Bronchodilator Drugs

November 2013

Conceptual model for the immunopathogenesis of asthma.

•Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. •On reexposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene C4, and platelet-activating factor (PAF). •These agents provoke contraction of airway smooth muscle, causing the immediate fall in FEV1. •Reexposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins 4 and 5, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. •These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. •These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late asthmatic response, indicated by a fall in FEV1 2-8 hours after the exposure.

•The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen. •Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. •Postganglionic fibers release acetylcholine (ACh), which binds to muscarinic receptors on airway smooth muscle. •Inhaled materials may provoke bronchoconstriction by several possible mechanisms. •First, they may trigger the release of chemical mediators from mast cells. •Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction.

Mechanisms of response to

inhaled irritants.

Asthma Treatment

The pharmacologic agents used to treat asthma are divided into two broad categories:

relievers and controllers (also called preventers).

Asthma Treatment In general, bronchodilators, which alleviate

smooth muscle bronchoconstriction, are used as relievers, and

anti-inflammatory medications, which decrease airway inflammation, are used as controllers.

There is also evidence that some medications—methylxanthines, for example—have both bronchodilatory and anti-inflammatory effects.

Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by beta-adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists.

Bronchodilation

Bronchodilator Drugs

Sympathomimetic Agents Beta-Adrenergic Agonists Anticholinergics (Muscarinic Antagonists) Methylxanthines

Bronchodilator DrugsSYMPATHOMIMETIC AGENTS The adrenoceptor agonists have several pharmacologic

actions that are important in the treatment of asthma. They relax airway smooth muscle and inhibit release of

bronchoconstricting mediators from mast cells. They may also inhibit microvascular leakage and

increase mucociliary transport by increasing ciliary activity.

The beta agonists stimulate adenylyl cyclase and increase the formation of intracellular cAMP .

Stimulation of beta-2 receptors relaxes airway smooth muscle, inhibits mediator release, and causes tachycardia and skeletal muscle tremor as side effects.

Bronchodilator Drugs

SYMPATHOMIMETIC AGENTS (2) The sympathomimetic agents that have been widely

used in the treatment of asthma include epinephrine, ephedrine, isoproterenol, and albuterol and other b2-selective agents.

Because epinephrine and isoproterenol increase the rate and force of cardiac contraction (mediated mainly by b1 receptors), they are reserved for special situations.

In general, adrenoceptor agonists are best delivered by inhalation because this results in the greatest local effect on airway smooth muscle with the least systemic toxicity.

Bronchodilator DrugsSYMPATHOMIMETIC AGENTS

Epinephrine is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff). Maximal bronchodilation is achieved 15 minutes after inhalation and lasts 60-90 minutes. Because epinephrine stimulates alpha and beta-1 as well as beta-2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are troublesome adverse effects. The cardiovascular effects of epinephrine are of value for treating the acute vasodilation and shock as well as the bronchospasm of anaphylaxis, but its use in asthma has been displaced by other, more beta-2 selective agents.

Ephedrine was used in China for more than 2000 years before its introduction into Western medicine in 1924. Compared with epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and b2-selective agonists, ephedrine is now used infrequently in treating asthma.

Isoproterenol is a potent bronchodilator; when inhaled as a microaerosol from a pressurized canister, 80-120 mcg isoproterenol causes maximal bronchodilation within 5 minutes. Isoproterenol has a 60- to 90-minute duration of action. An increase in the asthma mortality rate that occurred in the United Kingdom in the mid 1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol. It is now rarely used for asthma.

Bronchodilator DrugsBeta-2-Selective Drugs The beta-2-selective adrenoceptor agonist drugs are the most widely used

sympathomimetics for the treatment of asthma at present . These agents differ structurally from epinephrine in having a larger substitution on

the amino group and in the position of the hydroxyl groups on the aromatic ring. They are effective after inhaled or oral administration and have a long duration of

action. Albuterol, terbutaline, metaproterenol pirbuterol

A new generation of long-acting beta-2-selective agonists includes salmeterol and formoterol.

Both drugs are potent selective beta-2 agonists that achieve their long duration of action (12 hours or more) as a result of high lipid solubility.

This permits them to dissolve in the smooth muscle cell membrane in high concentrations or, possibly, attach to "mooring" molecules in the vicinity of the adrenoceptor.

These drugs appear to interact with inhaled corticosteroids to improve asthma control. They are not recommended in combination with corticosteroids in therapy for asthma.

Bronchodilator Drugs METHYLXANTHINE DRUGS The three important methylxanthines are; theophylline, theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee,

respectively). Of the xanthines, theophylline is the most effective bronchodilator,

and it has been shown both to relieve airflow obstruction in acute asthma and to reduce the severity of symptoms and in patients with chronic asthma.

Bronchodilator Drugs

ANTIMUSCARINIC AGENTS Muscarinic antagonists competitively inhibit the

effect of acetylcholine at muscarinic receptors. In the airways, acetylcholine is released from

efferent endings of the vagus nerves, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity.

Bronchodilator DrugsClinical Use of Muscarinic Antagonists Antimuscarinic agents are effective bronchodilators. The selectivity of atropine's effect can be increased

further by administering the drug by inhalation or by use of a more selective quaternary ammonium derivative of atropine, ipratropium bromide.

Ipratropium can be delivered in high doses by this route because it is poorly absorbed into the circulation and does not readily enter the central nervous system.

A longer-acting, selective antimuscarinic agent, tiotropium, is approved as a treatment for COPD. This drug is also taken by inhalation. Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition.

Anti-inflammatory Agents CORTICOSTEROIDS Corticosteroids are mediated in part by inhibition of production of

inflammatory cytokines. They do not relax airway smooth muscle directly but reduce

bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly.

Their most important action is inhibition of the lymphocytic, eosinophilic mucosal inflammation of asthmatic airways.

beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone

Anti-inflammatory AgentsCROMOLYN & NEDOCROMIL Cromolyn sodium (disodium cromoglycate) and nedocromil sodium are used

as aerosols (by nebulizer or metered-dose inhaler), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity.

However, these drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm.

They are only of value when taken prophylactically.

They cause an alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation. This action on airway nerves is thought to be responsible for inhibition of cough; on mast cells, for inhibition of the early response to antigen challenge; and on eosinophils, for inhibition of the inflammatory response to inhalation of

allergens. The inhibitory effect on mast cells appears to be specific for cell type, since

cromolyn has little inhibitory effect on mediator release from human basophils. when given after the early response to antigen challenge, ie, after mast cell degranulation has occurred.

Anti-inflammatory Agents LEUKOTRIENE PATHWAY INHIBITORS Because of the evidence of leukotriene involvement in many inflammatory

diseases and in anaphylaxis, considerable effort has been expended on the development of drugs that block the synthesis of these arachidonic acid derivatives or their receptors.

Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and are synthesized by a variety of inflammatory cells in the airways, including eosinophils, mast cells, macrophages, and basophils.

Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion.

Two approaches to interrupting the leukotriene pathway have been pursued: inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action.

zileuton, a 5-lipoxygenase inhibitor, and zafirlukast and montelukast, LTD4-receptor antagonists. All have been shown to improve asthma control and to reduce the frequency

of asthma exacerbations in outpatient clinical trials. Montelukast is approved for children as young as 6 years of age.

MANAGEMENT OF ACUTE ASTHMA The treatment of acute attacks of asthma in patients reporting to the

hospital requires close, continuous clinical assessment and repeated objective measurement of lung function.

For patients with mild attacks, inhalation of a beta 2-receptor agonist is as effective as subcutaneous injection of epinephrine.

Both of these treatments are more effective than intravenous administration of aminophylline (a soluble salt of theophylline).

Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6 hours).

Even this aggressive treatment is not invariably effective, and patients must be watched closely for signs of deterioration.

If all the interventions fail and respiratory failuse develops general anesthesia, intubation, and mechanical ventilation may be lifesaving.

Antitussives, Expectorants and Surfactants

November 2013

ANTITUSSIVE DRUGS The opioid analgesics are among the most effective

drugs available for the suppression of cough. This effect is often achieved at doses below those

necessary to produce analgesia. The physiologic mechanism of cough is complex, and

little is known about the specific mechanism of action of the opioid antitussive drugs. It is likely that both central and peripheral effects play a role.

Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions.

ANTITUSSIVE DRUGS The opioid derivatives most commonly used as

antitussives Dextromethorphan is the dextrorotatory stereoisomer of a

methylated derivative of levorphanol. It is free of addictive properties and produces less constipation than codeine. The usual antitussive dose is 15-30 mg three or four times daily. It is available in many over-the-counter products.

Codeine, as noted, has a useful antitussive action at doses lower than those required for analgesia. Thus, 15 mg are usually sufficient to relieve cough.

Levopropoxyphene is the stereoisomer of the weak opioid agonist dextropropoxyphene. It does not have opioid effects, although sedation has been described as a side effect. The usual antitussive dose is 50-100 mg every 4 hours.

EXPECTORANTS These drugs are also called “Mucolytics” They dilute the of respiratory tract secretions

and sputum with water. Terpine Bromhexidine Chloride Ambroxsole Gaifenezin Acetylsistein (mucolytic)

Pharmacology and Toxicology of Tobacco

November 2013

Terminology Drug abuse: use of any drug for nonmedical purposes. Physical Dependence: A state charcretized by signs

and syptoms Psychological dependence / Addiction: Compulsive

drug seeking behaviour Withdrawal / Abstinence Syndrome: The sings and

syptoms that occur on the absence of a drug in a phsically dependent person

Tolerance: Decrease response to the effects of a drug.

Drug Abuse Strong feelings of euphoria or alter

perception Repetitive exposure induces adaptive

changes in the brain Drug use becomes compulsive

Tobacco is an agricultural product, recognized as an addictive drug, processed from the fresh leaves of plants in the genus Nicotiana.

Smoking is the leading preventable cause of death worldwide and estimates that it currently causes 5.4 million deaths per year.

NICOTINE addiction to nicotine exceeds all other forms of addiction,

effecting more than 50% of all adults in some countries. Nicotine exposure occurs primarily through smoking of

tobacco, which causes associated diseases that are responsible for many preventable deaths.

The chronic use of chewing tobacco and snuff tobacco is also addicting.

Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine.

NICOTINE nicotinic acetylcholine receptor play an important role in

cognitive processes. Alzheimer's dementia with a loss of ACh-releasing

neurons in the brain. The rewarding effect of nicotine requires involvement of

the ventral tegmental area , where nAChRs are expressed on dopamine neurons.

When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs.

Nicotine-evoked dopamine release - the long-term changes induced by the drugs related to addiction.

Nicotine dependence is both psychological and physical dependence.

Nicotine withdrawal is mild compared with opioid withdrawal, and involves irritability and sleeplessness.

Nicotine is among the most addictive drugs and relapse after attempted cessation is very common.

Cigarette smoke Cigarette smoke is the most commonly encountered and important

toxin in the United States. It is responsible for about 30% of all U. S. cancer deaths and for

significantly increased risks of pulmonary disease and cardiovascular disease.

Tobacco smoke causes not only lung cancer but also cancers of the oral cavity, esophagus, pancreas, and bladder.

Passive smoking—that is, the exposure of nonsmokers to cigarette side-stream smoke—is also believed to cause cancer and cardiovascular disease, although the magnitude of these risks is less clear than it is for smokers.

The carcinogenicity of cigarette smoke is likely due to the combined actions of many of the dozens of carcinogens, including benzo(a)pyrene, among the 4,000 chemicals in cigarette smoke.

A number of these carcinogens are not limited to the particle phase, or “tar,” but are in the gas phase as well.

“Low tar” cigarettes are as carcinogenic and cause as much cardiovascular disease as “regular” cigarettes.

Chronic obstructive pulmonary disease (COPD) and tobacco

Chronic obstructive pulmonary disease (COPD) describes a spectrum of disorders that results in obstructive lung disease.

Unlike asthma, COPD is generally not reversible. COPD is caused by an abnormal inflammatory response to an inhaled environmental insult.

In 90% of cases, this insult to the lungs is tobacco smoke. Clinically, COPD is divided into two frequently overlapping diseases:

emphysema and chronic bronchitis. Pulmonary emphysema refers to alveolar enlargement caused by

destruction of alveolar walls, chronic bronchitis is a clinical diagnosis made on the basis of a

chronic cough, for 3 or more months during 2 consecutive years, that cannot be attributed to another cause.

COPD is caused by an abnormal response to inhalation of tobacco smoke or other toxic agents.

Chronic obstructive pulmonary disease (COPD) and tobacco (2) In contrast to asthma, where CD4+ T lymphocytes, B lymphocytes,

mast cells, and eosinophils are the primary inflammatory cells, the inflammatory response to tobacco smoke is primarily neutrophilic and monocytic.

Tobacco smoke stimulates resident alveolar macrophages to produce chemokines that attract neutrophils.

These neutrophils and resident macrophages release proteinases, particularly matrix metalloproteinases.

The proteinases degrade elastin, which provides elastic recoil to the alveoli, as well as other proteins that compose the matrix supporting the lung parenchyma.

Cell death follows, due to impaired attachment to the degraded matrix and to the toxic actions of inflammatory cells.

The result is that alveoli degrade and coalesce, forming the characteristic enlargement of air spaces typical of emphysema.

There is also enhanced mucus production and fibrosis, although the mechanisms underlying these pathologic phenomena have not been well characterized.

Nicotine addiction Nicotine directly activates nicotinic acetylcholine receptors that are

located centrally, peripherally, and at the neuromuscular junction. Centrally, nicotine produces a strong dependence, and the craving

for cigarettes is directly tied to decreases in the plasma levels of nicotine.

Cholinergic neurons arising from the laterodorsal tegmental area (near the border of the midbrain and pons) activate nicotinic and muscarinic acetylcholine receptors on dopaminergic neurons in the ventral tegmental area; stimulation of these nicotinic receptors by nicotine activates the dopaminergic brain reward pathway.

This strong and direct effect on the reward pathway explains the high addiction potential of nicotine, and hence of cigarettes and other forms of tobacco.

Role of cholinergic neurotransmission in the brain reward pathway.

•Nicotinic neurons (black) arising in the laterodorsal tegmental area (DTA) activate dopaminergic neurons (blue) in the ventral tegmental area (VTA). •These neurons, which make up the brain reward pathway, release dopamine in the nucleus accumbens (NAc).

Nicotine addiction Nicotine sustains tobacco addiction, a major cause of disability and

premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating

neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users.

Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal.

Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as

genes involved in neuroplasticity and learning, in development of dependence.

Nicotine is primarily metabolized byCYP2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk.

Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers.

Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.

Treatment Nicotine Replacement Therapy

Treatment for nicotine addiction includes substituting nicotine that is chewed, inhaled, or transdermally delivered for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke.

Bupropion In addition, the antidepressant bupropion has been approved for

nicotine cessation therapy. It is most effective when combined with behavioral therapies.

Many countries have banned smoking in public places to create smoke-free environments.

Nicotine Replacement Therapy Nicotine medications act on nAChRs to mimic or replace the effects of nicotine from

tobacco. Nicotine replacement medications are believed to facilitate smoking cessation in

several ways. The principal action is the relief of withdrawal symptoms when a person stops

tobacco use. Amelioration of these symptoms is observed with relatively low blood levels of

nicotine. A second mechanism of benefit is positive reinforcement, particularly for the arousal

and stress-relieving effects. The degree of positive reinforcement is related to the rapidity of absorption and the

peak nicotine level achieved in arterial blood. Positive reinforcement is most relevant to rapid-delivery formulations such as nicotine

nasal spray and, to a lesser extent, nicotine gum, inhaler, and lozenge. The use of these products allows smokers to dose themselves with nicotine when

they have the urge to smoke cigarettes. Nicotine patches, on the other hand, deliver nicotine gradually and produce sustained

nicotine levels throughout the day, thus not providing much positive reinforcement. A third possible mechanism of benefit is related to the ability of nicotine medications

to desensitize nicotinic receptors. This desensitization results in a reduced effect of nicotine from cigarettes; e.g., when

a person lapses to smoking while on nicotine replacement therapy, the cigarette is less satisfying and the person is less likely to resume smoking.

Bupropion

Bupropion was marketed as an antidepressant medication before it was marketed for smoking cessation.

The serendipitous observation of spontaneous smoking cessation among veterans treated with bupropion for depression led to the exploration of bupropion as a smoking cessation medication.

Bupropion increases brain levels of dopamine and norepinephrine, simulating the effects of nicotine on these neurotransmitters.

Bupropion also has some nicotine receptor–blocking activity, which could contribute to reduced reinforcement from a cigarette in the case of a lapse.

Varenicline

Varenicline was synthesized with the goal of developing a specific antagonist for the α4 β2 nAChR.

Varenicline is an analog of cytisine, a plant alkaloid that has been reported to have some benefit in smoking cessation but is thought to have generally poor oral bioavailability.

Varenicline was shown in in vitro receptor binding studies to have high affinity for the α4 β2 nAChR, and relatively little effect on other nAChR subtypes or neurotransmitter receptors. Varenicline is a partial agonist of the α4 β2 receptor in vivo, as demonstrated by studies of dopamine release, measured with microdialysis in the nucleus accumbens of conscious rats.

Nicotine, a full agonist, causes substantial dopamine release. Varenicline produces less of a response than nicotine (50%) but at the same time blocks the effects of any nicotine added to the system.

Clinical trials have found that varenicline is superior to bupropion in promoting smoking cessation, and prolonged administration of varenicline has been shown to reduce relapse in smokers who were abstinent 12 weeks after initial therapy.

Cardiovascular System Disorders - atherosclerosis

Cancer - overtime allows high quantities of carcinogens to deposit in the mouth, throat, and lungs.