IP4 Midterm

chronic obstructive pulmonary disease (COPD)

common preventable and treatable disease characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory responsein the airways and lungs to noxious particles or gases. -COPD includes both chronic bronchitis and emphysema.

Compare and contrast the conducting zone and respiratory zone

conducting zone- contains a continuum of over 20 branching air passageways in the lungs called the bronchial tree. respiratory zone- site of gas exchange. consists of the terminal bronchioles that feed into the alveolar ducts. The alveolar ducts feed into the alveolar sacs. The alveolar sacs contain many gas-filled alveoli which are tiny, thin-walled air sacs where gases are exchanged between air and blood. As the conducting tubes become smaller, and move toward the respiratory zone, the following structural changes occur: 1. The cartilage rings are replaced by irregular plates of cartilage. 2. Mucosal epithelium changes from a ciliated pseudostratified columnar cell type to a thinner epithelial cell with few cilia and few mucus-producing cells. 3. The amount of circular smooth muscle increases as the conducting tubes become smaller. The amount of smooth muscle is inversely proportional to the amount of cartilage. This is important because smooth muscle can control the diameter of the bronchioles by contracting and increasing resistance to airflow.

hypoxemia

decreased PO2 in blood

pulmonary surfactant

detergent-like complex of lipids and proteins that reduces the surface tension of water decreases the cohesiveness of water molecules Surfactant intersperses between water molecules and lowers the alveolar surface tension. Surfactant decreases the extent of hydrogen bonding between water molecules at the alveolar air-water interface.

why is β2-receptor activation helpful for management of COPD?

dilation of bronchial smooth muscle tissue

Compare the delivery and absorption of nicotine for each NRT.

Transdermal Nicotine Patches - Nicotine patches deliver a constant rate of nicotine via absorption across the epidermis and dermis for up to 24 hours Nicotine GUM - About 50% of the amount of nicotine in each piece of gum is absorbed across the buccal mucosa This inefficiency of absorption is partly due to inherent poor buccal absorption of the drug, and partly due to residual nicotine which is not effectively leeched from the gum. Therefore, a patient taking a fixed schedule of 10 pieces per day receives either 10 or 20 mg of nicotine from the 2 and 4 mg dosage forms, respectively. Nicotine Lozenge - result in the systemic absorption of about 60 - 75% of the nicotine contained in each lozenge Nicotine inhaler - Each cartridge contains 10 mg nicotine, of which about 4 mg is delivered to the oral cavity over approximately 80 puffs. As mentioned above, about half, or 2 mg, of the delivered nicotine is absorbed from the buccal mucosa. The majority of the remaining nicotine that is swallowedis absorbed from the stomach and upper intestines, but most is metabolized by first-pass metabolism before reaching systemic circulation. Most patients require between 6 to 16 cartridges per day. Nicotine Nasal Spray - most rapid delivery of nicotine of all the available NRT products, with a time to maximum blood concentration (Tmax) of about 12 minutes.

Identify the anatomical site(s) of drug absorption for each NRT.

Transdermal Nicotine Patches = Thought of as a "passive" method of nicotine delivery, as no further action is required by the patient after the patch is placed on the skin. Nicotine GUM = -Proper use of nicotine gum is essential, and patients must be counseled that nicotine gum is not to be chewed like ordinary gum - Gum is activated by chewing until a tingling "peppery" sensation is felt by the patient - Once this occurs, the gum should be "parked" in the buccal cavity for a minute or so until the sensation stops. The gum is then chewed again until the sensation recurs, followed by parking in the buccal cavity. - each piece of gum lasts for approximately 30 minutes. Nicotine Lozenge = The vapor is drawn into the mouth with light puffing where about half the nicotine is absorbed across buccal mucosa and about half the nicotine is swallowed in the saliva. A small portion of nicotine is absorbed from the lungs. Nicotine Nasal Spray = A dose consists of two sprays (1 mg), one spray to each nostril - The nicotine delivered by the spray is absorbed into the systemic circulation across the nasal mucosa, avoiding first-pass metabolism.

role of asthma action plans

Using a written asthma action plan to know when and how to take daily actions to control asthma, adjust medication in response to signs of worsening asthma, and seek medical care as appropriate. Patients should be educated and provided a written action plan so they have the ability to control their asthma with guidance from health care providers.

Classify phosphodiesterase-4 inhibition as selective or nonselective.

Roflumilast (Daliresp®) is the first selective PDE4 inhibitor to be marketed. Roflumilast selectively binds to and competitively inhibits PDE4. It is available as an oral tablet that is administered once daily. Theophylline is a narrow-therapeutic index drug that is associated with potentially life-threatening adverse effects - is a nonselective inhibitor of PDE (i.e., it inhibits multiple members of the PDE family) and at least part of its benefit in patients with asthma and COPD is believed to be due to this action.

Describe why β -receptor activation is helpful for management of asthma.

Role as Maintenance Medications -Long acting β -agonists should be considered when low doses of inhaled corticosteroids fail to achieve control of asthma. -Because long-term treatment with long-acting inhaled β -agonists does not appear to influence the persistent inflammatory changes in asthma, this therapy should never be used as monotherapy for patients with asthma. -Addition of long acting inhaled β -agonists to a daily regimen of inhaled corticosteroids improves symptoms, decreases nocturnal asthma, improves lung function, decreases the use of short-acting inhaled β -agonists, and reduces the number of exacerbations. -Short-acting inhaled β -agonists may be used to prevent exercise-induced bronchospasms when administered 15 minutes before exercise.

Explain why a β -agonist may cause tachycardia using autonomic nervous system concepts.

activating β2-receptors that are outside of bronchial tissue causes vasodilation

explain why a β2-agonist may cause tachycardia using autonomic nervous system concepts.

activating β2-receptors that are outside of bronchial tissue causes vasodilation

Identify the form of neurotransmission affected by non-NRT to reduce cigarette smoking reinforcing behavior.

Some studies have shown that bupropion reduces the rewarding (reinforcing) effect of cigarettes in patients who take bupropion and continue to smoke (i.e., smoking isn't as pleasurable while taking bupropion). Another effect of bupropion is to decrease the depressive symptoms associated with tobacco cessation, which, given its antidepressant properties, makes sense. Varenicline does not induce receptor desensitization and does not contribute to nicotine tolerance.

Interpret spirometry results from bronchodilator reversibility testing to determine if patients have reversible airflow limitation that suggests a diagnosis of asthma

Spirometry is a test that uses a spirometer to measure FEV1 and FVC. In the healthy lung, flow limitations on forced expiration results in FEV1/FVC ratios greater than 80% in adults and possibly greater than 90% in children. Any values less than these are suggestive of airflow limitation. Bronchodilator reversibility testing involves measuring the FEV1 before a short-acting β2-agonist is given. Then, FEV1 is measured10 to 15 minutes after the short-acting β2-agonist is given. An improvement in FEV1 of at least 10% is considered to be evidence of reversible airflow obstruction and favors a diagnosis of asthma. Alternatively, reversibility may be determined by an increase in FEV1 of at least 12% from baseline at a follow-up appointment after starting an inhaled corticosteroid.

rationale for administering mixtures of stereoisomers where appropriate

Stereoisomers, which have two asymmetric carbons, can be designated as the "threo" or "erythro" pair of enantiomers (Figure 3). The threo pair is used in all of the racemic formulations of methylphenidate. Of the 4 stereoisomers of methylphenidate, it is the d-threo-methylphenidate isomer that has the desired pharmacological activity.

Predict the effect on AUC, drug elimination half-life, and daily dose requirement for a drug affected by drug metabolism induction due to cigarette smoking when regular smoking is initiated and during successful tobacco cessation therapy.

The elimination half-life of nicotine is related to the dosage formulation it is delivered by. - When delivered directly and rapidly into the systemic circulation, such as with cigarette smoking, nicotine has a relatively short elimination half-life of 2 hours or less The duration and accumulation of nicotine in the body is often measured by the half-life of cotinine, one of the primary metabolites of nicotine, which has about 20% of the pharmacologic activity of nicotine but has a 16 hour half-life.

List the therapeutic range for theophylline, and when given a serum concentration of theophylline predict adverse effects of theophylline.

Theophylline is a narrow-therapeutic index drug with a therapeutic range of 5 to 15 mcg/mL. -At serum concentrations within the therapeutic range and between 15 - 20 mcg/mL, theophylline may cause insomnia, nervousness, irritability and mild gastrointestinal upset. -At serum concentrations > 20 mcg/mL theophylline may cause severe headache, tachycardia, nausea and vomiting. -At serum concentrations 25 - 40 mcg/mL theophylline may cause cardiac arrhythmias, and seizures (greater chance at concentrations closer to 40 mcg/mL). -At serum concentrations > 40 mcg/mL the patient is at high risk for permanent neurologic deficit and death.

List the mechanisms by which NRT and non-NRT produces beneficial effects during tobacco cessation therapy.

There are at least three major mechanisms of action by which NRT supports tobacco cessation: (1) Reduction of withdrawal symptoms, enabling patients to function while learning to live without cigarettes. (2) Reduction of reinforcing effects provided by nicotine delivered by cigarettes (e.g., the physical action of smoking a cigarette). (3) Possible provision of effects patients relied upon from cigarettes, such as sustaining a desirable mood, maintaining attention, and managing hunger and weight loss. For NRTS Patients should still pick a day to quit smoking and begin using NRT on their "quit day," even if they are not able to immediately stop smoking. Patients also may continue to use the NRT product beyond the indicated duration of therapy if they feel they need to continue using the product in order to quit.

tidal volume, inspiratory reserve volume, expiratory lung volume, and residual volume

Tidal volume (TV): During normal quiet breathing, about 500 mL of air are inspired and about the same quantity moves out of the lungs during a single breath. Inspiratory reserve volume (IRV): The amount of air that can be maximally inspired over and above the typical resting tidal volume. This is accomplished by maximal contraction of the inspiratory muscles and measures 2100 to 3200 mL. Expiratory reserve volume (ERV): The extra volume of air that can be maximally expired after tidal expiration. This volume is about 1000 mL. Residual volume (RV): The volume of air remaining in the lungs after maximal expiration. This volume is about 1200 mL.

treatment plan for children that will increase ADHD medication adherence

Timing of administration will have an influence on the potential to interfere with school schedules, trouble sleeping or "wearing off" at inopportune times. Immediate-release stimulants are dosed two to three times daily. This can pose a potential problem with medication administration during the school day. A special arrangement may be required with the on-site nursing staff, or a child may be embarrassed to take medications at school.

how do the following physical factors influence ventilation? airway resistance alveolar surface tension lung compliance

airway resistance- flow isinversely proportional to resistance. Anincrease in resistance decreases the airflow. The primary determinant of resistance is the radius of the conducting passageways. alveolar surface tension- measure of the cohesive forces within a fluid. Water has a very high surface tension and if water was the only fluid lining the alveoli, the high surface tension of water would exceed the opposing forces that keep the lungs open and the alveoli would collapse. Surfactant intersperses between water molecules and lowers the alveolar surface tension. lung compliance- how much effort is required to stretch or distend the lungs. It is a measure of how much change in lung volume results from a force that stretches the lungs. A highly compliant lung stretches farther for a given force as compared to a less compliant lung. In a healthy person, lung compliance is not a problem but replacement of elastic fibers with nonelastic tissue (fibrosis) can decrease lung compliance. A decrease in surfactant can also reduce lung compliance

general steps in pulmonary ventilation and the role of pressures and volumes

always remember that air flows down a pressure gradient. This means that during inspiration, Ppul must be less than Patm. In the opposite manner, during expiration, Patm must be less than Ppul. Boyle's Law PV= nRT or P1V1 = P2V2

acute respiratory failure in patients with COPD

an acute drop in PO2 of 10 to 15 mm Hg or any acute increase in PCO2 that decreases the serum pH to 7.3 or less

neurotransmitter that β2-agonists mimic and explain how this is important to their mechanism of action

epinephrine The endogenous ligand that activates β2-adrenergic receptors is epinephrine (norepinephrine has low affinity for β2-receptors, and both epinephrine and norepinephrine also activate β1-adrenergic and α-adrenergic receptors). The β2-agonists are designed to be chemical mimics of epinephrine that selectively bind and activate β2-receptors, with low affinity for β1-adrenergic or α-adrenergic receptors. However, the β2-agonists are not perfectly selective, and they can bind with and activate β1-receptors, particularly at high doses.

rationale for administration of α1-antiproteinase to patients with emphysema

in patients with inherited α1-antiproteinase deficiency-associated emphysema *COPD is more likely to develop* when α1-antiproteinase serum concentrations fall below a certain level.

protease-antiprotease balance and its role in COPD

neutrophils and macrophages release proteases that destroy the alveolar wall as well as stimulate mucus hypersecretion. Of importance, elastin that surrounds the alveoli is digested by the protease, elastase. α1-Antitrypsin is a protease inhibitor that normally inhibits trypsin, neutrophil elastase, and other proteases from destroying normal lung tissue. Some patients with COPD (1-2% of emphysema patients) have an inherited disease that results in a deficiency in α1-antitrypsin

patient population most likely to benefit from α1-antiproteinase administration

non-smokers with an FEV1 35% to 60% predicted

hypercapnia

increased PCO2 in blood

vaccination recommendations for patients with COPD

influenza covid 19 PPSV23 PCV13 tdap zoster

inspiration and expiration

inspiration- inspiratory muscles including the diaphragm and external intercostal muscles (muscles between the ribs) are stimulated to contract. Contraction of this set of muscles lifts and swings the rib cage outward, expanding the volume of the thoracic cavity. As the volume of the thoracic cavity increases, the lungsare forced to expand to fill the larger thoracic cavity. expiration- mostly depends on the elastic recoil of the lungs. The inspiratory muscles relax and resume their pre-inspiration state causing the rib cage to descend and both thoracic and intrapulmonary volumes to decrease

inspiratory capacity, functional residual capacity, vital capacity (forced vital capacity), and total lung capacity

inspiratory capacity (IC) is the maximum volume of air that can be inspired after a tidal expiration. It is the sum of TV and IRV. *IC = IRV + TV* The volume of air in the lungs remaining in the lungs after a tidal expiration is called functional residual capacity (FRC). *FRC = ERV + RV* Vital capacity (VC) also called forced vital capacity (FVC) is the maximum volume of air that can be moved out during a single breath following a maximal inspiration. *VC = IRV + TV + ER* The maximum volume of air contained by the lungs is the total lung capacity (TLC). *TLC = VC + RV*

Explain the term "narrow-therapeutic index drug" in terms of ED50 and TD50 and describe the clinical importance of a narrow-therapeutic index drug.

it is associated with potentially life-threatening adverse effects frequently require close therapeutic drug monitoring, perhaps in the form of serum concentration measurements there is a relatively small range between the effective dose and the toxic dose in patients. The dose that produces dose- limiting toxicity in half of the study subjects is referred to as the median toxic dose or TD50. The clinical therapeutic index (TI) is calculated by dividing the median toxic dose by the median effective dose.

Describe the chemical basis for the long duration of action for salmeterol.

long-acting β2-agonists due to their high log P value and their side-chain chemistry that anchors the drug into the β2-receptors. Onset = long Duration (half-life) = long 6hrs

pathophysiological changes that occur in both COPD and asthma

patients with COPD must work harder to breathe. Similarly to those suffering from asthma, patients with COPD have difficulty expelling air from their lungs.

asthma-COPD overlap syndrome (ACOS)

persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD

recommendations for behavioral interventions that can be used to improve therapeutic outcomes given a child with ADHD

positive reinforcement: Providing rewards or privileges contingent on the child's performance time-out: Removing access to positive reinforcement contingent on performance of unwanted or problem behavior response cost: Withdrawing rewards or privileges contingent on the performance of unwanted or problem behavior token economy: Combining positive reinforcement and response cost. Child earns rewardsand privileges contingent on performing desired behaviors and loses the rewards and privileges based on undesirable behavior.

Describe how α1-antiproteinase is produced as a drug product

prepared by pooling donated human plasma and separating out the α1-antiproteinase. As a result, α1-antiproteinase has a slight risk of containing infectious agents such as viruses. -Put simply, treatment of this patient population with α1-antiproteinase is analogous to treatment of patients with type 1 diabetes mellitus with human insulin: a protein that is normally produced, but is deficient in this patient population, is prepared external of the human body and delivered to the patient as a drug.

Explain the beneficial effect of modifying cysteinyl leukotriene activity in patients with asthma.

results in inhibition of synthesis of cysteinyl-leukotrienes (e.g., LTD4) as well as LTB4 and other eicosanoids that depend on LTA4 synthesis. *stops bronchoconstriction*

**Classify asthma severity in patients not currently taking maintenance medications. **Classify asthma control in patients currently taking maintenance medications.

see table 4 on page 21 for exam

when theophylline serum concentrations should be measured in terms of time after therapy initiation and time of day

serum concentration should be measured after the patient has reached steady-state blood levels (3 to 5 half-lives, or about 9 to 25 hours of regulardosing). The time that the serum concentration is checked relative to the time the dose is administered is also important. Serum concentrations should be checked 4 to 6 hours after the morning dose of Q12H theophylline sustained-release dosing and 8 hours after once-daily theophylline sustained-release dosing.

Classify β2-agonists as short- or long-acting and predict the duration of action in hours

short acting: albuterol levalbuterol racemic epinephrine (high log p) long acting: arformoterol formoterol olodaterol salmeterol vilanterol β2-agonists with a large log P value also have a longer duration of action because it is more difficult for the body to eliminate the drugs from the relatively polar bronchial tissue once they have distributed there.

target receptors of stimulant and non-stimulant agents

stimulants: methylphenidate and amphetamine block the presynaptic reuptake of dopamine and norepinephrine by inhibiting the dopamine transporter (DAT) andthe norepinephrine transporter (NET). They also inhibit the action of monoamine oxidase (MAO), an enzyme critical for clearing these transmitters in neurons. non-stimulants: -guanfacine and clonidine are both selective α2A adrenergic agonists. -atomoxetine and viloxazine selectively inhibit pre-synaptic reuptake of NE via NET.

Explain how the target of delivery relates to the mode of delivery

the target of topical delivery in asthma is the airways, and not the alveoli. The topical delivery mode also enhances the onset of action, which is important in rescue therapy.

classify phosphodiesterase-4 inhibition as selective or nonselective

theophylline- inhibits multiple members of the PDE family Roflumilast selectively binds to and competitively inhibits PDE4.

adverse effects and risks associated with α1-antiproteinase therapy

there is a risk for the patient's immune system to recognize it as foreign, and mount an immune response known by the general term as "hypersensitivity." Symptoms of hypersensitivity may progress as far as a life-threatening anaphylactic reaction. Common adverse effects (mostly related to infusion of a protein drug) include chills, malaise, headache, rash, hot flash, and pruritus.

Rank COPD in terms of causes of death and disability in the United States

third most common cause of death in the United States and the second leading cause of disability in the United States

structures of the respiratory system (e.g., trachea, pleurae, respiratory membrane, etc.) and their corresponding functions

trachea- conducts air and branches into the right and left bronchi pleurae- double-walled serosa (moist membranes) separate the thoracic cavity and the lungs respiratory membrane- where gas exchange occurs

type I and type II cells

type I- The walls of the alveoli are only one cell thick and primarily composed of the alveolar epithelial cells type II- cover the alveolar surface epithelium and secrete pulmonary surfactant

factors that can precipitate asthma exacerbations (aka triggers)

-Exposure to allergens and respiratory viral infections are the main factors responsible for causing exacerbations of asthma and/or the persistence of symptoms. The most common cause of severe exacerbations is a respiratory viral infection. -Exercise is probably the most common trigger of brief episodes of symptoms. Exercise incites airflow limitation in most children and young adults who have asthma. Exercise-induced airflow limitation is caused by either loss of heat, water, or both from the lung during exercise because of hyperventilation of air that is cooler and dryer than that of the airways. -Emotions worsen an attack in progress rather than precipitate an attack. Relaxation techniques may benefit the patient who becomes severely emotionally distraught during an asthma attack. Expressions of laughing, crying, anger, or fear can lead to hyperventilation and hypocapnia (abnormally low arterial carbon dioxide levels), which cause airway narrowing. -Gastroesophageal reflux can trigger an asthma exacerbation. Reflux of acid into the esophagus is thought to initiate a vagally mediated reflex bronchoconstriction. -Although the pathophysiology is unknown, menstruation can also trigger an asthma exacerbation. -Freezing temperatures, high humidity, and episodes of acute pollution have been associated with asthma exacerbations.

For a given drug-device combination, discuss the purpose of each ingredient contained in the product

-Most inhaled corticosteroids (e.g., fluticasone and beclomethasone) contain a halide (i.e., chloride or fluoride) atom which greatly increases their lipophilicity. This results in slow distribution into bronchial tissue and a prolonged duration of action.

environmental factors that influence the susceptibility to the development of asthma in predisposed individuals

-Respiratory viral infections (following a viral infection, patients may experience increased exercise intolerance for up to 4 weeks) -Allergens (e.g., pollens, dust mites, animal dander, and cockroaches) -Industrial smog (sulfur dioxide) -Photochemical smog (ozone and nitrogen oxides) -Diet (Patients may be allergic to specific foods or additives. The consumption of fruit rich in vitamin C may reduce wheezing symptoms in childhood. The severity of asthma in men has been linked to increased salt intake.) -Tobacco smoke -Higher socioeconomic status -Family size (Having no siblings or one sibling is associated with an increased risk of asthma compared with having more than one sibling.) -Occupational stimuli (e.g., flour dust (bakers), hay or mold (farmers), Arabic gum (printers), chemical workers, and plastics, rubber, and wood workers

risk factors that contribute to the development of COPD and identify the most common risk factor for COPD.

-Smoking is the most common risk factor for COPD -Genetic risk factor - a1-antitrypsin deficiency (a1-antitrypsin is a protease inhibitor that normally inhibits trypsin and other proteases from destroying normal lung tissue) -Occupational dusts and chemicals (working in gold and coal mining, working in the glass or ceramic industries with exposure to silica dust and in jobs that expose patients to cotton dust or grain dust, toluene, diisocyanate, asbestos, or pesticides) -Impaired lung growth -Asthma and airway hyperresponsiveness -Chronic bronchitis -HIV -Tuberculosis -Lower socioeconomic status -COPD results from a gene-environment interaction. For example, among patients with the same smoking history, not all will develop COPD due to differences in genetic predisposition to COPD.

plan to monitor tolerability and efficacy using the stimulant and non-stimulant ADHD medications

-Stimulant response is almost immediate; therefore, improvement in performance at school, work or home can be assessed by parents and teachers. -Rating scales that are useful to help with diagnosis can also be used to identify the response to treatments. -Some examples of rating scales include Vanderbilt ADHD Diagnostic Parent and Teacher Scales (35 symptoms and 8 performance items) and the ADHD Rating Scale-IV (18 item scale using DSM-IV criteria). -For adults, the Adult ADHD Self-Report Scale (assesses 18 symptoms based on adult activities) takes only about 5 minutes to complete. Considering that symptoms can continue throughout adulthood, it is recommended to assess patients periodically to determine if treatment should continue.

issue of addiction (use disorders) and the use of stimulant medications in ADHD

-Stimulants are classified as Schedule II Controlled Substances (have a high potential for misuse and dependence with prolonged use and have currently accepted medical use in treatment). As a result of this classification, parents are often concerned about the misuse potential with stimulant use in ADHD. -Evidence shows that treatment with stimulants has no association with the use of illicit drugs or alcohol. -To put parents at ease, clinicians can share that ADHD is considered a risk factor for maladaptive substance use and that evidence shows that adolescents and adults not treated are at an increased risk compared to groups who have received treatment.

Rank from slowest to fastest the onset of nicotine action for each NRT and compare to cigarettes and snuff.

-The rate of nicotine onset of action from slowest to fastest is: Transdermal patch < gum = lozenge < inhaler < nasal spray

asthma

-chronic inflammatory disorder of the airways in which many cells and cellular elements are involved. Airway inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning in patients with asthma.

List the three leading causes of death that are attributable to smoking.

(1) Lung Cancer (2) Chronic Obstructive pulmonary disease (COPD) (3) Ischemic Heart Disease

treatment plan that would reduce the risk of diminished growth in children treated with stimulants for ADHD

(1) Strategies to help limit growth risks include "drug holidays" (temporarily discontinuing treatment) which result in a return to normal growth. Unfortunately stopping the medication can lead to a resurgence of symptoms. (2) Lowering the dose or changing medications are alternative options to the drug holiday if parents are concerned with reemerging symptoms. (3) Taking the medication after a full, calorie dense meals can also help offset some effects of appetite suppression throughout the day. Remember, taking the medication with food can delay absorption and result in lower Tmax, especially with ER formulations.

Describe the pharmacodynamic effects of nicotine

(1)CNS affects Pleasure: Tobacco users commonly report they find tobacco use pleasurable. Arousal, enhanced vigilance: Tobacco use may help with thinking, concentration, and mood elevation. Improved task performance: Nicotine has been shown to increase vigilance and performance for some types of tasks (e.g., repetitive/monotonous tasks). It is not known whether the improvements in mood or task performance are due to relief of nicotine withdrawal symptoms or a direct effect of nicotine on the brain. Relief of anxiety: Many tobacco users report reduced anger, tension, and stress after administration. (2)Cardiovascular System Increased heart rate, cardiac output, and blood pressure as well as cutaneous and coronary vasoconstriction. After a cigarette is smoked, the smoker's blood pressure rises by 5-10 mm Hg for 15-30 minutes, and the heart rate increases an average of 10-20 beats/min for up to 60 minutes. (3) Other Effects Appetite suppression Modest acute increase in metabolic rate Tobacco cessation usually leads to weight gain, although the average person will gain less than 10 pounds.

ways that COPD can obstruct airflow

(A) bronchial wall hypertrophy (B) hypersecretion of mucus (C) loss of elastic fibers holding the airway open

Describe the role of cell-mediated and humoral immune responses in asthma

(Not 100% sure) The chemical factors that influence breathing rate and depth are CO2, O2, and H+ in arterial blood Chemoreceptors (neurons that respond to chemical concentrations) are located primarily in two locations. - - Central chemoreceptors are located bilaterally in the ventrolateral medulla in the central nervous system. The peripheral chemoreceptors are found in the aortic arch (the area where the ascending and descending aorta meet) and carotid arteries. LTB4 (and HETEs) mediate chemotaxis of neutrophils and eosinophils, and promote release of their lysosomal hydrolytic enzymes which can destroy normal tissue. LTC4 and LTD4 provoke 1) smooth muscle contraction, 2) constriction of pulmonary airways, the trachea, and intestine, 3) increases in capillary permeability (edema), and 4) mucus hypersecretion.

catecholamine synapse, differentiating between tonic and phasic pools of release

(see figure 1) In the absence of an action potential, there is a small amount of DA release, which binds both pre- and post-synaptically. This is called the tonic pool and binds primarily to D2 and D3 autoreceptors on the presynaptic membrane. The tonic pool helps provide feedback inhibition to inhibit further DA release. After an action potential, a large amount of DA is released, which is called the phasic pool. The phasic pool binds primarily to post-synaptic DA receptors, leading to varying downstream effects.

three consequences of emphysema

1. Accessory muscles are enlisted to breathe exhausting the patient as breathing requires 15-20% of their total body energy supply. 2. Smaller bronchioles collapse during expiration trapping large volumes of air in the alveoli (Figure 3). This is called hyperinflation and leads to a permanently expanded "barrel chest" and reduces ventilation efficiency (Figure 4). 3. Damage to pulmonary capillaries occurs as the alveolar walls disintegrate, increasing resistance in the pulmonary circuit (i.e., pulmonary hypertension), forcing the right ventricle to overwork and consequently become hypertrophic (i.e., right-sided heart failure).

goals of therapy for patients with chronic asthma

1. Reduce impairment -Prevent chronic and troublesome symptoms (coughing or breathlessness in the daytime, in the night, or after exertion). -Require infrequent use (< 2 days/week) of inhaled short-acting β2-agonists for quick relief of symptoms. -Maintain normal pulmonary function. -Maintain normal activity levels (exercise and attendance at work or school). -Meet patients' and families' expectations of and satisfaction with asthma care. 2. Reduce risk -Prevent recurrent exacerbations of asthma and minimize the need for ED visits or hospitalizations. -Prevent progressive loss of lung function (for children - prevent reduced lung growth). -Provide optimal pharmacotherapy with minimal or no adverse effects.

Describe the prevalence of tobacco use of adults and teens in the United States.

14% of Adults are current smokers- Males more than Females American Indian/ Alaska Native = 20.9% White = 15.5 % Black = 14.9% Hispanic = 8.8% Asian = 7.2%

epidemiology of attention-deficit/hyperactivity disorder (ADHD) in children as it relates to age groups and gender

5-7% of youth and 2.5% of adults Reports of symptoms continuing into adolescence are reported as 80% and continuing into adulthood are as high of 30-50%. ADHD is more prevalent in boys by 4:1, though ADHD is likely unrecognized in young girls due to differences in presentation. ADHD in adulthood is evenly distributed between men and women.

17.) **When given theophylline dose adjustment recommendations and a serum theophylline level for a patient, optimize a patient's theophylline therapy by recommending a new dosing regimen when appropriate.

< 10 10 - 14.9 = Increase dose by 25% Maintain dose if tolerated 15 - 19.9 = Consider 10% dose reduction 20 - 24.9 = decrease dose by 25% 25 -30 = Skip next dose, then decrease dose by 25% > 30 = Discontinue theophylline and treat theophylline toxicity; if theophylline is restarted, decrease dose by at least 50%

Relate aerosol particle sizes to sites of airway deposition.

> 10 micrometers = oropharynx 5-10 = trachea, large bronchi 1-5 = lower airways <0.5 = particles are exhaled

Explain the following consequences of chronic inflammation: airway remodeling, mucus production, and airway smooth muscle growth.

Airway remodeling = Although cellular changes and symptoms are reversible between episodes, asthmatic lungs exhibit remodeling with thickening of the airway walls, with increases in submucosal tissue and smooth muscle, and the presence of subepithelial fibrosis. The degree to which remodeling occurs varies between patients. As the parenchymal tissue is acutely damaged, replacement of original cell types occurs However, following chronic damage, cells are replaced with connective tissue (scarring). This process is not well understood but it is an irreversible process with serious consequences such as the development of chronic obstructive pulmonary disease (COPD), which will be covered in IP 4 COPD. Mucus production = During chronic asthma, bronchial glands are increased in size and goblet cells are increased in size and number. In conjunction with epithelial cell shedding and inflammatory cells, the expectorant mucus increases in viscosity and mucus plugs are often observed in the bronchial passageways. Airway smooth muscles = Smooth muscle appears to by hypertrophic, and hyperplasia occurs as a result of chronic inflammation.

Explain dead space.

An average tidal volume is 500 mL/breath. But not all of the inspired air reaches the alveoli. Some of it remains in the conducting respiratory passageways and never contributes to gas exchange. This volume is considered the anatomical dead space and typically amounts to about 150 mL

Explain how improper inhalation technique or airway obstruction can affect the efficiency of drug delivery via metered dose or dry powder inhalers

Anatomical variation also affects dosing efficiency. Differing airway geometry, particularly between adults and children, affects dosing, as does airway obstruction from bronchospasm, edema, and mucus hypersecretion. Appropriate inhalation technique is essential to achieve optimal drug delivery. Approximately 1/3 of all patients cannot master the use of an MDI. dry powder can clog easy so it is important for patients to turn their head away from the device while exhaling prior to inhaling the dose from the device.

Explain the term "narrow-therapeutic index drug" in terms of ED50 and TD50 and describe the clinical importance of a narrow-therapeutic index drug.

Any event that alters its metabolism may potentially cause a patient's serum concentration to change such that it is above or below the therapeutic range. - potentially life-threatening adverse effect -Potential drug-drug interactions are serious (IP 1 Principles of Pharmacodynamics and SAR will help you review how a drug is determined to be "narrow-therapeutic index" in terms of ED50 and TD50).

equivalent dosing schedules which the single pill sustained release formulations replace

Aptensio XR: 3 mg ER per 2 mg IR - mimics 2x daily dosing Concerta: 7 mg ER per 2 mg IR - mimics 3x daily dosing Metadate CD: 7 mg ER per 3 mg IR - mimics 2x daily dosing Ritalin LA: 1 mg ER per 1 mg IR - mimics 2x daily dosing

atmospheric pressure, intrapulmonary pressure, and intrapleural pressure

Atmospheric pressure (Patm) is the pressure exerted by the weight of the air in the atmosphere surrounding the body. At sea level, atmospheric pressure is 760 mm Hg. As you may have noticed by living here in Denver, atmospheric pressure decreases with increasing altitude. Intrapulmonary pressure (Ppul) is the pressure within the alveoli. Intrapulmonary pressure fluctuates with the different phases of breathing. Intrapleural pressure (Pip) is the pressure in the pleural cavity. Intrapleural pressure also fluctuates during breathing but typically stays approximately 4-6 mm Hg less than Ppul (~756 mm Hg). This is also referred to -4 mm Hg. This negative pressure plays a major role in keeping the lungs open and inflated. Anything that equalizes Pip with the Ppul or Patm will cause the lungs to immediately collapse (also called pneumothorax).

roles of non-stimulant medications used to treat a patient with ADHD

Atomoxetine- selectively inhibit pre-synaptic reuptake of NE via NET. Inhibition of the transporter has been shown to increase synaptic concentrations of norepinephrine in the prefrontal cortex. Guanfacine- selective α2A adrenergic agonists = These drugs mimic the effect of NE in the prefrontal cortex, which is believed to be their therapeutic action Clonidine- selective α2A adrenergic agonists = These drugs mimic the effect of NE in the prefrontal cortex, which is believed to be their therapeutic action. weak inhibitor of both CYP3A4 and CYP2D6 Viloxazine- selectively inhibit pre-synaptic reuptake of NE via NET. Inhibition of the transporter has been shown to increase synaptic concentrations of norepinephrine in the prefrontal cortex.

Identify the average cost of a pack of cigarettes and compare the cost of a pack of cigarettes to the daily costs of pharmacotherapy.

Average cost of a pack of cigarettes = $7.19 Daily costs of pharmacotherapy - The GUM, Lozenge, Patch and Bupropion are all bellow the Average cost of a pack of cigarettes - Nasal Spray, Inhaler and Varenicline are way above Average cost of a pack of cigarettes

characteristic symptoms associated with the clinical presentation of chronic COPD

*Dyspnea that is:* - Persistent, progressive (i.e., worsens over time), and worse when exercising - Described by patients as a sense of increased effort to breathe, heaviness, air hunger, or gasping - Dyspnea upon exertion typically occurs in patients with FEV1 < 50% predicted, and dyspnea at rest typically occurs in patients with FEV1 < 25% predicted. *Chronic cough:* - Often the first symptom of COPD to develop - May be intermittent initially and progress to being present every day and throughout the day - May be unproductive (i.e., no sputum production) or productive (i.e., with sputum production) - Recurrent wheeze and chest tightness - May precede the development of airflow limitation by many years *Chronic sputum production:* - Any pattern of chronic sputum production may indicate COPD - May precede the development of airflow limitation by many years *Fatigue* (i.e., subjective feeling of tiredness or exhaustion) *Family history of COPD and/or childhood factors* (e.g., low birth weight, childhood respiratory tract infections) *History of exposure to risk factors:* - Host factors (e.g., genetic factors, developmental abnormalities) - Tobacco smoke (It may take smoking at least 20 cigarettes per day for 20 or more years before symptoms develop.) - Occupational dusts and chemicals

generic drug + class

*Long-Acting Inhaled β2-Agonists* arformoterol formoterol indacaterol olodaterol vilanterol *Short-Acting Inhaled Anticholinergic* ipratropium *Long-Acting Inhaled Anticholinergics* aclidinium glycopyrrolate revefenacin tiotropium umeclidinium *Nonelective Phosphodiesterase Inhibitor* theophylline

Describe the basic properties of gases including partial pressures, partial pressure gradients, and Henry's Law, and explain how these properties impact gas movement in the body.

*Partial* *Pressure* = The atmospheric air is a mixture of gases consisting of 78.6% nitrogen (N2), 20.9% oxygen (O2), 0.04% carbon dioxide (CO2), and 0.46% water vapor (H2O). Collectively, these gases exert a total atmospheric pressure of 760 mm Hg at sea level This total pressure is the sum of the pressures exerted independently by each gas in the mixture (N2 + O2 + CO2 + H2O = 760 mm Hg). It is important to point out that every gas molecule exerts the same amount of pressure. In other words, the pressure exerted by each gas is directly proportional to the percentage of that gas in the gas mixture Gases dissolved in a liquid such as blood exert similar partial pressures. The higher amount of a gas dissolved in the liquid, the greater the partial pressure of that gas. *Partial* *Pressure* *Gradient* = The difference in partial pressure between two systems is called the partial pressure gradient. Similar to diffusion down a concentration gradient, a gas diffuses down its partial pressure gradient from an area of higher partial pressure to an area of lower partial pressure. A partial pressure gradient exists between the alveolar air and pulmonary capillary blood and between systemic capillary blood and the tissue that they feed. *Henry's* *Law* = When a gas is in contact with a liquid, the gas will dissolve in the liquid in proportion to its partial pressure (Henry's Law). the greater the concentration of a particular gas in the gaseous state, the greater that gas will dissolve in liquid Equilibrium will be met when the gas partial pressures in the gaseous and liquid states are the same. If one gas's partial pressure becomes greater in the liquid than in the gas state, some of that gas will reenter the gaseous state. The ability of a gas to dissolve in a liquid, at any given partial pressure, is dependent on the solubility of the gas in the liquid and on the temperature of the liquid. CO2 is highly soluble - N2 is only half as soluble as O2 which means that practically no N2 dissolves into solution. Increasing the temperature of the liquid will decrease the solubility of a gas

effect of blockade of muscarinic acetylcholine receptors on tissues and organs in the body

Blockade of muscarinic (M1 & M3) acetylcholine receptors in bronchial smooth muscle decreases bronchoconstriction and produces a *bronchodilation* effect if the smooth muscle is constricted. Anticholinergics may also minimize bronchial secretions in asthmatic patients.

Predict the effect of blockade of muscarinic acetylcholine receptors on tissues and organs in the body.

Blockade of muscarinic acetylcholine receptors in bronchial smooth muscle decreases bronchoconstriction and produces a bronchodilation effect if the smooth muscle is constricted. Anticholinergics may also minimize bronchial secretions in asthmatic patients.

Compare the role of systemic and inhaled corticosteroids in COPD therapy

Chronic treatment with systemic corticosteroids should be avoided in patients with COPD because of an unfavorable benefit-to- risk ratio. Inhaled corticosteroids are less effective in patients with COPD compared to asthma, and they also increase the risk of pneumonia in patients with COPD.

treatment plan for an adult with ADHD who has a comorbid drug use disorder

Both Concerta® and Vyvanse® are designed to minimize misuse potential and hopefully minimize drug diversion. -Neither medication can be injected or snorted. -Concerta turns into a viscous gel when mixed with water and -Vyvanse requires first pass liver metabolism before it becomes active. Recall that stimulants themselves do not lead to substance use disorders, yet untreated ADHD can increase the risk.

Explain the chemical difference between albuterol and levalbuterol.

Both are short- acting β2-agonists as well as racemic epinephrine They distribute relatively quickly into bronchial smooth muscle tissue due to their lower log P value, giving them a relatively quick onset of action. They are subsequently cleared from bronchial smooth muscle quickly, giving them a relatively short duration of action. Albuterol Onset = Quick(Short) Albuterol Duration (Half-life) = Short (4-6 hrs.) Levalbuterol Onset = Quick(short) Levalbuterol Duration (Half-life) = Short (3hrs)

Explain the role of the following cell types in the pathophysiology of asthma: bronchial epithelial cells, leukocytes, myofibroblasts, mast cells, and alveolar macrophages.

Bronchial Epithelial cells = During asthma, epithelial cell damage occurs, leading to epithelial shedding and alterations in the structural and functional integrity of the airway. This leads to heightened airway responsiveness, altered permeability of the airway mucosa, and loss of normal epithelial protective factors. Leukocytes = Eosinophils are a rich source of leukotrienes, particularly LTC4. LTC4 causes contraction of airway smooth muscle, increases vascular permeability, and may recruit more eosinophils to the airway. Eosinophils also release major basic proteins which directly destroy local tissue. Type 2 helper cells are also thought to play a role in asthma as they have been identified in excess in patients with asthma. Recall, this cell type produces cytokines that mediate allergic inflammation such as interleukin-4 and 5. Myofibroblasts = Myofibroblasts are cells that are in the process of differentiating into smooth muscle cells. They increase in number in asthma and they contribute to the inflammatory response by releasing proinflammatory mediators. Increased numbers of myofibroblasts thicken the mucosal basement membrane. Mast cells and Alveolar macrophages = Mast cells, alveolar macrophages, and neutrophils also play a role in chronic inflammation.

Identify neurophysiologic sites of action for bupropion and varenicline.

Bupropion -is intended to decrease cravings for nicotine during the weeks and months required for successful tobacco cessation - One theory for this effect is that blockade of dopamine reuptake in the areas of the brain that are involved in natural reward circuitry leads to an increase in dopamine levels - This partially replaces the release of dopamine in the reward circuitry that is associated with the pleasurable effect of smoking cigarettes - Another effect of bupropion is to decrease the depressive symptoms associated with tobacco cessation, which, given its antidepressant properties, makes sense. Bupropion therapy should be initiated one week prior to quitting smoking Varenicline - is a partial agonist at nicotinic acetylcholine receptors - Varenicline occupies these α4β2 nACh receptors and prevents the full agonist nicotine from binding and producing its pleasurable effects - First, Varenicline may reduce symptoms of nicotine withdrawal due to providing partial activation of α4β2 nACh receptors. - Second, varenicline blocks the reinforcement/reward effects associated with smoking, decreasing the benefit of cigarette smoking to smoker. Nausea is a common adverse effect of varenicline and occurs in 30% of patients. December 2016, the FDA removed the following black box warning for varenicline: Patients should stop taking varenicline and contact their healthcare provider immediately if agitation, depressed mood, or changes in behavior that are not typical for them are observed, or if the patient develops suicidal ideation or suicidal thoughts.

Identify the component of cigarette smoking that affects drug metabolism.

Cigarette smoking induces drug metabolism, mostly by increasing the expression of CYP1A2, resulting in an increase in drug metabolism catalyzed by CYP1A2 However, cigarette smoking may induce other metabolism pathways such as glucuronidation. This induction is due to several hydrocarbons present in cigarette smoke, and not nicotine. This is an important concept to understand, because smoking cessation will remove this CYP1A2 induction effect regardless of whether a patient is using NRT or not

List and describe the nicotine withdrawal symptoms.

Chest tightness -Body is tense because it is craving nic. Constipation, stomach pain, gas -Intestinal movement decreases Cough, dry throat, nasal drip -The body is getting rid of accumulated mucus in the airways Cravings for a cig -Withdrawal from nic. Depressed mood/ depression -Its common to feel sad for a period of time after you quit Difficulty concentrating -The body needs time to adjust to not have constant stimulation from the nic Dizziness -The body is getting extra oxygen Fatigue Irritability/frustration/anger - Bodys craving for nic Increased appetites/ weight gain - Craving for a cig can be confused with hunger pangs Insomnia -Nic affects brain wave function and influences sleep patterns ; coughing and dreams about smoking are common Anxiety Restlessness/impatience Impaired performance

symptoms/clinical presentation of ADHD in both children and adults using (DSM-5) criteria

Children may experience difficulties including poor grades in school due to the inability to sit still and study, finish homework, or pay attention to the teacher. Adults may have issues at work and home due to difficulty completing tasks, persistently interrupting others, or being easily distracted. Both adults and children may forget scheduled appointments or tasks that could ultimately lead to problems at home, work, or school. [see table 1 for DSM-5 symptoms of inattention, hyperactivity, and impulsivity] -diagnostic criteria specifies 6 symptoms for a childhood diagnosis and only 5 symptoms are needed to diagnose an adult with ADHD and symptoms must be present in at least two different settings (adult = 17 and up)

Compare and contrast the pathophysiology of chronic bronchitis and emphysema

Chronic bronchitis is a long-term inflammatory condition of the lower respiratory airways resulting from inhalation of irritants (e.g., cigarette smoke, polluted air, and allergens).This leads to chronic excessive mucus production by the mucosa and prolonged edematous thickening of the airway linings. Emphysema is distinguished by permanent enlargement of the alveoli accompanied by destruction of the alveolar walls, loss of elasticity, and collapse of small airways. Surface area is reduced because many alveolar walls are lost, resulting in larger but fewer chambers. Most commonly, emphysema results from excessive release of protein-digesting enzymes (i.e., proteases) such as trypsin from alveolar macrophages as a defense mechanism in response to chronic exposure to inhaled cigarette smoke or other irritants. The lungsare normally protected by molecules such as α1-antitrypsin that inhibitthe proteases.

drugs of choice for treating acute exacerbations of COPD

Cochrane review- Tiotropium appeared to be better than long-acting β2-agonists in preventing COPD exacerbations and reducing the number of COPD-related hospitalizations but not total hospitalizations. *there is insufficient evidence to recommend one class of inhaled long-acting bronchodilators over another. Although it is not an evidence-based medicine approach, you may see healthcare providers prescribe inhaled long-acting anticholinergic medications more frequently than inhaled long-acting β2-agonists as initial therapy for patients with COPD. Ideally, the choice between bronchodilators should be based on individual patient response in terms of perceived symptom relief and adverse effects. Consideration of comorbidities is also important.*

patient who has a contraindication for stimulant use and recommend appropriate and safe alternative treatment options

Contraindications of Methylphenidate Hypersensitivity to dexmethylphenidate, methylphenidate, or any component of the formulation; marked anxiety, tension, and agitation; glaucoma; motor tics, family history or diagnosis of Tourette's syndrome; use with or within 14 days following MAOI therapy. Contraindications of Amphetamines Hypersensitivity to dextroamphetamine, other sympathomimetic amines, or any component of the formulation; advanced arteriosclerosis, symptomatic cardiovascular disease, moderate-to-severe hypertension; hyperthyroidism; glaucoma; agitated states; patients with a history of substance use disorder; during or within 14 days following MAOI therapy.

Describe the drug elimination profile for each class of asthma medications.

Inhaled drugs Most drugs administered by inhalation are eventually distributed into the systemic circulation as either parent drugs or metabolite (this varies from drug to drug). However, the rate of drug appearance in the systemic circulation following inhalation for asthma drugs is slow and difficult to measure. As a result, the elimination profile of asthma drugs given by inhalation is somewhat unknown for most drugs. B2- Agonist β2-agonists are extensively metabolized by both lung CYP450 (if given by inhalation) and hepatic CYP450 (probably most are metabolized by CYP3A4, but this is still surprisingly unknown). cAnticholinergic (Antimuscarinics) Ipratropium and tiotropium are esters (Figure 26 on page 31) and are metabolized by ester hydrolysis, a non-CYP450 drug metabolism pathway. In addition, tiotropium is metabolized by CYP3A4 and CYP2D6. Selective Phosphodiesterase inhibitors (Roflumilast) for COPD only Roflumilast is metabolized by CYP450 to an active metabolite that also inhibits PDE4 (Figure 30). It is eliminated mostly in the urine as an inactive glucuronide metabolite.

Provide a pharmacologic explanation for once-daily dosing of revefenacin, tiotropium, and umeclidinium and twice-daily dosing of aclidinium versus the multiple-daily dosing of ipratropium.

Ipratropium has a short duration of action (about 4 hours) and needs to be dosed multiple times per day. Aclidinium, revefenacin, tiotropium, and umeclidinium have longer durations of action compared to ipratropium due to a slower dissociation rate from M1 and M3 receptors. Aclidinium is dosed twice daily, whereas revefenacin, tiotropium, and umeclidinium are dosed once daily.

pharmacologic explanation for once-daily dosing of revefenacin, tiotropium, and umeclidinium and twice-daily dosing of aclidinium versus the multiple-daily dosing of ipratropium

Ipratropium has a short duration of action (about 4 hours) and needs to be dosed multiple times per day. Aclidinium, revefenacin, tiotropium, and umeclidinium have longer durations of action compared to ipratropium due to a slower dissociation rate from M1 and M3 receptors. Aclidinium is dosed twice daily, whereas revefenacin, tiotropium, and umeclidinium are dosed once daily.

Describe the role of leukotrienes in asthma.

Leukotrienes (LTs) are a class of inflammatory mediators with roles in both the early- and late-phase reactions in asthma. They are synthesized as part of the metabolism of arachidonic acid. -Leukotrienes (arachidonic acid derivatives, see Figure 15 on page 14) play a major role in inflammation and consequently are important to the pathophysiology of asthma -Conversion of arachidonic acid to the various leukotrienes begins with the action of 5-LOX Leukotrienes can persist in the body for up to 4 hours. Activation of 5-LOX stimulates production of leukotrienes that promote bronchoconstriction and inflammation. Decreasing the effect of leukotrienes (i.e., "modifying" their effect) has been an active area of pharmacology research for many years In the U.S., there are currently three leukotriene modifiers marketed (see box at right) that either block the synthesis of leukotrienes or block their binding to specific leukotriene receptors

Describe two mechanisms by which asthma medications decrease the effect of leukotrienes involved in inflammation and match each leukotriene modifier drug to each mechanism.

Leukotrienes (arachidonic acid derivatives that play a major role in inflammation and consequently are important to the pathophysiology of asthma. Two types of mechanisms (1) CysLT1 Receptor Antagonists MOA: mimic the chemical structure of leukotriene D4 (LTD4) Montelukast (Singulair) Zafirlukast (Accolate) (2) 5-Lipoxygenase Inhibitors MOA: potent and selective inhibitor of 5-LOX, Zileuton (Zyflor CR)

role of long-term oxygen in the management of COPD and state when it should be used

Long-term oxygen therapy (greater than 15 hours/day), pulmonary rehabilitation programs, smoking cessation, and lung volume reduction surgery have been shown to *decrease mortality* in patients with COPD. Before patients are considered for long-term oxygen therapy, they should be stabilized in the outpatient setting for 1 month. Once this is accomplished, long-term oxygen therapy should be instituted if one of the following conditions exists: 1. A resting PO2 of less than 55 mm Hg or oxygen saturation (SaO2) at or below 88%. Resting PO2 and SaO2 values should be repeated twice over three weeks for confirmation. 2. A resting PO2 between 55 mm Hg and 60 mm Hg or SaO2 88% if there is pulmonary hypertension, peripheral edema suggesting heart failure, or polycythemia (hematocrit > 55%)

Compare and contrast the following neural systems that control respiration: medullary respiratory centers, pontine respiratory centers, and respiratory rhythm.

Medullary respiratory = TWO TYPES (1) Dorsal respiratory group (DRG), located dorsally near the root of cranial nerve IX consisting of mostly inspiratory neurons. When DRG neurons fire, inspiration occurs and when they cease firing, expiration occurs. (2) Ventral respiratory group (VRG), a network of neurons that extends in the ventral brain stem from the spinal cord to the ponsmedulla junction composed of inspiratory neurons and expiratory neurons. VRG supplements the DRG and can be activated during periods when demands for ventilation are increased. These neurons are especially important in active expiration. No impulses to this region are needed during quiet breathing. Pontine respiratory centers = The pontine respiratory center fine tunes the medullary center to produce normal, smooth transitions between inspirations and expirations. - Without this set of neurons, inspiration would be disrupted abruptly by very brief expirations (called apneustic breathing) Respiratory rhythms = It is thought that there are pacemaker neurons that have intrinsic rhythmicity like pacemaker cells found in the heart.

Describe the beneficial effects of tobacco cessation on lung function and mortality.

Most important intervention in preventing the development and progression of a variety of chronic diseases Most effective strategy to reduce the risk of disease and disease progression Very cost effective Decreases symptoms of a variety of diseases and slows the rate of decline pulmonary function even after significant abnormalities in pulmonary function test have been detected Only intervention proven at this time to affect long-term decline in FEV1 18% reduction in all cause mortality in pts that received the intervention FIGURE 7 2 weeks- 3 mo (Time since quit date) - Circulation improves, walking becomes easier - Lunch function increases 1-9 mo. -Lung cillia regain normal function -Ability to clean lungs of mucus increases -Coughing, fatigue, shortness of breath decreases 1 year -Excess risk of CHD decreases to half that of those who continue to smoke 5 years -Risk of stroke is reduced to that of people who have never smoked 10 years - Lung cancer death rate is similar to half that of those who continue to smoke - Risk of cancer of mouth, throat, esophagus, bladder, kidney, pancreases decrease After 15 years - Risk of CHS is similar to that of people who have never smokes

effect of inhaled corticosteroid chemistry on drug absorption and distribution

Most inhaled corticosteroids (e.g., fluticasone and beclomethasone) contain a halide (i.e., chloride or fluoride) atom which greatly increases their lipophilicity. This results in slow distribution into bronchial tissue and a prolonged duration of action. In addition, their lipophilicity reduces their systemic bioavailability, which in turn diminishes their potential for causing systemic corticosteroid adverse effects. This chemistry may be compared with prednisone, an oral corticosteroid, which does not contain a halide atom.

complementary medications that are considered possibly effective for patients with COPD

N-acetyl cysteine Panax ginseng 100 mg to 6 g PO TID

Identify the pathways of drug metabolism most affected by cigarette smoking.

NRT - Compared with cigarette smoking, NRT is associated with few clinically important drug-drug interactions. -Cimetidine may inhibit the metabolism of nicotine, and another H2-receptor antagonist should be recommended to patients taking NRT in the place of cimetidine. BuProPion (ZyBan®) - There are several important drug-drug interactions associated with bupropion. These interactions were presented in the IP 3 MDD notes; varenicline (chantix®) - To date, varenicline, a relatively new drug, has not been associated with clinically important drug-drug interactions.

Describe the drug delivery mechanism for each nicotine replacement therapy (NRT).

NRT -Short-acting (with exception of transdermal nicotine patches) - Allow for patient to self-titrate their therapy and provide relief of craving symptoms if needed (1) Transdermal Nicotine Patches = Patches that deliver a constant rate of nicotine via. Absorption across the epidermis and dermis for up to 24 hrs resulting in a consistent level of nicotine in the body. - Thought of as a "passive" method of nicotine delivery, as no further action is required by the patient after the patch is placed on the skin. - Advantages = easy to conceal under clothing and avoiding possible stigma associated with other products (e.g., chewing gum - Adherence to therapy may be less problematic than with other forms of NRT. Nicotine GUM -first NRT available to consumers. contains nicotine polacrilex, which is nicotine complexed to an ion-exchange resin that allows for gradual release from the gum once activated in the mouth Nicotine Lozenge - also contain nicotine polacrilex, an ion-exchange resin from which nicotine is gradually released. Nicotine inhaler seeks to replace the behavioral aspects of smoking a cigarette while simultaneously providing nicotine replacement. Nicotine Nasal Spray - same as Nicotine Inhaler - currently available only by prescription -formulated as a multidose vial with each 50 μL spray delivering 0.5 mg nicotine

**Compare the available NRT and non-NRT products with regard to advantages and disadvantages of each product to help a patient select appropriate tobacco cessation therapy.

NRT does not provide as rapid or as high of nicotine blood levels as cigarettes, and the penetration and delivery of nicotine into the CNS is not nearly as rapid. This distribution characteristic of nicotine provided by NRT strikes a balance between the addictive nature of ultra-rapid nicotine CNS delivery and providing a therapeutic agent that partially alleviates the withdrawal symptoms arising from a sudden lack of rapid nicotine delivery to the CNS NRT does not have the addictive potential of cigarettes but therefore will not satisfy all craving and other withdrawal symptoms for patients.

drug-drug interactions for COPD medications

Drugs that inhibit or induce either CYP1A2 or CYP3A isoforms (CYP3A4) have the potential to alter theophylline serum concentration. Smoking (either cigarettes or marijuana) will induce CYP1A2 and reduce the efficacy of theophylline, requiring a higher dose of theophylline to maintain a patient in the therapeutic range. The efficacy of β2-receptor agonists will, at least in theory, be reduced if given concomitantly with a β-receptor antagonist (β-blockers). This may lead to an increased use in β2-agonists in asthma patients. The non-selecti

Identify the biologic target(s) for each of the immunomodulators.

Omalizumab (Xolair®) is an anti-IgE monoclonal antibody product that functions as an immunomodulator for the management of asthma -Omalizumab selectively binds to IgE and prevents IgE from binding to receptors on mast cells and basophils, leading to a decrease in release of inflammatory mediators. It is dosed based on the patient's baseline IgE level and their weight. Benralizumab (Fasenra®), mepolizumab (Nucala®), and reslizumab (Cinqair®) are interleukin-5 (IL-5) antagonist monoclonal antibody products that function as an immunomodulator for the management of asthma. - Mepolizumab and reslizumab bind to IL-5 and prevents IL-5 from binding to receptors on eosiniophils, ultimately decreasing symptoms of asthma by lowering levels of serum eosinophils by decreasing eosinophil production and survival. Dupilumab (Dupixent®) is a human monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the alpha subunit shared by the IL-4 and IL-13 receptor complexes Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor

Identify and predict adverse effects associated with each form of NRT and non-NRT.

NTR (1) GUM Mouth and throat irritation Jaw muscle soreness Hiccups GI complaints (dyspepsia, nausea) May stick to dental work Adverse effects more commonly experienced when chewing the lozenge or using incorrect gum chewing technique (due to rapid nicotine release): Light headedness/dizziness Nausea/vomiting Hiccups Mouth and throat irritation (2) LOZENGE Mouth and throat irritation Jaw muscle soreness Hiccups GI complaints (dyspepsia, nausea) Adverse effects more commonly experienced when chewing the lozenge or using incorrect gum chewing technique (due to rapid nicotine release): Light headedness/dizziness Nausea/vomiting Hiccups Mouth and throat irritation (3) TRANSDERMAL PATCH Local skin reactions (erythema, pruritus, burning) Sleep disturbances (abnormal or vivid dreams, insomnia); associated with nocturnal nicotine absorption (4) NASAL SPRAY Nasal and/or throat irritation (hot, peppery, or burning sensation) Ocular irritation/tearing Sneezing Cough (5) ORAL INHALER Mouth and throat irritation Jaw muscle soreness Hiccups GI complaints (dyspepsia, nausea) (1) BUPROPION SR Insomnia Dry mouth Nausea Anxiety/difficulty concentrating Constipation Tremor Rash Seizures (risk is 0.15%) Neuropsychiatric symptoms (2) VARENICLINE Nausea Sleep disturbances Headache Flatulence Constipation Taste alteration Neuropsychiatric SYMp.

List the therapeutic range for theophylline, and when given a serum concentration of theophylline predict adverse effects of theophylline.- answered in question 17 as well

Theophylline is a narrow-therapeutic index drug that is associated with potentially life-threatening adverse effects

emphysema

a condition of the lung characterized by destruction of the gas-exchanging surfaces of the lung (alveoli) and describes only one of several structural abnormalities present in patients with COPD

chronic bronchitis

a condition of the lung characterized by the presence of cough and sputum production for at least 3 months of the year in each of 2 consecutive years

Compare and contrast early- and late-phase reactions in asthma.

*(1)* early-phase reaction occurs 10 to 20 minutes after exposure to an inhaled allergen. During the early-phase reaction, allergens bind to mast cell affiliated IgE antibodies provoking release of histamine. The production and release of leukotrienes also occurs. Collectively, these proinflammatory mediators induce contraction of airway smooth muscle, mucus secretion, and vasodilation. Leukotrienes (LTC4, LTD4, and LTE4) are much more potent than histamine in contracting nonvascular smooth muscles of bronchi LTD4 increases vascular permeability, and LTB4 stimulates chemotaxis of eosinophils and neutrophils. Bronchospasm, in which there is sudden constriction of the muscles in the walls of the bronchioles, can occur. Patients who experience only the early-phase reaction do not have increased airway responsiveness (bronchial hyperresponsiveness), in which bronchospasms are easily triggered. *(2)* late-phase reaction occurs 4 to 6 hours after exposure to an inhaled allergen and reaches maximal intensity 6 to 9 hours after exposure. Similar to allergic rhinitis, the late-phase reaction involves the recruitment and activation of eosinophils, basophils, neutrophils, and macrophages. The development of TH2 cells is also an important feature of the late-phase reaction During the late-phase reaction, cytokines are generated by resident inflammatory cells and recruited inflammatory cells. The late-phase reaction is often more severe than the early-phase reaction, which suggests an increase in the propensity of the airways to constrict to nonspecific stimuli. Patients who experience a late-phase reaction have bronchial hyperresponsiveness that may last up to 6 weeks.

Compare and contrast between stimulant medications used to treat patients with ADHD with regard to dosing, duration of action, method of administration

*-Methylphenidate-* peak concentration: Daytrana- 8-10 hours Concerta- 6-8 hours Delexis- 14 hours admin: oral- tablets, capsules, solutions, and chewable *-Dexmethylphenidate-* peak concentration: Focalin- IR 1.5 hr, ER 6.5 hr admin: oral- biphasic capsules *-Dextroamphetamine-* peak concentration: IR ~3 hours SR & ER- 7-8 hours admin: oral- capsules *-Lisdexamfetamine-* peak concentration: ~3.5 hours admin: tablets or capsules *-Serdexmethylphenidate-* duration: long acting admin: by mouth once daily *see dosing on pdf*

how can environmental factors that affect asthma be controlled?

*Animal allergen mitigation* if patient is sensitized to the allergen (i.e., confirmed with allergy testing) - If removal of the pet is not acceptable: --Keep the pet out of the main living areas and bedrooms. --Keep the patient's bedroom door closed. --Use a vacuum cleaner once or twice a week with integral HEPA filter. - Mouse allergen exposure can be reduced by a combination of blocking access, low-toxicity pesticides, traps, and vacuuming and cleaning. *House-dust mite allergen* if patient is sensitized to the allergen (i.e., confirmed with allergy testing) - Encase mattress, pillow, and quilt in impermeable covers. - Wash all bedding in the hot cycle weekly. - Reduce indoor humidity to ideally between 30% and 50%. *Stop smoking.* *Do not smoke around children with asthma.* *Formaldehyde and volatile organic compounds* from new linoleum flooring, synthetic carpeting, particleboard, wall coverings, furniture, and recent painting can worsen asthma.

Contrast pulmonary gas exchange and capillary gas exchange in the body tissues.

*Pulmonary* *Gas* *Exchange*= Blood high in carbon dioxide and poor in oxygen enters the lungs (1) As blood passes through the lungs it picks up oxygen and releases carbon dioxide. This exchange occurs simply by diffusion down partial pressure gradients that exist between the blood and alveoli. (2) After leaving the lungs, blood is now oxygen-rich and low in carbon dioxide. (3) Oxygen moves down its partial pressure gradient from the alveoli into the blood and pulmonary blood equilibrates with alveolar PO2 (see Pgas). Equilibrium of oxygen occurs in about 0.25 seconds, which is about one-third the time a red blood cell is in a pulmonary capillary In contrast, CO2, a byproduct of cellular metabolism, diffuses down its partial pressure gradient from the blood into the alveoli where it is subsequently removed from the body during expiration. The partial pressure gradient of carbon dioxide is not as steep as oxygen but equilibration still occurs. *Capillary* *gas* *exchange*= The same factors control gas exchange between systemic capillaries and the tissue cells. gas exchange occurs by simple diffusion driven by their partial pressure gradients that exist. The amount of O2 that diffuses from the blood to the tissues is directly proportional to the metabolic activity of the tissue. For example, exercising muscles will have a greater partial pressure gradient because of increased utilization of O2. Of course, this is also true for CO2 because increased metabolic activity results in greater production of this gas.

Using the American Academy of Pediatrics 2011 Guidelines: Develop a treatment plan for a patient with ADHD using stimulants and/or non-stimulants

*Stimulants* -most efficacious medications for the treatment of ADHD. Up to 80-90% of patients can show a clinical response to stimulants When comparing efficacy between stimulants, amphetamine is moderately more efficacious than methylphenidate. However, because stimulants work through slightly different mechanisms of action, the lack of response of one chemical class of stimulant (e.g., methylphenidate products), does not preclude a response to the other class (e.g., amphetamines). -If a patient is not responsive to one medication, it is recommended to try the other class of stimulant prior to trialing non-stimulants. *Non-Stimulants* -Second line therapy after the stimulants. -Atomoxetine is effective in both children and adults. Should be considered if the patient is intolerant to stimulant side effects (insomnia, tics and lack of appetite) or if the patient was nonresponsive to stimulant therapy. -Patients should be given at least 4-6 weeks before determining the efficacy of atomoxetine. The therapeutic effect can take 2-4 weeks and full benefit may not be seen for 6-12 weeks. Atomoxetine's effect on sleep and appetites less severe and has less potential for misuse as compared to the stimulants. - should be considered in pre-existing substance use disorders, if the patient has anxiety or if patients or parents do not want to use a controlled substance

stimulant and non-stimulant agents by name (brand and generic) and structure

*Stimulants* [structures in figure 2 page 6] -Methylphenidate: (Aptensio XRTM, Concerta®; Daytrana®; Metadate CD®; Metadate ER®; Methylin®; Ritalin LA®; Ritalin®; Quillivant XR®, Cotempla XR-ODT®, Adhansia XR®, Relexxii®, Jornay PMTM) -Dexmethylphenidate: (Focalin®) -Dextroamphetamine: (d-amphetamine; Dexedrine®; Spansule®; ProCentra®) -Lisdexamfetamine: (Vyvanse®) PRODRUG -Serdexmethylphenidate: (Azstarys®) new prodrug *Non-stimulants* [structures in figure 5 page 9] -Atomoxetine (Strattera®) -Guanfacine (Intuniv®) -Clonidine (Kapvay®) -Viloxazine (Qelbree®) ~MDDLS//GCAV~

difference between an extended release and sustained release formulation

*biphasic release/sustained-release* formulation- the drug is released from these tablets or capsules with two different time constants -part of the dose is immediate-release and part of the dose is extended-release. with both forms of the drug present in a single tablet or capsule. -This ensures a rapid onset of action in combination with slow, constant release to minimize daily dosing requirements. *extended release* delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body

generic drug + class

*corticosteroids* inhaled: beclomethasone budesonide ciclesonide fluticasone mometasone systemic: methylprednisolone prednisolone prednisone *β2-adrenergic agonists* short acting: albuterol levalbuterol racemic epinephrine long acting: arformoterol formoterol olodaterol salmeterol vilanterol systemic: albuterol tablets terbutaline *anticholingeric* short acting: ipratropium long acting: aclidinium glycopyrrolate revefenacin tiotropium umeclidinium *leukotriene modifiers* cysLT1 antagonists: montelukast zafrilukast 5-lipoxygenase inhibitor: zileuton *mast cell stabilizer* cromolyn *selective phosphodiesterase inhibitor* roflumilast *nonselective phosphodiesterase inhibitor* theophylline *immunomodulator* anti-IgE: omalizumab IL5 antagonists: benralizumab mepolizumab reslizumab IL4 & IL13 antagonist: dupilumab

onset of action for each asthma medication and apply this information to drug therapy decisions and patient counseling

*corticosteroids* oral corticosteroids have an onset of action of about 4 to 6 hours. Inhaled corticosteroids have a long onset of action due to their lipophilic chemistry that slows distribution into the relatively polar bronchial tissues. *β2-agonists* SHORT: albuterol, levalbuterol, racemic epinephrine, formoterol, indacaterol, olodaterol LONG: salmeterol, vilanterol *anticholinergic* ipratropium- short Aclidinium, revefenacin, tiotropium, and umeclidinium have longer durations of action compared to ipratropium due to a slower dissociation rate from M1 and M3 receptors *mast cell stabilizer* relatively quick onset

most significant adverse effects of asthma medications

*corticosteroids* oropharyngeal candidiasis, dysphonia, reflex cough and bronchospasm *β2-agonists* tremor, tachycardia, hypokalemia *anticholinergic* dry mouth, Worsening of urinary retention may occur in patients with benign prostatic hypertrophy bitter, metallic taste in the mouth *leukotriene modifiers* headache and neuropsychiatric effects (rare) *mast cell stabilizer* bad taste, sore throat, and cough *selective phosphodiesterase inhibitor* diarrhea, nausea, vomiting, and weight loss *theophylline* -At serum concentrations within the therapeutic range and between 15 - 20 mcg/mL, theophylline may cause insomnia, nervousness, irritability and mild gastrointestinal upset. -At serum concentrations > 20 mcg/mL theophylline may cause severe headache, tachycardia, nausea and vomiting. -At serum concentrations 25 - 40 mcg/mL theophylline may cause cardiac arrhythmias, and seizures (greater chance at concentrations closer to 40 mcg/mL). -At serum concentrations > 40 mcg/mL the patient is at high risk for permanent neurologic deficit and death. *immunomodulators* omalizumab- injection site reactions, anaphylaxis, a possible risk of malignancies, and a possible risk of cardiovascular and cerebrovascular events benralizumab- headache, pharyngitis, and hypersensitivity reactions mepolizumab- injection site reactions, headache, back pain, and fatigue reslizumab- oropharyngeal pain, myalgias, and anaphylaxis dupilumab- injection site reactions, oropharyngeal pain, eosinophilia headache, and hypersensitivity reactions

mechanism of action for each class of asthma medications

*corticosteroids* suppressing the generation of cytokines, suppressing the recruitment of airway eosinophils, & suppressing the release of inflammatory mediators. *β2-agonists* interacting with and modifying the function of the autonomic nervous system- activation of β2-receptors *anticholinergic* acting in the peripheral nervous system anddo not distribute into the CNS- blockade of M1 and M3 muscarinic acetylcholine receptors in bronchial smooth muscle *leukotriene modifiers* block the synthesis of leukotrienes or block their binding to specific leukotriene receptors *mast cell stabilizers* cromolyn inhibits the release of histamine from bronchial mast cells *selective phosphodiesterase inhibitor* selectively binds to and competitively inhibits PDE4 *nonselective phosphodiesterase inhibitors (methylxanthines (theophylline))* inhibition of phosphodiesterase-4, or PDE4 blockade of cell surface adenosine receptors *immunomodulators* anti-IgE: Omalizumab selectively binds to IgE and prevents IgE from binding to receptors on mast cells and basophils, leading to a decrease in release of inflammatory mediators IL-5 antagonists: Mepolizumab and reslizumab bind to IL-5 and preventsIL-5 from binding to receptors on eosiniophils mepolizumab and reslizumab act on IL-5 itself, benralizumab binds directly to the alpha subunit of IL-5 receptors IL-4 & IL-13 antagonist: binding to the alpha subunit shared by the IL-4 and IL-13 receptor complexes

different hypotheses that explain the development of ADHD

*hypOactive catecholamine hypothesis:* -Patients with ADHD have been shown to have lower than normal density of DA receptors in a variety of brain areas -Many genetic polymorphisms that affect DA receptors and the dopamine transporter (DAT) have been linked to ADHD. There is minimal evidence linking NE deficits to ADHD -it is believed that hypoactivity of the noradrenergic system is also involved with the symptoms of ADHD. *hypERactive catecholamine hypothesis:* -hyperactivity of theDA and NE systems can lead to ADHD. -Further genetic studies haveidentified links between ADHD and genes leading to increased DArelease and decreased reuptake of DA. -pharmacotherapy for ADHD might work by reducingDA release.

reversible and irreversible changes that occur in COPD

*irreversible* • Fibrosis and narrowing of airways • Reduced elastic recoil with loss of alveolar area • Destruction of alveolar support with reduced patency of small airways *reversible* • Presence of mucus and inflammatory cells and mediators in bronchial secretions • Bronchial smooth muscle contraction in airways • Hyperinflation during exercise

Categorize an asthma drug class as maintenance or rescue asthma medications, or both.

*maintenance* CAMPBIL Inhaled corticosteroids Systemic corticosteroids Inhaled long-acting β2-agonists Inhaled long-acting anticholinergics Mast cell stabilizers Nonselective phosphodiesterase inhibitors (i.e., methylxanthines) Leukotriene modifiers Immunomodulators *rescue* ABC Inhaled short-acting β2-agonists Inhaled short-acting anticholinergics Systemic corticosteroids

compare the role of systemic and inhaled corticosteroids in asthma therapy.

*systemic* role as maintenance: • Long term systemic corticosteroid therapy may be required to control asthma in some patients, but its use is limited by the risk of significant adverse effects. role as rescue: • Although the onset of action is 4 to 6 hours, they are important in the treatment of severe acute exacerbations because they prevent progression of the asthma exacerbation, decrease the need for emergency department visits and hospitalizations, prevent early relapse after emergency treatment, and reduce the morbidity of the illness. • A short "burst" of oral corticosteroids is effective as a rescue medication for acute exacerbations of asthma and consists of therapy for 5 to 10 days. • Methylprednisolone acetate 240 mg IM once may be used in place of a short burst of oral corticosteroids in patients who are vomiting or if poor adherence is a concern. *inhaled* role as maintenance: • The inhaled corticosteroids are the most effective maintenance medications available for asthma. other considerations: • Mouth rinsing and spitting and the use of a spacer device reduce the oral bioavailability and risk of oropharyngeal candidiasis. • Symptoms may improve during the first 2 weeks of therapy, but maximal therapeutic effect may take up to 8 weeks of therapy. In addition, symptoms may continue to improve for up to one year. • Consider supplementation of calcium and vitamin D to reduce the risk of osteoporosis. • No evidence indicates that the regular use of inhaled corticosteroids in patients with asthma will induce a state of steroid dependence. • Combination with long acting β2-agonists is more effective than combination with leukotriene modifiers. • Better control may sometimes be achieved with 4 times daily rather than twice daily dosing of inhaled corticosteroids. • Inhaled corticosteroids do not alter the early-phase reaction, but they prevent the late-phase reaction.

adverse effects of COPD medications

*β2-agonists* tremor, tachycardia, hypokalemia *anticholinergic* dry mouth, Worsening of urinary retention may occur in patients with benign prostatic hypertrophybitter, metallic taste in the mouth

mechanism of action and elimination profile for each class of COPD medications

*β2-agonists* CYP3A4 interacting with and modifying the function of the autonomic nervous system- activation of β2-receptors *anticholinergic* ester hydrolysis (tiotropium: eh + cyp3a4 + cyp2d6) acting in the peripheral nervous system anddo not distribute into the CNS- blockade of M1 and M3 muscarinic acetylcholine receptors in bronchial smooth muscle *nonselective phosphodiesterase inhibitor* CYP1A2>CYP3A4 inhibits multiple members of the PDE family

effect of β2-receptor activation on tissues and organs in the body

Activation of β2-receptors by β2-agonists results in an increase in intracellular cyclic-AMP (cAMP), leading to dilation of bronchial smooth muscle tissue (i.e., bronchodilation) and subsequent relief of asthma symptoms. In addition, β2-receptor activation may improve mucociliary clearance. GI tract: sphincters- contract smooth muscle walls- relax Genitourinary tract: bladder wall- relax uterus- relax Liver- gluconeogenesis/glycogenolysis

List and describe the health consequences of tobacco smoke.

Acute effects First, the resistance in airways is increased Second, Ciliary activity is depressed and particles are removed slowly Inhaled carbon monoxide absorbs into the blood and binds with hemoglobin in red blood cells with an affiinity af about 200 times higher than oxygen, limiting the ability of blood to carry oxygen Third, Nicotine increase metabolic rate especially during light exercise such as housework or occupational tasks Chronic Effects Cancer -Acute myeloid Leukemia -Kidney -Lung -GI -Cervical -Pancreatic -Bladder Pulmonary Diseases -Acute -Chronic Cardiovascular diseases -Abdominal aortic aneryesum - CHD - Cerebrovascular disease - Peripheral arterial disease Reproductive Effects -Reduced fertility in women -Pregnancy complications Other -Cataracts -Osteoporosis -Periodontitis -Peptic Ulcer disease -Poor surgical outcomes

black box warnings associated with therapeutic agents used in the treatment of patients with ADHD

Adderall- sudden cardiac death and serious cardiovascular adverse events with misuse. stimulants- substantial misuse potential, and long-term use may lead to dependence Atomoxetine- "suicidal ideation in children and adolescents" special care should be taken when initiating therapy to watch for signs of suicidal thoughts or self-harm.

For any given aerosol delivery device, describe the dosing mechanism and device characteristics critical to effective use of inhaled drug products.

Aerosol particles must have a certain size to reach the airways (Table 6). Particles which are too large are deposited in the mouth, throat, and trachea, while those which are too small are either exhaled or deposited in the alveoli and likely absorbed into the systemic circulation. Devices used for oral inhalation produce aerosols with particle sizes in the range of approximately 0.5 to 35 micrometers. *nebulizers* (jet/ultrasonic) -jet nebulizers use a stream of compressed air passing through a liquid solution or suspension to generate aerosolized particles. The aerosol passes through a tube to a mouthpiece or mask fitted to the patient. Jet nebulizers can be used to deliver suspensions of solid corticosteroid powders -ultrasonic nebulizers use a membrane that oscillates at very high frequency in contact with a medication solution to generate aerosolized particles which can create a more uniform particle suspension than a jet nebulizer, potentially allowing a greater fraction of the actuated dose to be delivered to the lung *dry powder inhalers* -capsule of medication is punctured and the powder is carried through the device on a stream of air generated by the patient's inhalation -quick and deep inhalation tends to be required, making DPI devices difficult for some patients to use *metered dose inhalers* -mixture of drug product concentrate (often the drug dissolved or suspended in an aqueous medium), a liquefied gas propellant, and the propellant vapor phase. -When the inhaler is pressed, the metering chamber is evacuated, releasing the drug into the atmosphere. *propellants* -HFA 134a is a commonly used propellant in metered dose inhalers -The force is generated by the high vapor pressure of the propellant, and pressure is maintained in the device by evaporation of the liquid propellant reservoir. Particles emerging from the orifice consist of product and propellant, and are relatively large (approximately 45 μm). *propellant-free metered dose inhalers* -relies on mechanical energy and a nozzle system to create a cloud of particles to be delivered to the airways -When the dose-release button is pushed, the mechanical energy stored in the spring is released and forces the drug into the uniblock nozzle system. The aerosolization of the drug is accomplished as two jet streams of the drug are forced through the uniblock nozzle system and collide at a precise angle to produce an aerosol cloud of appropriately-sized particles.

drugs/preservatives that can cause an asthma exacerbation

Aspirin NSAIDs Beta blockers do not precipitate bronchospasms, but they decrease the effectiveness of β2-agonists. Benzalkonium chloride Sulfite preservatives

Describe the blood gas abnormalities that can occur in severe asthma exacerbations.

Asthma causes impairments of gas exchange only during severe asthma exacerbations. Often, some airways are completely occluded, others severely narrowed, and still others unobstructed. The resulting mismatch of ventilation and perfusion widens the alveolar- arterial oxygen difference. The hypocapnia (low concentration of carbon dioxide in blood) that is seen in mild to moderate asthma exacerbations reflects an increase in respiratory drive. Hypercapnia (high concentration of carbon dioxide in blood) indicates that airway obstruction is so severe that the muscles of respiration are unable to maintain the ventilation rate set by the respiratory drive. The rise in arterial PCO2 then further inhibits muscle performance and respiratory drive precipitating respiratory failure and death.

Describe when theophylline serum concentrations should be measured in terms of time after therapy initiation and time of day.

At a minimum, theophylline serum concentrations should be measured: - At initiation of therapy; at occasional intervals in a patient stabilized on theophylline (e.g., once or twice per year); - when adverse effects occur; - when expected therapeutic outcomes are not achieved (serum concentration may be too low); and - when conditions known to alter theophylline drug metabolism exist

Identify and compare phase I and phase II drug metabolism pathways.

At this point you should be able to classify CYP450 metabolism and glucuronidation as phase I or phase II metabolism and as oxidative or conjugative metabolism, and recognize each if given a chemical structure pathway of metabolism; if you are unable to do this, then review the Drug Disposition notes of IP 1. - ill go back to find it

Compare and contrast the following factors that influence breathing rate and depth: carbon dioxide, oxygen, and arterial pH.

Carbon Dioxide Most potent and the most closely controlled chemical to influence respiration. Arterial P is typically 40 mm Hg and is maintained within plus or minus 3 mm Hg When PCO2 levels rise, a condition called hypercapnia, CO2 diffuses into the cerebrospinal fluid (CSF) where it is hydrated and forms carbonic acid (H2CO3). As the acid dissociates, H+ is liberated. When PCO2 is low, respiration is inhibited and becomes shallow and slow. Oxygen also controls respiration Cells in the aortic arch and in carotid arteries sense PO2. However, PO2 must change dramatically to have any impact on respiration ; In fact, arterial PO2 must drop to 60 mm Hg to stimulate increased ventilation. Arterial pH Arterial pH can also adjust respiration when CO2 and O2 levels are normal. As arterial pH declines, respiratory rate and depth increase

role of PEF monitoring and educate patients on using a PEF meter to monitor their asthma and establish a personal best

PEF is ideal for patients to use in home settings for day to day objective monitoring of asthma. Predicted values for PEF are based on age, gender, and height. However, in many patients, PEF values are consistently lower or higher than the average predicted values. PEF-based assessment of asthma should be determined by using each patient's personal best rather than on a percent of normal predicted value, particularly for patients with chronically impaired lung function.

Describe the action and effect of nicotine in the CNS.

Directly affects Acetylcholine receptors Primary effect in addiction is its capacity to increase synaptic dopamine levels in the Nucleus Accumbens region of the brain - The nACh receptors are found Pre-Synoptically - leading to increased DA release -Influx of Na+ and/or Ca2+ into the pre-synaptic neurons initiates an excitatory, depolarizing potential, leading to release of dopamine into the synaptic cleft Initial effect of nicotine is to activate nicotinic acetylcholine (nACh) receptors located on dopamine neurons in the Ventral Tegmental Area; however, these receptors are rapidly desensitized and likely do not contribute to the sustaine effects of nicotine - The nACh receptors in the Central tegmental area are found Post-Synoptically, on the cells that release dopamine into the nucleus Accumbens The release of dopamine triggered by nicotine leads to feelings of pleasure, arousal, and reduction in anxiety that reinforces repeated use of tobacco (i.e., positive reinforcement).

Explain the beneficial effect of phosphodiesterase-4 inhibition and adenosine receptor blockade in patients with asthma.

Part of its benefit in patients with asthma and COPD is believed to be due to this action of being non-selective. However, theophylline has a narrow therapeutic index, possibly due to its nonselectivity, leading to toxicity. However, it is an older drug and one of the least expensive asthma medications, a fact that contributes to its continued use for asthma.

Differentiate exercise-induced bronchospasms, nocturnal asthma, and intrinsic nonallergic asthma

Exercise-induced bronchospasms= Exercise-induced bronchospasm (EIB) is defined as a drop in forced expiratory volume in one second (FEV1) greater than 10% from the FEV1 obtained before exercise compared to the lowest FEV1 after exercise (with measurements taken before exercise and 5, 10, 15, and 30 minutes after exercise). During exercise, pulmonary function increases during the first few minutes, but then begins to decrease after 6 to 8 minutes A refractory period follows lasting up to 3 hours after exercise. During this period, repeat exercise of the same intensity produces either no decrease in pulmonary function or a drop of less than 50% of the initial response. Environmental factors that contribute to EIB include cold air, dry air, ambient ozone, and airborne particulate matter. Environments with warm humid air may inhibit or blunt EIB. Nocturnal asthma = Nocturnal asthma is defined as worsening of asthma during sleep. Factors that may cause or worsen nocturnal asthma include improper environmental control of allergen triggers, gastroesophageal reflux, and sinusitis. intrinsic nonallergic asthma = Nonallergic asthma involves epithelial malfunction that is not linked to IgE, and the response to injury or stress facilitates the development of a TH2 response - Epithelial cells are a source of cytokines and chemokines that are capable of sustaining eosinophilic inflammation. Patients with nonallergic asthma show negative skin tests and have no clinical or family history of atopy. This form of asthma is associated with nasal polyps and aspirin sensitivity. - Sputum examination of these patients may be neutrophilic, eosinophilic, or contain only a few inflammatory cells. Patients with nonallergic asthma often do not respond well to inhaled corticosteroids.

Explain the role of ventilation-perfusion coupling.

For gas exchange to be efficient, ventilation (the amount of air reaching the alveoli) and perfusion (the blood flow in pulmonary capillaries) must be matched or coupled In alveoli where ventilation is insufficient, PO2 is low - Because of this, terminal arteries constrict and blood is redirected to respiratory areas where PO2 is high and oxygen pickup maybe more efficient PO2 changes the diameter of the vasculature feeding the pulmonary capillaries. Changes in PCO2 direct changes in the diameter of the bronchioles. In the alveoli where PCO2 levels are high, the bronchioles dilate allowing PCO2 to be eliminated from the body more rapidly. - If PCO2 is low, bronchioles servicing that area constrict. Because these two auto regulatory systems work together, ventilation and perfusion are synchronized. Poor alveolar ventilation results in low oxygen and high carbon dioxide levels in the alveoli; consequently, the pulmonary arteries constrict and the airways dilate, bringing air flow and blood flow into closer physiological match

patient specific factors that predispose individuals to developing asthma

Genetic predisposition to the development of asthma or atopy Gender (see Epidemiology section regarding differences between boys and girls) Obesity -There is some evidence of a correlation between higher body mass index (BMI) and greater risk of developing asthma -There is also some evidence that weight loss improves lung function, symptoms, morbidity, and health status in obese patients.

When given renal dosing information and patient data, calculate an appropriate dose of varenicline for a patient.

Renal Function ≥ 30 mL/min (Normal dosing) - Initiate therapy with 0.5 mg once daily days 1 - 3 Increase therapy to 0.5 mg twice daily days 4 - 7 - Maintenance dose (≥ day 8) is 1 mg twice daily < 30 mL/min - Initiate therapy with 0.5 mg once daily - Maintenance dose is 0.5 mg twice daily Hemodialysis - Initial and maintenance dose is 0.5 mg once daily

Describe CNS nicotinic ACh receptor desensitization induced by nicotine.

Repeated use of tobacco provides strong and persistent exposure to nicotine, which in turn results in desensitization of the pre-synaptic nACh receptors via phosphorylation

**When given the estimated comparative adult daily doses for inhaled corticosteroids table, convert a patient from one inhaled corticosteroid to another inhaled corticosteroid.

Inhaled corticosteroids have low systemic bioavailability. The portion of the dose that is absorbed into the systemic circulation is mostly metabolized by a combination of oxidation by CYP3A4 and hydrolysis (a non-CYP450 metabolism pathway). ??

Describe how certain beverages can affect the absorption of nicotine from the buccal mucosa.

Nicotine is a weak base with two sites that may accept a proton (pKa = 3 and 7.8) A pH of less than 6, most of nicotine is ionized and does not absorb well across mucosa cells Anything that lowers the pH at the site of absorption ( acidic beverages consumptions combine with nicotine gum) will lower the absorption of nicotine and decrease the efficacy of NRT

Describe the effect of cigarette smoking on drug metabolism.

Nicotine is extensively metabolized to over 20 different metabolites directly by CYP450 or glucuronidation, or first by CYP450 followed by subsequent glucuronidation Flavin monooxygenase (FMO) also plays a minor role in oxidative metabolism of nicotine. Most nicotine CYP450 metabolism is catalyzed by CYP2A6 and CYP2B6. Major nicotine metabolites include nornicotine and cotinine.

Compare the role of β -agonists as maintenance or rescue medications.

Short-acting β -agonists are the drugs of choice for acute exacerbations of asthma due to their rapid onset of action. 2 The early-phase reaction is easily blocked with short-acting b -agonists. 2 Racemic epinephrine is a nonselective adrenergic agonist which can lead to peripheral vasoconstriction, positive chronotropic, and positive iontropic effects, ultimately increasing the risk of cardiovascular disease in some patients. The prescription short-acting

Explain the term "parking" with respect to buccal drug delivery.

Once this occurs, the gum should be "parked" in the buccal cavity for a minute or so until the sensation stops. The gum is then chewed again until the sensation recurs, followed by parking in the buccal cavity.

risk factors for the development of persistent asthma in patients less than 3 years of age

One of the following: parental history of asthma, history of atopic dermatitis, or evidence of sensitization to aeroallergens -OR- Two of the following: evidence of sensitization to foods, > 4% peripheral blood eosinophilia, or wheezing not related to colds

role of oxidative stress in COPD

Oxidative stress from cigarette smoke or from inflammatory cells (especially neutrophils and macrophages) generates highly reactive oxygen species (ROS) including superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxy radical (OH-), and peroxynitrate (ONOO-) These reactive molecules exacerbate COPD through several mechanisms including reacting with and damaging various proteins and lipids, leading to cell and tissue damage. Activation of NF-kB also occurs resulting in the production of pro- inflammatory genes, as previously described.

beneficial effect of phosphodiesterase-4 inhibition and adenosine receptor blockade in patients with COPD

PDE4 is selective for hydrolysis of cAMP, and inhibition of PDE4 causes a beneficial anti-inflammatory effect in lung tissue of patients with COPD. Activation of adenosinereceptors by adenosine has been shown to decrease intracellular cAMPand cause bronchoconstriction; therefore, blockade of these receptors by methylxanthines would explain the bronchodilation effect of methylxanthines.

Compare and contrast the pathophysiological characteristics associated with COPD and asthma.

Patients with COPD develop respiratory failure manifested as hypoventilation. Hypoventilation is insufficient ventilation in relation to metabolic needs, causing CO2 retention in the alveoli. When airway resistance increases, a larger pressure gradient must be established to maintain even a normal airflow rate. For example, if resistanceis doubled by narrowing of the airway lumen, ΔP (change in pressure) must be doubled through increased respiratory muscle exertion to induce the same flow of air in and out of the lungs as a healthy person accomplishes during quiet breathing. see asthma notes

Differentiate between physiological and behavioral factors that contribute to tobacco use.

Physiological Addiction Tolerance = Desensitized CNS nACh receptors lead to tolerance to nicotine - Tolerance is suggested to promote increased use of addictive drugs and lead to adaptation in the brain that promote dependence -Can result in with-drawl symptoms which serves as Negative Feed Back Euphoric effects of Nicotine can positive reinforce repeated use Cravings -Users typically experience a strong desire or craving for tobacco -Tend to titrate their tobacco intake Behavioral Addiction -Includes the desire to smoke in certain situations such as while driving, drinking coffee, or drinking alc. -Certain Emotions : Stressed, aggravated etc. -All drug behavior is learned- a result of conditioning, a major factor that causes relapses.

Use chemical structure concepts to explain why inhaled anticholinergic medications are not associated with CNS anticholinergic adverse effects.

Quaternary amine provides permanent positive charge, preventing CNS distribution permanent positive charge makes these drugs too polar to distribute into lipophilic tissues extensively and too polar to cross the blood-brain barrier and enter the CNS This is an important property, because it prevents extensive distribution of these drugs to non-lung tissue, mostly preventing the occurrence of anticholinergic adverse effects.

common or severe adverse effects associated with stimulants and non-stimulants

STIMULANTS- cardiovascular stimulation misuse potential long-term use may lead to dependence inhibit growth in children receiving long-term treatment headache *appetite suppression insomnia* irritability/anxiety dry mouth nausea diarrhea weight loss NONSTIMULANTS- atomoxetine: cardiac/psychiatric events, dizziness, fatigue, sedation, dry mouth, nausea, decreased appetite, abdominal pain, headache, insomnia, irritability and aggression, and somnolence guanfacine: *somnolence*, dizziness, headache, fatigue, dry mouth, constipation, rash (discontinue) -bradycardia, hypotension, orthostasis, and syncope (first month) clonidine: sedation and hypotension Avoid abruptly stopping clonidine and guanfacine due to rebound hypertension, tachycardia, and anxiety.

rationale for administering extended or sustained released formulations in the treatment of patients with ADHD

The biphasic formulations are characterized by two onsets of action. The initial response is observed on the same time scale as with the immediate-release formulation, while the extended-release formulation sees peak activity between 4 and 7 hours after dosing. Most of the extended/sustained-release formulations (including transdermal) have a duration of action of at least 8-12 hours. (someone who needs it to be effective in the morning would benefit more from sustained release than extended)

Predict clinically important drug-drug interactions for asthma medications.

Selective Phosphodiesterase - Inhibitors (Roflumilast) For COPD Only Data from clinical trials indicate that roflumilast: does not cause drug-drug interactions by inhibiting metabolism of other drugs, and is susceptible to altered pharmacokinetics by CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital). Nonselective Phosphodiesterase Inhibitors (Methylxanthines (Theophylline)) -Drugs that inhibit or induce either CYP1A2 or CYP3A isoforms (CYP3A4) have the potential to alter theophylline serum concentration. -Smoking (either cigarettes or marijuana) will induce CYP1A2 and reduce the efficacy of theophylline, Leukotriene Modifiers -Zileuton is an inhibitor of CYP3A4, 1A2, and 2C9, and may increase serum concentrations of other drugs metabolized by these isoforms. -It is recommended to reduce the dose of theophylline by 50% when starting zileuton in a patient taking theophylline and to monitor theophylline serum concentrations. -Zafirlukast is an inhibitor of CYP3A4 and CYP2C8/9, but this has not been routinely associated with clinically important drug-drug interactions. β2-Receptor Agonists and β-Receptor Antagonists -The efficacy of β2-receptor agonists will, at least in theory, be reduced if given concomitantly with a β-receptor antagonist (β-blockers).

Describe the signs and symptoms associated with chronic asthma.

Symptoms of asthma occur with exercise and/or exposure to known allergens. Symptoms of chronic asthma include dyspnea, chest tightness, and coughing. Signs of chronic asthma include expiratory wheezing on auscultation, dry hacking cough, or signs of atopy (allergic rhinitis and/or eczema). A wheeze is a high-pitched, whistling sound created by turbulent airflow through an obstructed airway. Not all wheezes are asthmatics and all asthmatics do not necessarily wheeze. Any condition producing significant obstruction can result in wheezing.

role of inflammatory cells and mediators involved in COPD

The major inflammatory cells involved in COPD include macrophages, neutrophils, and CD8+ lymphocytes. Eosinophils are not prominent except in patients who also have asthma. Macrophages are stimulated by irritants and release inflammatory chemoattractant factors such as tumor necrosis factor-α (TNF-α), leukotriene B4 (LTB4) and interleukin-8 (IL-8). Macrophages are derived from monocytes and their role is primarily phagocytic. ~TNF-a is a cytokine that induces the transcription factor nuclear factor-kB (NF-kB). NF-kB transcriptionally regulates many inflammatory mediators such as IL-8 and TNF-a. ~LTB4 is a chemotactic factor for neutrophils and T cells. ~IL-8 is a chemotactic factor for neutrophils and monocytes (which mature into macrophages). ~IFN-g is a multifactorial cytokine that augments the inflammatory response. ~IL-1β and IL-6 have also been identified in COPD and they amplify the inflammatory process. ~Transforming growth factor-β (TGF-β) induces fibrosis in the airways.

Create and describe the rationale for a treatment plan that addresses the physiological and behavioral aspects of tobacco dependence.

The physiologic addiction can be treated with medications for tobacco cessation EX: The addiction to nicotine - Treatment = Medications for cessation the behavioral habit can be treated through behavioral change programs, such as individualized counseling and group or online cessation programs EX: The habit of using tobacco - Treatment = Behavior change program

how is spirometry used to diagnose COPD?

The presence of a *postbronchodilator FEV1/FVC < 70%* confirms the presence of persistent airflow limitation (i.e., COPD). When the FEV1/FVC is between 60% and 80%, spirometry should be repeated on a separate visit. Spirometry should be measured 10 to 15 minutes after a short-acting β2-agonist is given or 30 to 45 minutes after a short-acting anticholinergic (with or without a short-acting β2-agonist) is given.

beneficial pharmacologic effects of corticosteroids in asthma patients

The systemic corticosteroids are mostly useful as rescue medications due to their suppression, control and reversalof airway inflammation that contributes to the symptoms of asthma. Their systemic adverse effects limit long-term use as maintenance asthma medications, although this may be necessary for some patients.

Describe alveolar ventilation

The volume of air exchanged between the atmosphere and alveoli per minute is called alveolar ventilation rate (AVR) This takes into account the volume of air wasted in the dead space and measures the flow of air in and out of the alveoli during a defined time period. AVR is calculated by the following equation: AVR (mL/min) = frequency (breaths/min) X (tidal volume (in mL/breath) - dead space volume) In effect, even though 500 mL of air are moved in and out with each breath, only 350 mL of it is involved in gas exchange, also called alveolar ventilation.

Identify the neurotransmitter that β2-agonists mimic and explain how this is important to their mechanism of action.

The β2-agonists are designed to be chemical mimics of *epinephrine* that selectively bind and activate β2-receptors, with low affinity for β1-adrenergicor α-adrenergic receptors.

Predict the effect of β -receptor activation on tissues and organs in the body.

The β2-agonists are designed to be chemical mimics of epinephrine that selectively bind and activate β2-receptors, with low affinity for β1-adrenergic or α-adrenergic receptors. However, the β2-agonists are not perfectly selective, and they can bind with and activate β1-receptors, particularly at high doses. β2-agonists with a large log P value also have a longer duration of action because it is more difficult for the body to eliminate the drugs from the relatively polar bronchial tissue once they have distributed there. In addition, the long lipophilic side-chains of indacaterol and salmeterol appear to bind to a pocket in the β2-receptor, resulting in a particularly long duration of action.

Describe the difference between a full and partial receptor agonist.

Varenicline is partial agonist at α4β2 nACh receptors located on dopaminergic neurons found in the reward circuitry of the brain Varenicline occupies these α4β2 nACh receptors and prevents the full agonist nicotine from binding and producing its pleasurable effects (recall from IP 1 that partial agonists also function as antagonists with regard to preventing binding by a full agonist). However, since it is a partial agonist, varenicline does not induce receptor desensitization and does not contribute to nicotine tolerance. We know the difference