

which may radiate to the throat ,shoulder or back.• Pain usually occurs soon after eating and is exacerbated by bending at the

waist,lying down or anything that increase intraabdominal pressure such as a tight belt or waistband.

• Persistent GERD can lead to Barett’s esophagus in which the esophagus displays strictures ,scar tissue ,spasms and edema caused by repeated injury to the mucosa.• This is associated with the increased risk of esophageal cancer.• Peptic ulcer disease is another group of ulcerated disorders that

occur in the upper GI tract(stomach and duodenum).• An ulcer can affect one or all the layers of the stomach and

duodenum.• Many of the peptide ulcer disease result from helicobacter pylori

infection.This is a gram negative bacillus that cause chronic gastritis.• Gastritis and ulceration results from the host immune responses to

eradicate the organism which induces proinflamatory cytokine expression and inflammation as well as reducing somatostatin levels.

• Somatostatin regulates gastrin production.Therefore the bacteria increases gastrin and acid release.• Aspirin ans non-steriodal antiinflammatory drugs(NSAIDs) also acount

for many gastric and duodenal ulcers.

Acid-Supressive Drugs• Antacids,histamine blockers and PPIs are the primary drugs used to

supress gastric hyperacidity.• Antacids can be administered with histamine blockers for optimal results

but the histamine blockers need to be taken at least 1 hour before the antacids.

Antacids• There are several basic preparations:aluminum based,magnesium-

based ,calcium based and sodium bicarbonate based solution.• The mechanism of the action is to neutralize the gastric acidity.• Antacids enhance gastric mucosal defensive properties by stimulating

secretion of mucus ,prostagladins and bicarbonate which results in a reduction of pain and an improve resistance to irritation.• Side effects are minimal,however the effervescent products eg(Alka-

Seltzer) contain a lot of sodium and should not be used regularly if patient is on a sodium restricted diet.• Other side effects include GI disturbances,magnesium preparation

may produce diarrhea and aluminum and calcium preparations produce constipation.

Histamine 2 Receptor Antagonists• Histamine 2 antagonists reduce stimulated acid secretion.They are able to inhibit

not only histamine-stimulated release but also gastrin and Ach-stimulated acid release ,inhibiting nearly 90% of all acid secretion in the stomach.• These drugs also promote the healing of ulcers but unfortunately ulcers often

reappear after therapy is stopped.• The prototypic drugs are cimetidine and ranitidine.These drugs are available in low

doses without prescription for self administeration.• Newer H2 antagonists include nizatidine and famotidine.They generally well

tolerated and can produce diarrhea,dizziness,muscle pain and rashes,hypergastrinemia has been reported.• Cimetidine can cause gynecomastia because of its affinity for the androgen

receptors and this drug also inhibits the P450 enzymes,therefore it ca slow down the metabolism of several drugs including anticoagulants and some tricyclic antidepressants.

Mucosal ProtectorsA few drugs that either enhance the mucosal protective mechanisms or provide a physical boundary over the surface of an ulcer are available.

Bismuth Chelate

Bismuth chelate offers numerous protective properties against an H. pylori-induced ulcer. It is believes to coat the base of the ulcer, enhance prostaglandin synthesis, and increase gastric mucous epithelial cell growth. It also has a direct toxic effect on the bacillus. Blackening of the tongue and faeces, as well as nausea and vomiting, are some side effects.

Sucralfate• This drug is used to protect the mucosal lining in cases of active stress

ulcerations and chronic peptic ulcer disease. The term stress ulcer refers to a GI ulceration that develops during periods of major physiological stress.

• Patients who are at high risk for this ulcer include those with large surface area burns, trauma, liver failure and acute respiratory distress syndrome and those undergoing major surgery.

• Sucralfate acts locally by binding directly to the surface of the ulcer. When it is exposed to an acid environment, the drug associates into aluminium hydroxide (an antacid) and sulphated sucrose. The sulphated molecules attach to the ulcer, forming a protective covering over the area.

• One advantage of this drug is that it stays local and therefore does not interact with other drugs in circulation. However, the drug can decrease the absorption of other medications.

• Side effects are minor and include constipation and nausea.

MisoprestolThis is a synthetic drug prostaglandin analogue. It is believed to inhibit acid secretion, enhance the production of mucus and bicarbonate, and maintain blood flow to the mucosa. Diarrhoea is a common side effect.

Management of H. pylori Infection

The presence of H. pylori infection leads to chronic gastritis and peptic ulcer disease and also to gastroesophageal reflux disease (GERD) and cancer. Combination therapy is the standard regimen for eradication of H. pylori and treatment of the associated ulcer. Because eradication of the bacterium decreases ulcer recurrence and enhances healing, antibiotics must be combined with acid-controlling drugs.

Management of Nonsteroidal Anti-inflammatory Drug-Induced Ulcers

Long term NSAID use leads to gastritis and ulcerations, probably through blockade of prostaglandin production. Treatment regimens for H. pylori infection with NSAID use initially include the eradication of the bacterium, followed by acid suppression therapy. NSAIDs should also be discontinued if possible. If these drugs must be continued, it is imperative to have the patient to continue suppression therapy, particularly with a protein pump inhibitor (PPI).

Nausea & Vomiting

• Vomiting is the forceful expulsion of stomach contents through the mouth. It is usually preceded by nausea and repeated contractions of the abdominal muscles (retching). Vomiting can be a protective response to the ingestion of toxic chemicals or to an overdose of drugs but may also be an annoying or disabling side effect of medication. Vomiting also accompanies many serious disease processes.• Although antiemetic drugs are quite helpful, it is important to acknowledge that

even with treatment, nausea and vomiting from chemotherapy still occur in more than 50% patients receiving strong emetogenic drugs for cancer such as cisplatin and in more than 40% of patients receiving mild to moderate emetogenic drugs such as doxorubicin.

Neural Mechanisms Involved in Vomiting• Two separate areas in the medulla regulate vomiting. The chemoreceptor trigger zone (CTZ) is located on

the floor of the fourth ventricle of the cerebrum. Here it is exposed to both blood and cerebrospinal fluid where it can respond to the presence of drugs and toxins.

• The vomiting centre located in the dorsal reticular formation of the medulla is responsible for the integration of the signals from the GI tract, pharynx, vestibular system and the CTZ. Hypoxia of this area produces vomiting, which accounts for events that occur during a myocardial infarction or brain ischemia caused by increased intracranial pressure.

• Information from abdominal organs, the liver, gallbladder, and other areas is communicated to the vomiting centre through visceral afferent neurons.

• Mechanoreceptors located in the muscular wall of the stomach and chemoreceptors located in the mucosa of the upper GI tract also send information regarding stretch and chemical makeup of the stomach to the vomiting centre.

• The neurotransmitters involved in vomiting include dopamine, serotonin and opioid receptors in the GI tract and CTZ and norepinephrine and Ach receptors on the vestibular centre.

Labyrinth (Inner Ear)

Gastrointestinal Tract Cerebral Cortex

Chemoreceptor Trigger Zone (CTZ)

Vomiting Centre

Antiemetic Drugs Antiemetic drugs are mainly used to combat nausea and vomiting produced by many chemotherapy agents and illnesses related to vestibular motion. They include anticholinergic agents, antihistamines, neuroleptic agents, prokinetic drugs, serotonin inhibitors and tetrahydrocannabinol. Steroids with or without anxiolytics may also be used.

• Anticholinergics- Scopolamine is the primary anticholinergic used to prevent vomiting related to motion. It binds to Ach receptors on the vestibular nuclei located in the inner ear and blocks the communication between this area and the vomiting centre. The most common form of scopolamine is a transdermal patch with a duration of action up to 72 hours. The patch is applied to hairless skin behind the ear at least 4 hours before travel. Side effects include dizziness and drowsiness, blurred vision, dilated pupils, dry mouth and difficulty with urination.

• Neuroleptic Drugs- These are antipsychotic agents that block dopamine receptors in the CTZ. Many of these drugs also have anticholinergic actions. Prochlorperazine and promethazine are commonly used for preventing nausea and vomiting during or immediately after surgery. Side effects include orthostatic hypotension, tachycardia, blurred vision, dry eyes and urinary retention.

• Antihistamines- Cyclizine, dimenhydrinate, and diphendryamine are H₁-blocking agents that act by inhibiting vestibular input to the CTZ. Specifically, they block Ach binding to H₁ receptors in the vestibular nuclei. They are used to treat motion sickness. Dizziness and sedation are the main side effects.

• Prokinetic Drugs- These drugs block dopamine in the CTZ, but their primary action is to stimulate peristalsis, facilitating emptying of the stomach. Metoclopramide is used for delayed gastric emptying, GERD and chemotherapy-related vomiting. It has both central and peripheral antiemetic effects. Side effects include sedation, diarrhoea, weakness and prolactin release. Patients taking prokinetic drugs may also experience hypotension, hypertension and tachycardia.

• Serotonin Blockers- The serotonin antagonists used to prevent emesis specifically block the serotonin receptors in the GI tract, CTZ and vomiting centre. They represent one of the newest classes of drugs for the prevention of nausea and vomiting caused by cancer chemotherapy. They include dolasetron, granisetron, ondansetron and palonosetron. They can be administered in intravenous or oral formulations. Side effects include headache, dizziness and diarrhoea.

• Cannabinoids- Dronabinol, a schedule II controlled substance, is a synthetic derivative of THC used in the treatment of chemotherapy-related emesis. It is also used as an appetite stimulant for patients with AIDS. Its antiemetic effects were originally observed in patients who were using marijuana during chemotherapy. Its mechanism of action in this role is unclear, but it may possess some antiadrenergic activity and block prostaglandin synthesis. It is considered a second line agent in the treatment of emesis because of its side effects, which include ataxia, light-headedness, blurred vision, dry mouth, weakness, tachycardia or bradycardia, and central nervous system effects such as confusion, mood changes and anxiety.

• Corticosteroids- These are useful for decreasing emesis when mildly emetic chemotherapy drugs are administered but not with highly emetogenic agents when used alone. The mechanism of action for this effect is poorly understood, but when steroids are combined with a serotonin blocker, this regimen is more effective than treatment with each drug alone.• Neurokinin 1 Receptor Antagonists- This category of drugs contain several

compounds that are currently under study for the treatment of emesis related to chemotherapy. The focus of these drugs is to antagonize substance P³³. Substance P binds to the tachykinin neurokinin receptor 1 and is capable of producing emesis through this mechanism. Side effects are mild but annoying.

Constipation

Irritable Bowel Syndrome

Therapeutic concerns with Gastrointestinal Agents

A movement disorder of the colon and rectum resulting in infrequent or painful defecation, hard stools, or the sense that thereis evacuation.

Can be symptom of BOWEL IMPACTION or due to ENDOCRINE or NEUROGENIC

DISORDERS

Causes: SEDENTARY LIFESTYLE

LOW ROUGHAGE OR FLUID DIETCERTAIN MEDICATIONS

IMPROVE DIET

WAYS TO MANAGE CONSTIPATION

Use laxative

Surgery

EXERCISE

LAXATIVE- nonsurgical treatment

• DIVIDED INTO 3 CATEGORIES• 1 IMPROVED FIBER & FLUID SUPPLEMENTATION• 2 INCREASE PHYSICAL ACTIVITY• 3 PHARMACOLOGICAL TREATMENT

TYPESBULK –FORMING

EMOLLIENT

HYPEROSMOTIC

SALINE

STIMULANT

LAXATIVES

Laxative Description

Bulk- forming laxatives Increase water absorption, resulting in softening and greater bulk of the intestinal contents. Causes increase peristalsis.Safe for prolong use.Taken with lots of water to prevent esophageal obstruction and fecal impaction

Emollient Laxative aka fecal softener and lubricant laxatives

Facilitates water and fat absorption into stool and lubricates fecal material and wall of intestine

Hyperosmotic laxatives Works mainly in large intestine by drawing fluid into colon.

Saline laxatives Increase osmotic pressure by increasing water and electrolyte secretions into small bowel.Results in watery stool

Stimulatant laxative Includes natural plant extracts products and also synthetic chemical agents that stimulate peristalsis.

Characterised by a constellation of symptoms including intermittent bouts of abdominal pain, bloating, diarrhea and constipation.

Treatment of Irritable Bowel Syndrome • Treatment consists mainly of agents designed to control the bouts of

diarrhea and constipation.• Fiber supplementation= use to reduce constipation • Antispasmodics= used to treat diarrhea

Treatment of Irritable Bowel Syndrome

• Fibers supplementation e.g. psyllium & methylcellulose• Provide needed bulk

Bulking Agents

• E.g. Diphenoxylate and loperamide• Have efficacy for the treatment of diarrhea in IBS

Antidiarrheal Agent

• Used to treat IBS include drugs that act directly on the intestinal smooth muscle anticholinergics, and calcium blockers.

Antispasmodics

Serotonergic Agonists and Antagonists

Other Therapies

Therapeutic concerns with gastrointestinal Agents• Influences physical therapy• Presence of dehydration • Physical therapy can aids with constipation• Dyssynergia

Reference

• Pharmacology for Physical Therapists by Barbara Gladson,PhD,PT,OTR