PHARM 331 Drug actions, effects, and etc Exam 2

Asthma and COPD drugs 

• Antiinflammatory agents → glucocorticoids

• Bronchodilators → B2 agonists + Anticholinergic

• *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 

• Must prime by spraying 2-3 actuations before first use or if not used for several days

• Shake it well before use (keep cap on, wash it, keep it clean)

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 

• Could get a fungal infection (candida) in the mouth, SO PLEASE RINSE THE MOUTH (USE ALCOHOL or MOUTHWASH) AFTER USE OF INHALER

• May increase the number of bronchial beta2 receptors and their responsiveness to beta2 agonists

Uses 

• control inflammation in asthma and COPD

• Dosing must be on a fixed schedule

Glucocorticoids adverse effects 

• oropharyngeal candidiasis (thrush) → treated with antifungal med

• dysphonia (hoarseness, speaking difficulty)

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

• May increase the number of bronchial beta2 receptors and their responsiveness to beta2 agonists

• bone loss, cataracts, and glaucoma

Oral Glucocorticoids adverse effects 

oral 

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

• You can not quit oral use after you start it (after 7-10 days), the body gets lazy and doesnt wanna produce its own steroids. SO ONCE YOU START IT, KEEP USING ORAL USE/ OR SLOW DOWN PROGRESS OF ORAL USE

• Can cause hypertension, hyperglycemia (acute)

• Osteoporosis, cytosis (chronic)

 

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

Leukotreiene modifiers

Anti-inflammatory drugs

• Promote smooth muscle constriction, blood vessel permeability, and inflammatory responses through direct action and recruitment of eosinophils and other inflammatory cells

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

Adverse effects 

•  neuropsychiatric effects, including depression, suicidal thinking, and suicidal behavior

Zileuton [Zyflo]

inhibitor of leukotriene synthesis (enzyme that converts aricidonic acid into leukotrienes)

• 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.

• can also increase levels of warfarin and propranolol.

Zafirlukast [Accolate]

LTRAs, blocks leukotriene receptors

• reduced infiltration of inflammatory cells

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

Adverse effects 

• headache + Can cause flu like symptoms

• 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 [Singulair]

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

• 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

• -taken daily on a fixed schedule. For prophylaxis of exercise-induced bronchospasm, cromolyn is taken 15 minutes before anticipated exertion

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

• 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

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

• viscous, is administered subcutaneously

Adverse effects 

• injection-site reactions

• viral infection

• upper respiratory infection

• sinusitis

• headache

• pharyngitis

• Cardiovascular events 

• 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 hypersensitivity.

• 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, highly protein bound 

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 (dosing is fixed)

• Oral B2 agnoists = long-term control 

• *Blocker is preferred over enhancer

• *Don't give beta blocker and propranolol

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 

• levels of 20-25 = nausea, vomiting, diarrhea, insomnia, restlessness

• Above 30 = severe dysrhythmias and convulsions

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 antibiotics (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 

• Therapeutic effects begin within 30 seconds, reach 50% of maximum in 3 minutes, and persist about 6 hours

Adverse effects 

• dry mouth and irritation of the pharynx.

• Glaucoma

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

Tiotropium

Anticholinergic drug, long-acting

• 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.

• continues to improve, reaching a plateau after eight consecutive doses (8 days) 

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

• it is intended only for maintenance therapy and not for acute symptom relief

Adverse effects

• headache

• nasopharyngitis

• cough

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)

• Indicated for long-term maintenance in adults and restricted use in children

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

Management of Chronic Asthma + acute 

• Treatment goals

  • Reducing impairment

  • Reducing risk for future occurrence

• Long-term drug therapy

  • Agents for long-term control (eg, inhaled glucocorticoids)

  • Agents for quick relief of ongoing attack (eg, inhaled SABAs)

• Stepwise therapy

  • Step chosen for initial therapy is based on pretreatment classification of asthma severity

  • Moving up or down a step is based on ongoing assessment of asthma control

• Important to reduce exposure to allergens and triggers

• Sources of allergens: House dust mites, pets, cockroaches, mold

• Factors that can exacerbate asthma: Tobacco smoke, wood smoke, household sprays

• Preferred inhaled than oral 

Drugs for Acute Severe Exacerbation

• This condition requires immediate attention 

• Goals: Relieve airway obstruction and hypoxemia, and normalize lung function as quickly as possible 

• Initial therapy consists of administering:

  • Oxygen—To relieve hypoxemia

  • A systemic glucocorticoid—To reduce airway inflammation 

  • A nebulized, high-dose SABA—To relieve airflow obstruction 

  • Nebulized ipratropium—To further reduce airflow obstruction

Drugs for Exercise-Induced Asthma

• Cause: Bronchospasm secondary to loss of heat and/or water from the lung

• Starts either during or immediately after exercise, peaks in 5 to 10 minutes, and resolves 20 to 30 minutes later

• SABA or cromolyn administered prophylactically

  • Inhaled SABAs generally preferred over cromolyn

• Beta2 agonists should be inhaled immediately before exercise

• Cromolyn should be inhaled 15 minutes before exercise

 

Management of Stable COPD

• Pharmacologic management 

  • Bronchodilators

  • Glucocorticoids

  • Phosphodiesterase-4 inhibitors

  • Want to reduce inflammation

Management of COPD Exacerbations

• Pharmacologic management  

  • SABAs (specifically inhaled, either alone or in combination with inhaled anticholinergics) are preferred for bronchodilation during COPD exacerbations

  • Systemic glucocorticoids

  • Antibiotics- if individual have infection (the mucus which traps the organisms)

    • Use systemic glucocortidoids. 

  • Supplemental oxygen to maintain an oxygen saturation of 88% to 92%

Classes of Drugs Used for Allergic Rhinitis

• Glucocorticoids (intranasal)

• Antihistamines  (ANTICOLNERGIC) (oral and intranasal)

  • Benedryl 

  • Sedation will occur

  • If used too much they will have constipation, dryness of mouth

  • A LOT OF DRYNESS

• Sympathomimetics (oral and intranasal) 

  • Long acting will increase blood pressure

  • Long acting products can have vasoconstriction for long period of time

  • Don't have it in vacuum, we want vasodilation 

  • For the nasal we have rebound reconstruction, and the body gets addicted to nasal medication. We take it once a day, the congestion will come back the next day. 

• Allergic rhinitis is the most common allergic disorder. It is treated primarily with antihistamines, intranasal glucocorticoids, and sympathomimetic decongestants.

Intrasnasal glucocorticoids 

First choice—most effective for treatment and prevention of rhinitis

• prevention and treatment of seasonal and perennial rhinitis (congestion, rhinorrhea, sneezing, nasal itching, and erythema)

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

• Reduces the effect of histamine

Oral antihistamines

first-line drugs for mild to moderate allergic rhinitis

• relieve sneezing, rhinorrhea, and nasal itching

• Most effective if taken prophylactically

Adverse effects

• sedation

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

Intranasal antihistamines

azelastine (Astelin, Astepro) and olopatadine (Patanase)

• Indicated for allergic rhinitis in adults and in children over 12 years old

Adverse effects 

• 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

• Response develops in 1 to 2 weeks

• Minimal adverse reactions: Less than with any other drug for allergic rhinitis

Sympathomimetics (Decongestants)

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

• relieve only congestion

• Ex: Phenylephrine and Pseudoephedrine, ephedrine

Adverse effects 

• Rebound congestion 

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

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

• ABUSE

Oral/nasal

• Should not use longer than 3 to 5 consecutive days

• Topical agents act more quickly

Ipratropium bromide (Atrovent)

Oral sympathomimetics reduce nasal congestion slowly and cause central nervous system (CNS) and cardiovascular stimulation

• 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

• Oral sympathomimetics reduce nasal congestion slowly and cause central nervous system (CNS) and cardiovascular stimulation

• 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

• Oral sympathomimetics reduce nasal congestion slowly and cause central nervous system (CNS) and cardiovascular stimulation

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

• Opioid = codeine/hydrocodone

• clearly effective against chronic nonproductive cough and experimentally induced cough → not with common cold 

• Pt education: Do not operate machinery if we take codeine

  • AKA DRIVING. 

• Nonopioid antitussives- low doses are safe, high doses are NOT SAFE. Pt education is take PRN.

• dextromethorphan, diphenhydramine, henzonatate

• Dextromethorphan is the most effective nonopioid cough suppressant

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

• Pt education: Do not operate machinery if we take codeine

  • AKA DRIVING

Dextromethorphan

over-the-counter (OTC) nonopioid cough medicine → most effective nonopioid cough suppressant

• 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)

• Side effect is GI side effect

Mucolytics

reacts directly with mucus to make it less viscous

• make cough more productive

• Ex: hypertonic saline and acetylcysteine → bronchospasm + smelling like rotten eggs 

Cold treatments 

• For 1st week of common cold, DO NOT USE ANTIBOTICS. 

  • Use them after the 1st week

Remedies

• Nasal decongestant

• Antitussive

• Analgesic

• Antihistamine (for cholinergic actions)

• Caffeine (to offset effect of antihistamine)- if you are sedated, caffeine will make you more awake.

• *MILLIGRAM TO KILOGRAM, unless the child is bigger than normal then speak to the provider

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 neurons 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

Symptoms

• Dyskinesias - disorders of movement = TRAP

• In addition to motor symptoms:

•  Autonomic disturbances

•  Depression

•  Psychosis and dementia

Dopaminergic drugs

Levodopa is converted to dopamine, which activates dopamine receptors directly (severe symptoms)

• 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

•  Benztropine [Cogentin]

• Pseudoparkinson- have symptoms of parkinson, but don't actually have Parkinson’s disease

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 dopaminergic drugs (DAs, COMT inhibitors, MAO-B inhibitors) or an adenosine antagonist.

• The only drug recommended for dyskinesias is amantadine.

• “On- off”= Even though we are compliant, medication can still stop working

• Does not mean to increase dose of medication

• Neuroprotection = Slowing the progression, not treating the disease

Levodopa

dopamine precursor → active form

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

*activity of decarboxylases is enhanced by pyridoxine (vitamin B6)

• 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 precursor, 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

• Low initial doses and administration with food can reduce therapeutic effects by decreasing levodopa absorption

• 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

Levodopa/Carbidopa [Sinemet and Parcopa] advantages/disadvantaged

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

*Off and on times so do not go off the medicine 

Dopamine receptor agonists (DA)

first-line drugs for PD

• Beneficial effects result from direct activation 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

•  Lower incidence of response failure

•  Less likely to cause dyskinesias

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

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

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

Pramipexole [Mirapex]

Nonergot Dopamine 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 [Requip]

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 [Neupro]

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 [Apokyn, Movapo]

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

- Not by mouth 

• 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 [Comtan]

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

• *Treatment should be limited to 3 weeks in the absence of a beneficial response

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

• Combination with levodopa can reduce the wearing-off effect

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) 

• Can suppress the destruction of dopamine derived from levodopa and prolong the effects of levodopa

• benefits decline dramatically 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)

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 mottled discoloration of the skin

Drug interactions

• metoclopramide = commonly prescribed drug to promote gastric motility, can decrease the therapeutic effect of amantadine

• 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 [Cogentin,Kynesia]

Centrally Acting Anticholinergic Drugs, used as second-line therapy for tremor

• 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

-Risks =  Nicotine in cigarette smoke + Sedentary lifestyle

-Symptoms = Memory loss, Confusion, Personality changes, sundowning 

Drugs for treating AD dementia

• cholinesterase inhibitors = Donepezil, galantamine, and rivastigmine

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

• monoclonal antibodies

• may delay or slow progression of disease but will not stop it

Cholinesterase inhibitors for AD

Ex: Donepezil (Adlarity, Aricept)

to treat AD → prevent the breakdown of acetylcholine by acetylcholinesterase (AChE)

• mild to moderate 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

•  Intensify symptoms in patients with peptic ulcer disease, bradycardia, sick sinus syndrome, urinary obstruction, and lung disease, bradycardia, fainting, falls, and fall-related fractures

Galantamine (Razadyne, Razadyne ER, Reminyl ER )

Reversible Cholinesterase inhibitor

• indicated for mild to moderate AD

Adverse effects

• nausea, vomiting, diarrhea, and anorexia

• Weight loss

•  Bradycardia, fainting, falls, and fall-related fractures

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 damaged 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 immunosuppressant 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