Conference on Therapy Case 1: Respiratory Problem 1

Conference on Therapy Case 1: Respiratory Problem

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Mario, 30 y/o known asthmatic (in remission for past 10 yrs), presents w/

cough 2 mos. duration

Chief complaint: difficulty breathing

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HPISeveral years PTC• Frequent sneezing, nasal stuffiness (esp. on

waking up in the morning)• Sx abate as day wears on

2 mos. PTC• Persistent nasal stuffiness (whole day),

more severe Sx at night when lying down• Wife says that he “snores loudly”• Started having productive cough and itchy

throat 3

2 mos. PTC (cont’d)• Px took cough and colds OTC w/ partial

relief of Sx

1 mo. PTC• Cough increased in severity esp. in a.m.,

disrupting sleep• paroxysms of retching cough soon after

going to bed• Wife noted “wheezing” sounds while px

is asleep

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1 mo. PTC (cont’d)• Px complains of easy fatigability, cannot talk

long w/ clients; voice noted to be “hoarse”

1 wk PTC• Developed more severe colds w/ increased

mucopurulent discharge, anosmia, headache• Noted frequent regurgitation• Self medicated w/ amoxicillin 500 mg q 8 hrs

Few hours PTC• All Sx persistent, px developed difficulty

breathing, leading to ER consult5

Personal Hx

Dietheavy soda, tea, coffee & chocolate

consumption for years now

Environmentcarpeted home; indwelling dogs; 2nd

hand cigarette smoke at workplace

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PE findingsVital signs

RR = 24/min HR = 100/min BP = 120/80

Gen survey• Wt = 90kg Ht = 170cm BMI = 31 (obese)• Ambulatory• Mild respiratory distress w/ loud deep throaty

tight cough

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HEENT• + dark shadows on both lower lids• Tympanic membranes bulging w/ erythema &

opaque effusions• Nares w/ severe congestions, obstructed

passages, turbinates swollen & violaceous, w/ thick purulent disharge

PE findings (cont’d)

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Respiratory• Symmetrical chest expansion• Mild suprasternal retractions• Fair air exchange w/ inspiratory & expiratory

wheezes• PFR = 200 L/min (ideal for age and ht = 600)

PE findings (cont’d)

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Salient features (subjective)• 30 y/o, male• history of asthma• cough of 2 months duration• frequent sneezing & nasal stuffiness esp. in a.m.• snoring loudly• productive cough & itchy throat• easy fatigability• hoarse voice• severe colds w/ increased mucupurulent discharge• anosmia• paroxysms of retching cough soon after going to bed• frequent regurgitation• Heavy soda, coffee, tea, chocolate intake• carpeted home; indwelling dogs; 2nd hand cigarette smoke at

workplace

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Salient features (objective)

Pertinent positives• obese (BMI=31)• mild respiratory distress (mild

suprasternal retractions)• loud deep throaty tight cough• PFR=200 L/min (normal=600)• + dark shadows on both lower

lids• tympanic membranes bulging w/

erythema & opaque effusions• inspiratory & expiratory wheezes• nares w/ severe congestion,

obstructed passages, turbinates swollen & violaceous, w/ thick purulent discharge

Pertinent negatives

• symmetrical chest expansion

• fair air exchange

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Clinical impressionMario has the ff conditions:

•known asthmatic (10 yr remission)•Acute severe asthma•Allergic rhinitis (co-morbidity)•Sinusitis (bacterial)•Acute otitis media (bacterial)•GERD•Obesity (predisposing him to GERD and obstructive sleep apnea)

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• Acute severe asthma– history of asthma– cough of 2 months duration– loud deep throaty tight cough– inspiratory & expiratory wheezes– easy fatigability, hoarse voice– mild respiratory distress (mild suprasternal

retractions)– PFR = 200 L/min (normal for age & height = 600)

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Clinical impression

Evidences

-allergic rhinitis (early am sneezing, nasal stuffiness, postnasal drip, env. exposure; asthmatic)- sinusitis (anosmia, nares w/ severe congestion, obstructed passages, turbinates swollen & violaceous, w/ thick purulent discharge)

Clinical impression

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Evidences

- acute otitis media (tympanic membranes bulging w/ erythema & opaque effusions) - GERD (paroxysms of retching cough soon after going to bed, frequent regurgitation)

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Clinical impression

United Airway Disease Hypothesis

“any disease process that affects the upper airway is likely to affect the lower airway, and vice versa, by both direct and indirect means. It is postulated that rhinitis and asthma represent the manifestations of one syndrome in two parts of the respiratory tract, the upper and lower airways, respectively.”

What happened to our patient?

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Rimmer, J. & Ruhno, J. (2006). Rhinitis and asthma: United airway disease. The Medical Journal of Australia. 185 (10): 565-571

What happened to our patient? (cont’d)

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Allergic rhinitis sinusitis

ASTHMA

Acute otitis media

GERD obesity


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Allergic rhinitis and asthma

• Allergic asthma and AR are often considered clinical manifestations of the same condition, the chronic allergic respiratory syndrome.

• approx 80% of asthmatics also have AR


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• Sinusitismost common cause of acute sinusitis is an upper respiratory tract infection (URTI) leading to inflammation of the sinuses

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Acute Otitis mediausually arises as a complication of a preceding upper respiratory infection (URI).The secretions and inflammation cause a relative obstruction of the eustachian tubes.

*infection due to sinusitis may be from S. pneumoniae, H. influenzae, or M. catarrhalis


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Acute otitis media Normal tympanic membrane


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GERD and Asthma• estimated that more than 75% of patients with

asthma also experience GERD. • People with asthma are twice as likely to have GERD

as those people who do not have asthma. • Of those people with asthma, those who have a

severe, chronic form that is resistant to treatment are most likely to also have GERD.


Source: Cleveland Clinic health information website at http://my.clevelandclinic.org/disorders/gastroesophageal_reflux_gerd/hic_gerd_and_asthma.aspx

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GERD and Asthma1. Acid flow causes injury to the lining of the

throat, airways and lungs, making inhalation difficult and often causing a persistent cough.

2. When acid enters the esophagus, a nerve reflex is triggered, causing the airways to narrow in order to prevent the acid from entering. This will cause a shortness of breath.


Source: Cleveland Clinic health information website at http://my.clevelandclinic.org/disorders/gastroesophageal_reflux_gerd/hic_gerd_and_asthma.aspx

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Plan of Action (Therapy)

1. Address respiratory distress2. Address long term treatment for asthma3. Treat the nasal & ear infection4. Treat allergic rhinitis5. Treat GERD6. Non-pharmacologic measures

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1. Address respiratory distress- Give reliever to immediately dilate narrowed airways (short acting β2 agonists)

- SALBUTAMOL recommended- Give supplemental O 2


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SABA

Drug Efficacy Safety Suitability Cost Total

Terbutaline +++ ++ +++ ++ 10

Salbutamol +++ ++ +++ +++ 11

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Medicines for short term asthma relief

1. SABA (salbutamol or terbutaline)

MOA: activate β2 receptors; activate adenylyl cyclase; inc. cAMP; activate proein kinase A to phosphorylate several target proteins leading to cell muscle relaxation

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β2 Agonists

Pharmacokinetics10% is deposited in the bronchial airway after inhalation Absorbed in systemic circulation Most of the inhaled dose is swallowed and absorbed from

GIT Rapidly metabolized Rapidly excreted in urine and stools A portion in the systemic circulation is excreted in the

kidneys unchanged

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β2 Agonists

PharmacodynamicsActivation of β2 leads to activation of adenylyl cyclase

Activation of protein kinase A Phosphorylates target proteins within the cell Muscle relaxation thru :

– Activate uptake of Ca++ from cell into intracellular stores– Inhibition of phosphoinositide hydrolysis– Inhibition of myosin light chain kinase prevents interaction of myosin

with actin– Opening of large conductance Ca++ activated K+ channels that

repolarize

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Drug interactions

• Effect of high doses may be exacerbated by concomitant administration of high doses of corticosteroids.

• effects are antagonized by propanolol or other beta- receptor blocking agents.

• Concomitant aminophylline or xanthine administration may enhance beta agonist effects.

• Hypokalemia associated with high doses may increase the susceptibility to digitalis-induced cardiac arrhythmias.

β2 Agonists

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AE of β2 agonists

• Muscle cramps, arythmia, tachycardia, palpitaion, tremors

• inc. in: lactate, glucose, FFA, insulin• Inc. V-P mismatch (that’s why give O 2

nebulizer)• headache, restlessness, tension, dizziness,

nervousness, insomnia

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2. Systemic oral corticosteriods (prednisone or prednisolone)

- Give for 5 to 10 days for treatment of acute severe asthma, no tapering of dose needed

MOA: anti-inflammatory effects due to inhib. of production of pro-inflammatory cytokines & chemokines; dec. lymphocytes & leukocytes in airways; dec. bronchial hyperreactivity; dec. mucus production; potentiate β2 agonist effect

Medicines for short term asthma relief (cont’d)

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Corticosteroids in Asthma

• PharmacokineticsMajority of the ICS that are swallowed and absorbed from the GIT undergo extensive first pass effect in the liver ↓ systemic toxicity. ICS that are deposited into the respiratory system are absorbed systemically and may potentially cause adverse effect

• PharmacodynamicsAnti-inflammatory effects due to inhibition of

production of proinflammatory cytokines and chemokines ↓ trafficking of lymphocytes, eosinophils and other leukocytes into airways ↓ bronchial hyperreactivity

• Potentiates β2 agonist effect by ↑ synthesis of β2 receptors

• ↓ mucus production


Some AE of sys. corticosteroids

• Truncal obesity, moon facies• Ulcers, striae, acne, hirsutism, alopecia, poor

wound healing, skin thinning• Osteoporosis, inc. risk of fractures, growth

stunting, muscular atrophy• Inc. susceptibility to infection• Hyperacidity, PUD• Inc. renal loss of calcium & dec. GIT

metabolism37

• NOTE: High doses of CS treatment of < 1 to 2 wks therapy unlikely to cause HPA axis suppression & adverse effects

• Tell px not to worry as systemic CS will only be 7 days duration

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• Drug Interactions

Efficacy may be reduced by rifampicin, ephedrine, barbiturates, phenytoin, primidone. Corticosteroids may reduce effects of diuretics, hypoglycemics, anticholinesterases in myasthenia gravis, salicylates. May impair glucose tolerance when used with antidiabetics.


2. Address long term treatment for asthma- Give Long acting β2 agonist with corticosteroid (inhalational)


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Medicines for control of asthma


LABA + ICS +++ ++ +++ ++ 10

Methylxanthines ++ ++ ++ +++ 9

Mast cell stabilizers

+ +++ ++ + 7

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Medicines for control of asthma

1. LABA- Pk, Pd, MOA, AE, drug interactions are same

as SABA- LABA lipophilicity, affinity, selectivity > SABA- LABA can be used vs. nocturnal asthma - Formoterol may be used for both control +

relief to fast onset of action

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2. Give inhalational corticosteroid (Budesonide or Fluticasone)Pk, Pd, MOA: (same as sys. corticosteriod)

AE: usually hoarseness/dysphonia, oral candidiasis, throat irritation and cough

* Use spacer between MDI & mouth; ask px to gargle after inhalation

Medicines for long term asthma relief (cont’d)

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3. Treat the nasal and ear infection- Antibiotic for the most likely causative pathogen (e.g. S. pneumoniae, H. influenzae, M. catarrhalis)


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antibiotics

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Co-amoxiclav +++ +++ +++ +++ 12

Cefuroxime +++ ++ +++ ++ 10

Clarithromycin +++ ++ +++ +++ 11

Azithromycin +++ + +++ + 8

Co-amoxiclav

Pharmacokinetics• 75 % oral absorption with or without food• 20-30% protein boundPharmacodynamics, MOA• Binds irreversibly to the catalytic site of beta-lactamases

rendering them inactive• Binds with one or more PBPs causing selective inhibition

of transpeptidase, carboxypeptidase and endopeptidase reactions required for cross linkage between peptide chains in the synthesis of mucopeptide

• Activates endogenous autolytic enzymes in the cell wall

Co-amoxiclav

• Adverse ReactionsDiarrhea, nausea, skin rashes & urticaria, vaginitis,

abdominal discomfort, flatulence & headache• Drug interactionsConcomitant administration of probenecid may

result in increased & prolonged blood levels of amoxicillin. Increased incidence of skin rashes with allopurinol. Must not be given with disulfiram

4. Treat allergic rhinitis- Give oral 2nd Gen. H1 antagonist to control AR

- When px with co-morbid AR have AR controlled: LESS risk of hospitalizations or emergency department visits for asthma *


*Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108:S147–S334.

* Thomas M. Allergic rhinitis: evidence for impact on asthma. BMC Pulm Med. 2006;6:S4.

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Choices for AR treatment


2nd gen H1 antagonist

++ + ++ ++ 7

Cromolyn Na + ++ + + 5

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Loratadine

• A second generation antihistamine (H1 blocker) drug

• Used to prevent or treat the symptoms of allergic reactions

Loratadine: MOA

Reversible competitive antagonism at the H1 receptor

Reversible competitive antagonism at the H1 receptor

Blocks action of histamineBlocks action of histamine

Loratadine: Pharmacokinetics

• Given orally, well absorbed from the GI tract, peak effect occurs in 1–2 hours, duration of action 12-24 hours

• Has rapid first-pass hepatic metabolism; metabolized by CYP450 (including CYP3A4)

• Less lipid soluble, acts as substrate of p-glycoprotein transporter in the brain

Loratadine: Pharmacokinetics

• Almost totally bound to plasma proteins

• Active metabolite: desloratadine – binds to plasma proteins only moderately

• About 40% is excreted as conjugated metabolites into the urine, and a similar amount is excreted into the feces.

Loratadine: Pharmacodynamics

• Competitive antagonism at the H1 receptor– Negligible potency at the H2 receptor, little at the

H3 receptor

• 2nd generation H1 antagonists have less sedating characteristics than the 1st generation– Less distribution in CNS

Loratadine: Adverse Effects

• Headache, fatigue, dry mouth, thirst, hoarseness– should lessen as your body adjusts to the

medication

• Rarer effects:– nervousness, rapid or pounding heartbeat,

unusual weakness, stomach pain, dizziness, diarrhea

Loratadine: Drug Interactions

• Drug interaction with CYP3A4 enzyme inhibitors can cause ventricular arrhythmia (Torsades de pointes)– Ketoconazole, macrolide antibiotics– Significant increase in the blood concentration of

loratadine

5. Treat GERD- give proton pump inhibitor to decrease HCl secretion


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GERD


PPI +++ ++ +++ + 9

Pro-kinetics + +++ ++ ++ 8

H2 blockers ++ + ++ ++ 7

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Omeprazole

Proton Pump Inhibitor

MOA:suppresses gastric acid secretion by specific

inhibition of the enzyme system hydrogen/potassium adenosine triphosphatase (H+/K+ ATPase) present on the secretory surface of the gastric parietal cell.

Omeprazole

Pharmacokinetics:Administered as inactive prodrug Lipophilic weak bases, that diffuse readily across

lipid membranes becomes protonated in gastric parietal cell

canaliculusReactivates to thiophilic sulfonamideIrreversibly inactivates H+/K+ ATPase

Omeprazole

Pharmacodynamics:

Inhibits both fasting and meal-stimulated secretion

Blocks the final common pathway of acid secretion, the Proton Pump

Omeprazole

Indication:• Most effective agent for treatment of erosive

and non-erosive reflux disease• Peptic ulcer disease• Non-ulcer dyspepsia• Stress-related mucosal bleeding

Omeprazole

Dosage :• 20-40mg should be administered 1 hr before

meal ( usually breakfast or dinner)

Omeprazole

Adverse effect:• PPI are extremely safe, however diarrhea,

headache, and abdominal pain are reported (1-5%)

Omeprazole

Drug interactions:• Metabolized by hepatic P450 cytochromes• Inhibits the metabolism of Coumadin,

Diazepam and Phenytoin

6. Non-pharmacological treatment (asthma & AR)- remove all carpeting at home- place dogs outside the home or get rid of them- keep home clean by using air cleaners; vacuum well (minimize dust, molds, pollen)- be mindful to avoid 2nd hand cigarette exposure


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6. Non-pharmacological treatment (GERD)- cease soda, chocolate, tea, coffee intake- small frequent feedings (no heavy meals)- ask px not to lie down shortly after a meal- lie semi-upright or left lateral recumbent- reduce weight (diet and exercise) as obesity worsens GI reflux & may predispose to obstructive sleep apnea


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6. Non-pharmacological treatment (obesity)– Control diet– After asthma has been controlled, start

exercising (i.e. swimming – may also be good for his asthma)

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*Obese px w/ loud snoring

• May use continuous positive airway pressure (CPAP) machine to control loud snoring during sleep (esp. if he is eventually diagnosed with obstructive sleep apnea since he is obese)

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Prescriptions

• Prednisone (salbutamol at ER only)• Formoterol + Budesonide (Symbicort)• Co-amoxiclav• Loratadine• Omeprazole

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Juan Dela Cruz, M.D.Internal Medicine

MAB Rm. 2012Santo Tomas University Hospital

España, Manila

Name: ___Mario_Silvestre_______ ____ Date: _Feb. 26, 2009__Address: __ Quezon City_ ___________ Age: _30_Sex: _M__

_ Juan dela Cruz_____ M.D.

License no. 2003001234

PTR no. 12051986

Prednisone 30 mg tab

Dispense 7 tablets

Sig. Take 1 tablet by mouth after breakfast daily for 7 days.

For asthma



España, Manila

Name: ___Mario_Silvestre____________ Date: _Feb. 26, 2009__Address: __ Quezon City_ ___________ Age: 30__Sex: _M ___

_ Juan dela Cruz_____ M.D.

License no. 2003001234

PTR no. 12051986

Budesonide + formoterol fumarate 80/4.5 mcg turbuhaler

Dispense 1 turbuhaler

Sig. Take 2 puffs by mouth twice daily, in the morning and evening everyday

For asthma



España, Manila

Name: ___Mario_Silvestre_______ Date: __Feb. 26, 2010_Address: ____Quezon City_ Age: _30__Sex: _M__

Juan dela Cruz___M.D.

License no. 2003001234PTR no. 12051986

Co- Amoxiclav 1 g tab

Dispense 20 tablets

Sig. Take 1 tablet by mouth before meals twice a day for 10 days

For acute sinusitis and otitis media



España, Manila

Name: ___Mario_Silvestre____________ Date: __Feb. 26, 2010_Address: __ Quezon City_ ___________ Age: _30__Sex: _M__

Juan dela Cruz___M.D.

License no. 2003001234PTR no. 12051986

Loratadine 10 mg tab

Dispense 30 tablets

Sig. Take 1 tablet by mouth after a meal once a day for 4 weeks.

For allergic rhinitis



España, Manila

Name: ___Mario_Silvestre_________ Date: _Feb. 26, 2010__Address: ___Quezon City__________ Age: _30_Sex: _M__

_ Juan dela Cruz_ __M.D.

License no. 2003001234PTR no. 12051986

Omeprazole 20 mg capsule

Dispense 30 tablets

Sig. Take 1 tablet by mouth before meals once daily for 4 weeks

For Gastroesophageal reflux disease

Documents

Conference on Therapy Case 1: Respiratory Problem 1