PHARM 331 Drug actions, effects, and etc Exam 2

Asthma and COPD drugs 

• Antiinflammatory agents → glucocorticoids

• Bronchodilators → B2 agonists 

• *Both are inhaled and on fixed schedules 

Administering drugs by inhalation

• enchanced by delivering drugs directly to site of action

• systemic effects are minimized

• relief of acute attack is rapid

Metered dose inhalers 

• small handheld pressurized devices, wait for 1 min in between inhalation 

• Educate pt on how to use it plus written instructions 

• Spacers avaiable if pt cannot use regular MDI 

Respimats

• deliver drugs as fine mist

• does not use propellants

Dry-powder inhalers

• breath activated and directly to the lungs

Nebulizers

• Mist through mask or mouthpiece 

• Takes several mins to deliver meds 

Glucocorticoids

• Decreased synthesis and release of inflammatory mediators + infiltration/activity of cells + edema of airway mucosa 

Uses 

• control inflammation in asthma and COPD

Glucocorticoids adverse effects 

• oropharyngeal candidiasis (thrush) → treated with antifungal med

• dysphonia (hoarseness, speaking difficulty)

• Some adrenal suppression (hypoglycemia, hypotension, mental status alterations) 

• bone loss

oral 

• adrenal suppression, osteoporosis, hyperglycemia, immunosuppression, fluid retention, hypokalemia, peptic ulcer disease, and, in young patients, growth suppression

*Rinse mouth with water after each use 

*patients must be given increased doses of oral or IV glucocorticoids at times of stress

Leukotreiene modifiers

Antiinflammatory drugs

• promote inflammatory responses through direct action and through the recruitment of eosinophils and other inflammatory cells resulting in blood vessel permeability and smooth mus- cle constriction

• In patients with asthma, these drugs decrease inflammatory responses such as edema, mucus secretion, and bronchoconstriction

Zileuton

inhibitor of leukotriene synthesis

• approved for asthma prophylaxis and maintenance therapy

• requires monitoring for liver injury 

• improvement within 1-2 hrs so not for acute cases 

Zileuton adverse effects

• Liver injury (check ALT activity) 

• Neuropsychiatric effects, including depression, anxiety, agitation, abnormal dreams, hallucinations, insomnia, irritability, restlessness, and suicidal thinking and behavior

Drug interactions 

• metabolized by cytochrome, CYP450, where it acts as an inhibitor of CYP1A2 isoenzymes and can slow the metabolism of drug substrates metabolized by this pathway, increasing their levels.

• Combined use with theophylline can markedly increase theophylline levels, so the dosage of theophylline should be reduced.

• Zileuton can also increase levels of warfarin and propranolol.

Zafirlukast

LTRAs, blocks leukotriene receptors

• approved for maintenance therapy of chronic asthma in adults and children 5 years and older

Adverse effects 

• headache

• gastrointestinal (GI) disturbances

• depression, suicidal thinking, hallucinations, and other neuropsychiatric effects

• Churg-Strauss syndrome, a potentially fatal disorder characterized by weight loss, flu-like symptoms, and pulmonary vasculitis (rare) 

• liver injury (e.g., abdominal pain, jaundice, fatigue). If these occur, zafirlu- kast should be discontinued, and liver function tests (espe- cially serum ALT) should be performed immediately

Drug interactions

• Concurrent use can raise serum theophylline to toxic levels. Theophylline levels should be closely monitored, especially when zafirlukast is started or stopped.

• Zafirlukast can also raise levels of warfarin (an anticoagulant) and thus may cause bleeding.

Montelukast

leukotriene receptor blocker

• (1) prophylaxis and maintenance therapy of asthma in patients aged at least 1 year

• (2) prevention of exercise-induced bronchospasm (EIB) in patients aged at least 15 years

• (3) relief of allergic rhinitis

• *not for acute cases, takes 24 hrs for maximal effects 

Montelukast adverse effects

• montelukast and neuropsychiatric effects, especially mood changes and suicidality (rare) 

Drug interactions 

• Concurrent use of phenytoin (an anticonvulsant that induces P450 isoenzymes) can decrease levels of montelukast 

Cromolyn

Mast cell stabilizer

• suppresses bronchial inflammation → inhibits eosinophils, macrophages, and other inflammatory cells

• used for prophylaxis—not quick relief— in patients with mild to moderate asthma + allergic attacks + risk for EIB

• When glucocorticoids create problems, however, cromolyn may be prescribed as an alternative therapy

*Administered as nebulizer 

*should be administered 10 to 15 minutes before anticipated exertion but no longer than 1 hour before exercise

Cromolyn adverse effects

safest of all antiasthma meds

• cough 

• bronchospasm 

*rare 

Monoclonal antibodies

newest drug category for the management of airway inflammation in asthma

Categories

• IgE antibody antagonist

• interleukin-4 receptor antagonist

• interleukin-5 receptor antagonist

• thymic stromal lymphopoietin blocker.

• *None of these are approved as first-line agents and none are approved for the management of acute asthmatic episodes

Omalizumab

IgE Antibody Antagonist → reduces the amount of IgE available to bind with its receptors on mast cells

• second-line agent indicated only for allergy- related asthma and only when preferred options have failed (glucocorticoid)

Adverse effects 

• injection-site reactions

• viral infection

• upper respiratory infection

• sinusitis

• headache

• pharyngitis

• Life-threatening anaphylaxis characterized by urticaria and edema (rare) 

*To minimize injury from anaphylaxis, patients should be observed for 2 hours after the first three doses and for 30 minutes after all subsequent doses.

Interleukin-5 Receptor Antagonists

Benralizumab, Mepolizumab, and Reslizumab

• By inhibiting IL-5, IL-5 receptor antagonists decrease the production of eosinophils

• approved use is restricted for the treatment of severe eosinophilic asthma

• indicated for add-on management when traditional therapy is inadequate

Interleukin-5 Receptor Antagonists adverse affects

• Headache

• Pharyngitis

• Injection site reaction

• Back pain

• Fatigue

• Sore throat 

• CPK increase 

• Immunogenicity 

*Hypersensitivity is currently the only contraindication for IL-5 receptor antagonists

Interleukin-4 Receptor α Antagonists

Dupilumab

• approved for the management of moderate to severe asthma.

• with dependence on oral glucocorticoids

• moderate to severe atopic dermatitis

Adverse effects 

• local injection site reaction

• conjunctivitis

• oral herpes

• Eosinophilia

• There are no contraindications for dupilumab other than hyper- sensitivity.

• For patients with helminth infestation, treatment of the infection is warranted before starting therapy with dupilumab.

Thymic Stromal Lymphopoietin Blocker

Tezepelumab-ekko

• decrease in inflammation

• add-on drug, for the maintenance treatment of severe asthma

Adverse effects 

• pharyngitis, joint pain, and back pain.

• Patients taking tezepelumab-ekko should not be vaccinated with live vaccines

Phosphodiesterase-4 Inhibitor

Roflumilast

• raise levels of cAMP that reduce inflammation + pulmonary infiltration 

• exacerbation prophylaxis in patients with severe COPD with a primary chronic bronchitis component and a history of frequent exacerbations

• effects take an 1hr but can be delay if taken with food 

Adverse effects 

• diarrhea

• reduced appetite

• weight loss

• nausea

• headache

• back pain

• insomnia

• *anxiety and depression to suicidal behavior

β -Adrenergic Agonists

activate β2- adrenergic receptors → bronchodilation

• limited role in suppressing histamine release in the lung and increasing ciliary motility

• relieving acute bronchospasm and preventing EIB

• SABAs = PRN to abort ongoing attack + before exercise for EIB

• LABAs = frequent attacks + combined with glucocorticoid + stable COPD

• Oral B2 agnoists = long-term control 

β -Adrenergic Agonists adverse effects

• tachycardia, angina, and tremor

• risk for severe asthma and asthma-related death when used as monotherapy for long-term control

• some activation of β1 receptors in the heart like angina pectoris + tachydysrhythmias for oral

• ^Tremor

Methylxanthines

central nervous system stimulants

• (1) central nervous system (CNS) excitation

• (2) bronchodilation

• Other actions include cardiac stimulation, vasodilation, and diuresis

Theophylline

principal methylxanthine employed in asthma.

• Bronchodilation + blockade of receptors for adenosine

• has a narrow therapeutic range, so dosage must be carefully controlled

• no longer routinely recommended for asthma and COPD

• levels between 5 and 15 μg/mL are appropriate for most patients

Adverse effects 

• Toxicity 

• nausea, vomit- ing, diarrhea, insomnia, restlessness

• severe dysrhythmias

Treatment 

• Absorption can be decreased by administering activated charcoal together with a cathartic

• Depends on the type of dysrhythmia = IV benzodiazepines

Theophylline drug interactions

• Caffeine → CNS and heart

• Tobacco and marijuana → increased drug clearance

• Drugs That Reduce Theophylline Levels = phenobarbital, phenytoin, and rifampin

• Drugs That Increase Theophylline Levels = cimetidine and the fluoroquinolone anti- biotics (e.g., ciprofloxacin)

Aminophylline

theophylline salt that is considerably more soluble than theophylline itself

• pharmacologic properties of aminophylline and theophylline are identical

• incompatible with many other drugs. Therefore, compatibility must be verified before mixing aminophylline with other IV agents

Anticholinergic Drugs

improve lung function by blocking muscarinic receptors in the bronchi, reducing bronchoconstriction

• COPD

Ipratropium

Anticholinergic drug

By blocking muscarinic cholinergic receptors in the bronchi, ipratropium prevents bronchoconstriction

• bronchospasm associated with COPD

• asthma 

Adverse effects 

• dry mouth and irritation of the pharynx.

• Adverse cardiovascular events (heart attack, stroke, death) 

Tiotropium

Anticholinergic drug

• LAMA approved for maintenance therapy of bronchospasm associated with COPD

• Therapeutic effects begin about 30 minutes after inhalation, peak in 3 hours, and persist for about 24 hours.

Adverse effects 

• Dry mouth 

• constipation, urinary retention, tachycardia, blurred vision are minimal

• Cardio events (rare) 

Aclidinium

LAMA approved for the management of bronchospasm associated with COPD

• Peak levels have occurred within 10 minutes of drug delivery; however, it is intended only for maintenance therapy and not for acute symptom relief

Adverse effects

• headache, nasopharyngitis, and cough.

• there is a theoretical risk for worsening narrow-angle glaucoma, urinary retention, and other systemic anticholinergic effects (not reported) 

Umeclidinium

newest LAMA indicated for the management of bronchospasm associated with COPD

• indicated for COPD maintenance therapy only

Adverse effects 

• severe hypersensitivity reactions when taken by people who have milk protein allergies

• Nasopharyngitis

• upper respiratory tract infections

Glucocorticoid/Long-Acting β2-Agonist Combinations

reserved for patients whose asthma has not been adequately controlled with an inhaled glucocorticoid alone

• Budesonide/formoterol (Symbicort)

• Fluticasone/vilanterol (Breo Ellipta)

• Fluticasone propionate/salmeterol (Advair Diskus, Advair HFA),

• Mometasone/formoterol (Dulera)

β -Adrenergic Agonist/Anticholinergic 2 Combinations

• promote bronchodilation by stimulating adrenergic receptors

• Cholinergic antagonists (anticholinergics) promote bronchodilation by blocking cholinergic receptors

• Albuterol/ipratropium (Combivent Respimat, Combivent UDV)

• Olodaterol/tiotropium (Stiolto Respimat)

• Inhaled vilanterol/umeclidinium (Anoro Ellipta)

Lung function tests

• Forced expiratory volume in 1 second (FEV1) = patient inhales completely and then exhales as completely and forcefully as possible into the spirometer

• Forced vital capacity (FVC) = total volume of air the patient can exhale after a full inhalation

• Peak expiratory flow (PEF) = maximal rate of airflow during expiration. This measurement is used to monitor, but not diagnose, asthma

Intrasnasal glucocorticoids 

prevention and treatment of seasonal and perennial rhinitis

Adverse effects 

• drying of the nasal mucosa

• burning or itching sensation

• Sore throat

• epistaxis (nose- bleed)

• headache

• adrenal suppression and the slowing of linear growth in children

Oral antihistamines

first-line drugs for mild to moderate allergic rhinitis

• relieve sneezing, rhinorrhea, and nasal itching

Adverse effects

• sedation

• drying of nasal secretions, dry mouth, constipation, urinary hesitancy

Intranasal antihistamines

azelastine (Astelin, Astepro) and olopatadine (Patanase)

• somnolence

• nosebleeds and headaches

• unpleasant taste

Intranasal cromolyn sodium

suppressing the release of histamine and other inflammatory mediators from mast cells

• best suited for prophylaxis and hence should be given before symptoms start

• If nasal congestion is present, a topical decongestant should be used before cromolyn

Sympathomimetics (Decongestants)

reduce nasal congestion by activating α1-adrenergic receptors on nasal blood vessels → vasoconstriction 

• relieve only congestion

• Ex: Phenylephrine and Pseudoephedrine

Adverse effects 

• Rebound congestion 

• CNS stimulation = restlessness, irritability, anxiety, and insomnia

• CV effects = HTN, CAD, cardiac arrhythmias, and cerebrovascular disease

• ABUSE

Ipratropium bromide (Atrovent)

anticholinergic agent

• allergic rhinitis, asthma, common cold 

• Adverse effects = nasal drying and irritation

Montelukast (Singulair)

Leukotriene Receptor Antagonist = relieves nasal congestion, although it has little effect on sneezing or itching

• asthma

• seasonal and perennial allergic rhinitis

Adverse effects 

• agitation, aggression, hallucinations, depression, insomnia

• restlessness, and suicidal thinking and behavior

Monoclonal antibodies

• Omalizumab (Xolair), an anti-IgE monoclonal antibody

• Dupilumab (Dupixent), anti-interleukin (IL-)4 receptor α monoclonal antibody

used to manage allergic rhinitis and allergy-mediated asthma

Antitussives

drugs that suppress cough

• fall into two major groups: (1) opioid antitussives and (2) non-opioid antitussive

• major antitus- sives (codeine, dextromethorphan, and diphenhydramine) are clearly effective against chronic nonproductive cough and experimentally induced cough → not with common cold 

Opioid Antitussives

Codeine and Hydrocodone

• act in the CNS to elevate cough threshold

• codeine can suppress respiration

• potential for abuse

• *An opioid antagonist (e.g., naloxone) should be used to reverse toxicity

Dextromethorphan

over-the-counter (OTC) nonopioid cough medicine

• acts in the CNS

• taken in high doses, dextromethorphan can cause euphoria

• mild inebriation to a state of mind-body dissociation, much like that caused by phencyclidine (PCP)

Other Nonopioid Antitussives

• Diphenhydramine = sedative and anticholinergic properties

• Benzonatate (Tessalon, Zonatuss) = decreasing the sensitivity of respiratory tract stretch receptors → sedation, dizziness, constipation

CHILDREN

• ^overdose can cause seizures, dysrhythmia, and death

• Smaller doses can cause confusion, chest numbness, visual hallucinations, and a burning sensation in the eyes

• benzonatate capsules should be swallowed intact → capsules are sucked or chewed, rather than swallowed, the drug can cause laryngospasm, bronchospasm, and circulatory collapse

Expectorants

renders cough more productive by stimulating the flow of respiratory tract secretions

Ex: guaifenesin (Mucinex, Humibid, others)

Mucolytics

reacts directly with mucus to make it less viscous

• make cough more productive

• Ex: hypertonic saline and acetyl- cysteine → bronchospasm + smelling like rotten eggs 

CNS drugs

act on brain and spinal cord

• uses = relief of pain, suppression of seizures, production of anestheisia, and treatment of mental helath conditions

• Types = Neurotransmitters of CNS and Blood-brain barrier 

Neurotransmitters of CNS

use action of neurotransmitters and their receptors in the brain and spinal cord

• Ex: Acetylcholine, norepinephrine, and epinephrine 

Blood-brain barrier 

tight junctions between cells that impede entry of drugs into brain 

• limited to lipid-soluble agents and to drugs tha cross by specific tanspor systems

• *protein-bound drugs and highly ionized drugs cannot cross the BBB

Adaptation of the Central Nervous System to Prolonged Drug Exposure

altered effects are believed to be the result of adaptive changes that occur in the brain in response to prolonged drug exposure

Ex: Antipsychotics and antidepressents that take several weeks to develop from adaptive changes

Another ex: pehnobarbital (antiseizure drug) produces sedation during the initial phase of therapy; however, with continued treatment, sedation declines while full protection from seizures is retained

Tolerance and Physical Dependence

• Tolerance is a decreased response to drug effects occurring in the course of prolonged drug use.

• Physical dependence is a state in which abrupt discontinuation of drug use will precipitate a drug withdrawal syndrome.

Patho of Parkison disease

dopamine depletion results from the degeneration of the neu- rons that supply dopamine in the brain

• α-synuclein degradation does not occur, it accumulates inside the cell, forming neurotoxic fibrils (lewy bodies) 

• extrapyramidal function is disrupted, dyskinesias (disorders of movement) result like tremors and bradykinesia 

• *Dopamine inhibit GABA and acetylcholine release GABA, imbalance of these in PD

Dopaminergic drugs

Levodopa is converted to dopamine, which activates dopamine receptors directly

• inhibitors of monoamine oxidase-B (MAO-B) prevent dopamine breakdown

• amantadine promotes dopamine release (and may also block dopamine reuptake)

• inhibitors of catechol-O-meth-yltransferase (COMT) enhance the effects of levodopa by blocking its degradation

Anticholinergic agents

blockade of muscarinic receptors in the striatum

MAO-B inhibitors

provide mild benefits, but they have fewer side effects

• treatment of choice for mild symptoms

Management of Motor Fluctuations

associated with two types of motor fluctuations: “off” times (loss of symptom relief) and drug-induced dyskinesias (involuntary move- ments)

• “Off” times can be reduced with three types of dopa- minergic drugs (DAs, COMT inhibitors, MAO-B inhibitors) or an adenosine antagonist.

• The only drug recommended for dyskinesias is amantadine.

Levodopa

dopamine precursor

drug is highly effective, beneficial effects diminish over time. The most troubling adverse effects are dyskinesias

• 50% reduction in symptom severity and full therapeutic responses may take several months to develop

• Action = increasing dopamine synthesis in the striatum that restore a proper balance between dopamine and acetylcholine

• Because of peripheral metabolism, less than 2% of each dose enters the brain if levodopa is given alone. For this reason, levodopa is available in combination preparations with either carbidopa or carbidopa and entacapone

Acute Loss of Effect Levodopa

Gradual loss—“wearing off”—develops near the end of the dosing interval and simply indicates that drug levels have declined to a subtherapeutic value. Wearing off can be minimized in three ways

• (1) shortening the dosing interval, (2) giving a drug (e.g., entacapone) that prolongs levodopa’s plasma half-life, and (3) giving a direct-acting DA.

Abrupt loss of effect, often referred to as the “on-off” phenomenon, can occur at any time during the dosing interval— even while drug levels are high

• Avoid high protein meals 

• Drugs to help DA precursoe, DA receptor agonists, COMT inhibitors, MAO-B inhibitors, Adenosine receptor antagonist, and anticholinergics 

Levodopa adverse effects

• Nausea and vomiting 

• Dyskinesias 

• Cardio effects = Postural hypotension + dysrhythmias 

• Psychosis = visual hallucinations, vivid dreams or nightmares, and paranoid ideation → treat by clozapine and quetiapine

• Anxiety and agitation to memory and cognitive impairment

• Insomnia and nightmares

• Darken sweat and urine

• Activate malignant melanoma??

Levodopa drug and food interactions

• First-Generation Antipsychotic Drugs = decrease therapeutic effects of levodopa

• Monoamine Oxidase Inhibitors = can cause a hypertensive crisis if administered to an individual taking a nonselective inhibitor of MAO

• Anticholinergic Drugs = can enhance responses to levodopa

• Pyridoxine = accelerates decarboxylation of levodopa in the periphery; however, because levodopa is now always combined with carbidopa, a drug that suppresses decarboxylase activity

• High-protein meals = can reduce therapeutic responses to levodopa. Neutral amino acids compete with levodopa for absorption from the intestine and for transport across the blood- brain barrier

Carbidopa

inhibits decarboxylation of levodopa in the intestine and peripheral tissues, thereby making more levodopa available to the CNS

• reduces both cardiovascular responses to levodopa and nausea and vomiting

• eliminates concerns about decreasing the effects of levodopa by taking a vitamin preparation that contains pyridoxine

*abnormal movements and psychiatric disturbances can occur sooner and be more intense than with levodopa alone

Dopamine receptor agonists (DA)

first- line drugs for PD

• Beneficial effects result from direct activa- tion of dopamine receptors in the striatum

• cause serious side effects—especially hallucinations, day- time sleepiness, and postural hypotension.

• As a result, these drugs are usually reserved for younger patients, who tolerate their side effects better than older patients do

Two groups = derivatives of ergot (an alka- loid found in plants) and nonergot derivatives

• nonergot derivatives—pramipexole, ropinirole, rotigotine, and apomor- phine—are highly selective for dopamine receptors.

• In contrast, the ergot derivatives—bromocriptine and cabergoline—are less selective

Pramipexole

Nonergot Derivative

• binds selectively to dopamine-2 (D2) and dopamine-3 (D3) receptor subtypes

• Uses = early stage PD and combined with levodopa at advanced-stage PD, severe restless legs syndrome (RLS)

Adverse effects

• alone are nausea, dizziness, daytime somnolence, insomnia, constipation, weakness, and hallucinations

• When the drug is combined with levodopa, about half of patients experience orthostatic hypotension and dyskinesias

• sleep attacks 

• impulse control disorders = gambling, shopping, binge eating, and hypersexuality

Ropinirole

nonergot DA → highly selective for D2 and D3 receptors

• Uses = PD management and RLS

Adverse effects 

• Alone = nausea, dizziness, somnolence, and hallucinations

• Combined with levodopa = dyskinesias, hallucinations, and postural hypotension 

• can promote compulsive gambling, shopping, eating, and hypersexuality

Rotigotine

nonergot DA that is specific for selected dopamine receptors

• approved for PD management from early to advanced stages.

• It is also approved for the management of moderate to severe primary RLS

Adverse effects 

• sleep disorders, dizziness, headache, dose-related hallucinations, and dose-related dyskinesia.

• Orthostatic hypotension and peripheral edema

• Nausea and vomiting

• skin reactions + hyperhidrosis (excessive perspiration)

Apomorphine

nonergot DA approved for the treatment of hypomobility during “off” episodes in patients with advanced PD

• Adverse effects = injection-site reactions, hallucinations, yawning, drowsiness, dyskinesias, rhinorrhea, and nausea and vomiting

• Serious cardiovascular events: angina, myocardial infarction, cardiac arrest, and/or sudden death.

• Postural hypotension and fainting

• Daytime sleep attack 

• promote hypersexuality and enhanced erections

Bromocriptine

ergot derivative

• approved for PD and in combination with levodopa in advanced PD

Adverse effects

• Nausea

• Psychological reactions (e.g., confusion, nightmares, agitation, hallucinations, paranoid delusions)

• dyskinesias and postural hypotension

• retroperitoneal fibrosis, pulmonary infiltrates

• Raynaud-like phenomenon and erythromelalgia (vasodilation in the feet, and sometimes hands, resulting in swelling, redness, warmth, and burning pain)

Cabergoline

ergot derivative

approved for treatment of hyperprolactinemic disorders, is used occasionally in PD, although it is not approved by the U.S. Food and Drug Administration (FDA) for this disorder

• used unless other management attempts have failed

Common side effects

• headaches, dizziness, nausea, and weakness.

• Development of cardiac valve regurgitation and subsequent development of heart failure.

• Pulmonary and pericardial fibrosis

COMT inhibitors

entacapone, opicapone, and tolcapone

• prescribed along with levodopa.

• Benefits derive from inhibiting metabolism of levodopa in the periphery

Entacapone

selective, reversible inhibitor of COMT indicated only for use with levodopa

• prolongs the plasma half-life of levodopa and thereby prolongs the time that levodopa is available to the brain

• levodopa blood levels to be more stable and sustained

Adverse effects 

• dyskinesias

• orthostatic hypotension

• nausea, hallucinations, sleep disturbances

• impulse control disorders

Other 

• vomiting, diarrhea, constipation, and yellow-orange discoloration of the urine

Drug interactions

• increase levels of other drugs metabolized by COMT.

• These include methyldopa (an antihypertensive agent), dobutamine (an adrenergic agonist), and isoproterenol (a β-adrenergic agonist)

Tolcapone (Tasmar)

inhibitor of COMT, improves motor function and may allow for a reduction in levodopa dosage

• serious risk of severe hepatocellular injury → signs of emergent liver dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine)

• reserved for patients who cannot be treated, or treated adequately, with safer drugs

• Check ALT and AST every 2 weeks for 1st year, every 4 weeks for the next 6 months, and every 8 weeks thereafter

Opicapone (Ongentys)

newest COMT inhibitor

• expensive

• prescribed once daily, it may be beneficial for patients who have problems adhering to complex drug regimens

MAO-B inhibitors examples 

selegiline, rasagiline, and safinamide

• are considered first-line drugs for PD even though benefits are modest

Selegiline (Eldepryl, Emsam, Zelapar)

MAO inhibitor

• approved for PD. The drug may be used alone or in combination with levodopa

• selective, irreversible inhibition of MAO-B (inactivates dopamine in the striatum) 

• benefits decline dramati- cally within 12 to 24 months

Adverse effects 

• alone =  insomnia, orthostatic hypotension, dizziness, and GI symptoms

Selegiline food and drug interactions 

hypertensive crisis can be triggered by taking certain drugs, including sympathomimetics, and by ingesting foods that contain tyramine

• Tyramine is especially high in foods that are aged, cured, or fermented

• Levodopa = can intensify adverse responses to levodopa-derived dopamine

• opioid drugs = can increase the opioid’s adverse effects

• meperidine, methadone = cause serotonin syndrome, a life- threatening condition characterized by signs and symptoms such as delirium and other mental status changes, rigidity, and hyperthermia

• selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac) = fatal serotonin syndrome

Rasagiline (Azilect)

MAO-B inhibitor, selective, irreversible inhibitor of MAO-B

• approved for initial monotherapy of PD and for combined use with levodopa

• not converted to amphetamine or methamphetamine

• may increase the risk for malignant melanoma, a potentially deadly cancer of the skin

Safinamide (Xadago, Onstryv )

MAO-B inhibitor, A benefit is its level of selectivity

• it is less likely to inhibit MAO- A, hypertensive crises are much less likely.

• Subsequently, FDA-approved labeling states that dietary restrictions are not required unless tyramine intake exceeds 150 mg

Amantadine (Gocovri, Osmolex ER)

only N-methyl-d-aspartate (NMDA) receptors antagonist approved for management of PD

• promotes the release of dopamine

• helps to manage dyskinesias caused by levodopa

Adverse effects

• confusion, light-headedness, anxiety

• blurred vision, urinary retention, dry mouth, constipation

• livedo reticularis, a condition characterized by mot- tled discoloration of the skin

Drug interactions

• metoclopramide = commonly prescribed drug to pro- mote gastric motility, can decrease the therapeutic effect of aman- tadine

• decrease the effectiveness of live influenza virus vaccines

• Alcohol promotes the dissolution of these coatings → drug overdose 

Istradefylline (Nourianz)

Adenosine Receptor Antagonist

• opposes that of dopamine

• approved for manage- ment of “off” episodes in patients who are taking levodopa/ carbidopa

Adverse effects

• dyskinesias, Insomnia, hallucinations, dizziness, nausea, and constipation

• aggression, agitation, mania

• disorientation, paranoia, delirium

• Impulse control disorders

*people who smoke 20 or more cigarettes daily or who use an equivalent amount of tobacco in other forms require higher doses of istradefylline

Benzotropine

Centrally Acting Anticholinergic Drugs

• alleviates symptoms by blocking muscarinic receptors in the striatum

• can reduce tremor and possibly rigidity but not bradykinesia

• most appropriate for younger patients with mild symptoms

Adverse effects 

• dry mouth, blurred vision, photophobia, urinary retention, constipation, and tachycardia

Drug interactions 

• enhance the anti-cholinergic effects of many drugs

• Trihexyphenidyl shares the same basic drug profile as benztropine

Patho of Alzheimer’s disease 

Neuronal degeneration occurs in the hippocampus early in AD

• followed later by degeneration of neurons in the cerebral cortex and subsequent decline in cerebral volume

• include complete loss of speech, loss of bladder and bowel control, and complete inability for self-care

• levels of acetylcholine are 90% below normal

• Neuritic plaques = beta-amyloid is present in high levels

• Neurofibrillary tangles

• One form—apoE4—is asso- ciated with the impairment of amyloid beta clearance in AD

Drugs for treating AD dementia

• cholinesterase inhibitors

• N-methyl-d-aspartate (NMDA) inhibitors

• monoclonal antibodies

Cholinesterase inhibitors

Ex: Donepezil (Adlarity, Aricept)

to treat AD → prevent the breakdown of acetylcho- line by acetylcholinesterase (AChE)

• mild to moderate symptoms, and one agent—donepezil—is also approved for those with severe symptoms

Adverse effects  

• nausea, vomiting, dyspepsia, diarrhea

• Dizziness and headache

• bronchoconstriction

• symptomatic bradycardia, leading to fainting, falls, fall-related fractures, and pacemaker placement

Drug interactions 

• Drugs that block cholinergic receptors can reduce therapeutic effects and should be avoided.

• In addition to anticholinergic drugs, these include first-generation antihistamines, tricyclic antidepressants, and conventional antipsychotics.

Donepezil (Adlarity, Aricept)

Cholinesterase inhibitor

indicated for mild, moderate, or severe AD

• causes reversible inhibition of AChE but is more selective for the form of AchE found in the brain

• 15 days for donepezil to achieve steady state

Adverse effects 

• bradycardia, fainting, falls, and fall-related fractures.

• Patients are stabilized on the initial dosage for 1 to 3 months before increasing dosage to minimize the side effects

Rivastigmine (Exelon)

Cholinesterase inhibitor

approved for AD and for dementia of Parkinson disease

• irreversible inhibition of AchE

Adverse effects

• nausea, vomiting, diarrhea, abdominal pain, and anorexia

• Weight loss

Galantamine (Razadyne, Razadyne ER, Reminyl ER )

Cholinesterase inhibitor

indicated for mild to moderate AD

• reversible cholinesterase inhibitor

Adverse effects

• nausea, vomiting, diarrhea, and anorexia

• Weight loss

Memantine (Namenda, Namenda XR, Ebixa )

NMDA receptor antagonist approved for management of AD

• only for moderate or severe AD

• blocks calcium influx when extracellular glutamate is low but permits calcium influx when extracellular glutamate is high

Adverse effects 

• dizziness, headache, and confusion

• diarrhea or constipation

• worsen bradycardia, hypertension, and angina

• increased seizure activity

Drug interactions 

• combining memantine with another NMDA antago- nist, such as amantadine (Symmetrel) or ketamine (Ketalar), could have an undesirable additive effect

• Sodium bicarbonate and other drugs that alkalinize the urine can greatly decrease the renal excretion of memantine

Aducanumab (Aduhelm)

MONOCLONAL ANTIBODY

• first new drug for AD → mild stage

• targets and binds to a protein in beta-amyloid → reduce beta-amyloid plaques that form in the brain of patients with AD

• Monitoring with follow-up MRI studies demonstrated success in removal of much of the plaques

• screened for taking anticoagulants, which could increase bleeding

• uncontrolled hypertension should also be considered for exclusion

Aducanumab (Aduhelm) adverse effects

• Amyloid-related imaging abnormalities (ARIAs) → localized edema or microhemorrhages

• headaches, confusion

• visual disturbances, dizziness, and nausea

• Hypersensitivity reactions = angioedema and urticaria

Risperidone (Risperdal) and Olanzapine (Zyprexa)

atypical antipsychotics that reduce AD neuropsychiatric symptoms

• slightly increase mortality, mainly from cardiovascu- lar events and infection

• For patients with severe psychosis, however, the improvement in quality of life may outweigh the risks

• Benzodiazepines and first- generation antihistamines are not recommended because risks (excessive sedation, dizziness, falls) are greater than benefits, which are minimal

MS patho

presence of multifocal regions of inflammation and myelin destruction in the CNS (brain, spinal cord, and optic nerve)

• axonal conduction is slowed or blocked, giving rise to a host of neurologic signs and symptoms

• forming scars known as scleroses

• demyelination appears to be autoimmune

some degree of recovery occurs

• (1) partial remyelination

• (2) functional axonal compensation (axons redistribute their sodium channels from the nodes of Ranvier to the entire region of demyelination)

• (3) development of alternative neuronal circuits that bypass the dam- aged region

Multiple Sclerosis Subtypes

• Clinically isolated syndrome (CIS) = first episode of MS

• Relapsing-remitting (RRMS) = recurrent, clearly defined episodes of neurologic dysfunction (relapses) separated by periods of partial or full recovery (remissions)

• Primary progressive (PPMS) = symptoms grow progressively more intense from the outset

• Secondary progressive (SPMS) = patient with RRMS develops steadily worsening dysfunction—with or without occasional plateaus, acute exacerbations, or minor remissions

Disease-modifying drugs (DMDs)

• decrease the frequency and severity of relapses

• reduce the development of brain lesions

• decrease future disability, and help maintain quality of life

• Types = immunomodulators and immunosuppressants

• begin as soon as possible after diagnosis

• If treatment fails, treatment with an immunosup- pressant should be considered

• expensive 

Treating an Acute Episode (Relapse) of MS

short course of a high-dose IV glucocorticoid (e.g., 500 mg to 1 g of methylprednisolone daily for 3 to 5 days)

• suppress inflammation

Immunomodulators

Disease-modifying drug

• risk for a severe reaction (e.g., anaphy- laxis) is increased by the presence of neutralizing antibodies

• Hypersensitivity 

• Infections 

• Hematologic changes = decreases in white blood cell (WBC) numbers

• Liver injury → check for ALT, AST, and bilirubin

• report symptoms = malaise, fatigue, nausea, vomiting, anorexia, jaundice [yellow color of skin and eyes], dark brown urine, and pale stools

• vaccine risks → infections 

• Other immunosuppressants should be avoided

Interferon beta

produced in response to viral inva- sion and other biologic inducers

• inhibits the migration of proinflammatory leukocytes across the blood-brain barrier

• suppresses T-helper cell activity

• Ex: interferon beta-1a (Avonex, Rebif) and interferon beta-1b (Betaseron, Extavia)

• Uses = approved for relapsing forms of MS

Interferon beta adverse effects

• Flu-like reactions = headache, fever, chills, malaise, muscle aches, and stiffness

• Hepatotoxicity = liver function tests (LFTs) should be performed at baseline, 1 month later, then every 3 months for 1 year, and every 6 months thereafter

• Myelosuppression = CBCs should be obtained at baseline, every 3 months for 1 year, and every 6 months thereafter

• Injection-site reactions = pain, erythema (redness), maculopapular or vesicular rash, and itching

• Depression

• Neutralizing antibodies 

Drug interactions 

• Exercise caution when combining interferon beta with other drugs that can suppress the bone marrow or cause liver injury

• Cladribine = increases the risk of lymphopenia (low lymphocytes)

Immunosuppressants

mitoxantrone and cladribine for treating MS

• provide greater immunosuppression than the immunomodulators but are also more toxic

Mitoxantrone (generic)

• significant risk for toxicity

• generally reserved for patients who cannot be treated with safer agents

• approved for decreasing neurologic dis- ability and clinical relapses in patients with worsening RRMS and with SPMS

• binds with DNA and inhibits topoisomerase II 

Mitoxantrone adverse effects

• Myelo-suppression

• cardiotoxicity

• fetal injury

• Extravasation can cause severe local injury

• Reversible hair loss

• Injury to the gastrointestinal (GI) mucosa, resulting in stomatitis and GI distress

• nausea, vomiting, menstrual irregularities (e.g., amenorrhea)

• symptoms of allergy (itching, rash, hypotension, shortness of breath)