Drugs acting on pulmonary system

 1st generation – SABA (10-15 min start and 4-6

hrs duration of action
 2nd generation – LABA (12 hrs duration)
 (salmeterol – starts gradually, formoterol – 1st
phase of effect 5-15 min)
 3rd generation – LABA (12-24 hrs, start effect
about 5-15 min)
 Selective prolinged beta2agonist (24 hrs)
 Adenylatcyclaze catalyzing ATP to cyclic AMP
transformation
 Increase of CAMP leads to bronchodilation
 Action on beta2 receptors 24 times more than
beta1 and 20 times more than beta3
 FEV elevation for 24 hrs
 Acts 5 min post inhalation (comparable to
salbutamol)
 Maximal action 2-4 hrs
 Decreases hyperinflation (increase of volumes
at the end of spontaneous expiration) in
midsevere and severe COPD
 Decrease of risk of COPD exacerbations and
demand of short time beta2 agonists,
ipmrovement of life quality
 Cmax reached in 15 min post inhalation
 Bioavailability 43%
 Systemic exposition due to absorbtion in
lungs and intestine increases as dose increase
(from 150 to 600 mcg)
 Excreted with urine – 2% of dose; in oral intake –
90% through intestine
 T1/2 45,5 - 126 ч. T1/2, basing on the cumulation
after repeated use – 40-56 days

 Prolonged treatment in COPD
 Contraindication
 Hypersensitivity, pregnancy, brestfeeding, age
< 18
 Limitations
 Cardiovascular diseases, convulsive disorders,
thyrothoxicosis, diabetes, QT prolongation
(congenital or drug induced), inadequate
response to beta mimetics in case history
 Most – mild degree
 Nasopharyngitis, upper respiratory infections,
,muscular spasm, sinusitis
 Hypersensitivity
 Cough, throat pain, rhinorrhea, rare – paradoxal
bronchospasm
 Rash, itching
 Dizziness, paresthezy
 IHD, palpitation, Afib, tachycardia
 Dry mouth
 Hyperglycemia/onset of diabetes
 Peripheral edema, non cardiogenic chest pain
 With drugs causing QT prolongations – arrhytmias
 With sympathomimetics –higher risk of systemic
actions
 With drugs causing K decrease – hypokaliemia
(incl.with GCS, methylxantines)
 With beta blockers – decrease of action (accurately
selectives can be used)
 With inhibitors of CYP3A4 and P-glycoprotein –
with verapamil and erythromycin Cmax increases
1.2 times
 After single use of the dose 10 times higher than
therapeutic in COPD patients – moderate increase
of heart rate, BP, QTc prolongation
 150, 300 mcg capsels
 Onbrez breezhaler
 150 once daily usual dose, 300 mcg daily
maximal dose
 High selectivity beta2 mimetic
 QT prolongation with no influence on the heart
rate or rhythm disorders
 5 mcg once daily leads to significant
improvement of FEV1 during 5 min after first
dose
 Cmax 10–20 min after inhalation
 Bioavailability 30%
 CYP2C9 and CYP2C8 of cytochrome Р450 are
participating in metabolism
 T1/2 45hrs
 No significant changes in aged and
concomitant diseases
 Prolonged treatment of COPD
 Possibility of use in asthma was not studied
 Contraindications: age <18 (not studied),
individual intolerance
 Limitations: unstable course of IHD, QT
prolongation and rhythm disorders,
obstructive CMP, AH, hyperthyrosis, crapms,
in patients with recent MI or heart failure
decompensation (last year), paroxysmal
tachycardia, heart rate > 100/ min
 Nasopharyngitis, cough
 Dizziness
 Hypertension
 Rash
 Back pain and arthralgia
 Pneumonia; lung cancer was observed in 0,7%,
0,3% и 0,2% of patients receiving 10 mcg, 5 mcg
and placebo
 Hyperthermia
 Diarrhea, constipation
 Same as Indacaterol
 Interaction with ketaconazol – increase Cmax
1.7 times
 5 mcg once daily (inhalation)
 Prolonged bronchodilation (12 hrs)
 Prevents histamine, LT and PGD2 deliberation
from mast cells
 Antiinflammatory properties
 Asthma, COPD
 Contraindications
 Intolerance, age <4 yrs
 Limitations
 Thyrotoxicosis, arrhythmia, IHD, uncontrolled
hypertension, hypoxial pheochromocytoma,
pregnancy, breastfeeding, aged
 Increase SBP/decrease DPB, rhythm disorders
(SVT, PAC, Afib)
 Diarrhea, abdominal pain, vomiting, viral
gastroenteritis, mucosal irritation of throat
 Dizziness, headache, tremor, anxiety
 Paradoxal bronchospasm (drug to be cessated),
cough
 Arthralgia, hypokaliemia, allergy rhinitis, laryngitis
 2×25 mcg twice daily
 Maximal dose 4×25 mcg 2 times daily
 High selective
 QT prolongation
 Cmax 5 min
 T1/2 10 hrs
 Asthma, COPD
 Contraindication – intolerance
 Limitations – coronary insufficiency AH,
cramps, thyrotioxicosis, preganncy, breast
feeding, age <5yrs
 Tremor, dizziness, insomnia
 Pulmonary infections, dyspnoe, tonsillitis,
dysphonia
 Viral infections, chest pain, rash
 Capsels 12 mcg for inhalation
 12–24 mcg 2 times daily
 4,5 mcg in one inhalation
 1-2 inhalations 1-2 times daily
 Start of action 5 min
 Maximal 30–90 min
 Duration 3–6 hrs
 T1/2 – for 30% of drug 11 min, for 70% - 120
min
 100 mcg
 Tremor, nervousness, headache, dizziness,
accomodation disorder, psychical changes in rare
cases
 Tachycardia, palpitations, rare SBP increase DBP
decrease, arrhtytmia
 Rare cough, pharyngitis, paradoxal bronchospasm
 Nausea, vomiting
 Rare rash angioedema urticaria
 Hypokaliemia, weakness, cramps, urine retention
 T1/2 — 3,8 hrs, circulation at therapeutic level in
blood 2-9 hrs
 Excreted with urine and bile
 Maximal effect at 4–5 min, increases to 20 min
and reach maximal at 40-60 min, duration 4-5
hrs
 Maximal effect in 2 doses inhalation
 100 mcg
 1st generation – SAMA ( 15 min start and 6-8
hrs duration of action
 2nd generation – LAMA (24 hrs duration)
 (Tiotropium bromide)
 3rd generation – LAMA (12-24 hrs)
 Selective
 M3 receptors longer than M2 (M3 in smooth
muscles of bronchi)
 FEV1 improvement 30 min after 1st dose,
maximal 1-3 hrs, lasts more than 12 hrs
 No influence on QT
 Cmax 5-15 min (healthy and COPD)
 T1/2 2-3 hrs
 COPD
 Contraindications – individual intolerance, age
<18, lactose intolerance
 Headache
 Nasopharyngitis
 Angioedema , rash
 Dizzinesss
 Palpitations, tachycardia
 Dry mucosa
 Urine retention, worsening of glaucoma
 No symptoms in healthy after 6000 mcg
 Asthma – not to be used (no experience)
 Accurately with recent MI, rhythm disorders,
HF III-IV class
 Dry mouth may lead to caries
 322 mcg
 One inhalation 2 times daily
 Seebri Breezhaler - 50 mcg (once daily)
 High selective to M3
 Effect is due to local, not systemic action, and
lasts 24 hrs
 Bioavailability (systemic) 19.5%
 Minimal biotransformation
 T1/2 5–6 days
 COPD
 Contraindications – 1st trimester of pregnancy,
<18
 Mild dryness in mouth, constipation
 Cough, local irritation, bronchospas,
 Tachycardia, urine retention in males with
predisposing factors
 Angioedema
 Vision disorder, acute glaucoma
 One capsule inhaled once daily
 M-blockers
 Minimally absorbed
 Bronchodilative effect 5-10 min, lasts 5-6hrs
 Dilates mostly large and medium bronchi
 Decreases mucus secretion
 For tachycardia 500 doses needed
 10% reaches bronchiols and alveols
 Headache, dry mouth
 Tachycardia, accomodation disorders, decreased
perspiration, GI motorics disorder, urine retention
 Cough, rare paradoxal bronchospasm
 Rask, urticaria, angioedema, rare anaphylaxia
 Glaucoma exacerbation
 2 doses 2 times daily
 0.021 mg in one dose
 Decreases cells migration and activation
 Decreases mucus secretion
 Dilates smooth muscles and normalizes its
sensitivity to adrenomimetics
 Increases number of active beta receptors
 Effect starts in 4-5 days and reachs maximum
for several weeks
 Hoarse voice
 Laryngitis, sneezing, cough, paradoxal
bronchospasm, eosinophilic pneumonia,
candidosis (>400 mcg daily)
 In dose >1.5 mg daily – systemic effects
 50 mcg, 100 mcg, 250 mcg
 25% of dose comes to alveoli
 90% of dose in GI is destroyed during first
passage (bioavailability 10% of all drug passed
to intestine)
 Dysphonia, throat pain, rare – candidosis,
nausea, pharyngitis
 250 mcg, 500 mcg (suspension for nebulizer)

 Pulmicort®Turbuhaler® 100 and 200 mcg

 Alvesco
 Low affinity to receptors
 Pulmonary esterases transform it to
desciclesonide which has proinflammatory
activity
 Less pharyngeal and systemic side effects
 Active metabolite is metabolized with use of
CYP3A4 in liver
 Asthma
 Contraindication <6yrs old
 Accurately in active TB, in pulmpnary
infections
 Diarrhea, dyspepsia
 Angioedema, paradoxal bronchospasm
 Oral candidosis – equal to placebo
 Exema, rash
 Mild to moderate asthma – 160-640 mcg daily,
640 mcg should be separated to 2 intakes
 Severe – maximal 1280 mcg
 In one dose 40, 80, 160 mcg
 Aclidinium bromide + Formoterol (COPD only)
 Budesonide + Salbutamol Biasten
 Budesonide + Formoterol Symbicort Turbuhaler®Foradil
Combi
 Vilanterol + Umeclidinium bromide ANORO ELLIPTA®
(22 + 55 mcg /dose – once daily)

 Vilanterol + Fluticasone furoate Relvar Ellipta (40+200

mcg) – asthma, COPD
 Glycopyrronium bromide + Indacaterol Ultibro Breezhaler
 Mometasone + Formoterol (Zenheyl (200 mcg+5 mcg)
 Olodaterol + Tiotropium bromide Spiolto® Respimat®
 Salmeterol + Fluticasone Seretide®
 Ipratropium bromide + Fenoterol Berodual®
 Blocks leucotrien receptors and prevents
smooth muscles contraction (LTC4, LTD4 , LTE4)
 Cmax 3 hrs
 Т1/2 10 hrs
 Excreted by fects 89%, urine and breast milk
10%
 Mild and midsevere asthma
 Contraindications – liver failure, cirrhosis, age
< 5 yrs
 Insomnia, headache, weakness
 Rare hemabomas after traumas, hypermenorrhea,
decreased platelets, rare agranulocytosis
 Nausea, vomiting, abdominal pain , rare hepatitis,
liver failure and fulminant hepatitis
 ASA – 1.5increases blood levels
 Erythromycin, theophyllin – decrease 40% and
30%
 If used with warfarin, prothrombin time
increases 35%
 In smokers clearance in s20% increased
 20 mg 2 times daily
 No age correction
 Specifically inhibits CysLT1- receptors of LTC4,
LTD4, LTE4


 Cmax 2–3 hrs, bioavailability 64–73%.

 Decreases bronchial spasm and edema, Eo and
macrophages migration, improves mucociliar
transport
 Effect develops in one day
 Possibility of extremities abnormalitis in fetus (if taken by
pregnant)
 Hallucinations, agressions, insomnia, paresthesia, hedache,
cramps
 Nausea, vomiting, dyspepsia, diarrhea, abdominal pain
 Myalgia, arthralgia
 Anaphylaxy, angioedema, rash, urticaria, rare liver
eosinophilic infiltrates
 Trend to increased bleeding
 Palpitations
 ASAT ALAT increase, hepatitis incl fulminant
 Flu like syndrome
 Edemas
 10 mg daily (once, in the evenling)
 Adenosine receptors blockers
 Phosphodiestheraze inhibitor
 stabilizes cAMP
 Decreases intracellular calcium concentration
 Dilates smooth muscles
 Supresses degranulation of mast cells
 Increases tonus of respiratory muscles (intercostal and
diaphragm)
 Dilates pulmonary vessels, improves oxygenations
 Suppresses platelet aggregation factor and PGE2alpha,
improves stability of RBC to deformation
 Coronary arteries dilation
 Bioavaolability > 90%
 Cmax 2 hrs (non-retard) and 6 hrs (retard)
 Excreted by kidneys and partially breast milk
 Asthma (including status)
 COPD
 Sleep apnoe
 Hypersensitivity including to other xantines
(coffein, pentoxyphyllin, theobromin)
 Hemorrhagic stroke, retinal bleeding, MI,
recent bleeding, peptic ulcer,
 Marked coronary arteries atherosclerosis
 Epilepsy
 Hypotension, hypertension, severe
tachyarrhytmia
 Marked coronary insufficiency (unstable angina)
 Advanced atherosclerosis
 Obstructive CMP
 Heart failure
 Trend to convulsions
 Porphyria
 Hypothyrosis
 Peptic ulcer
 GERD
 Prolonged hyerthermia
 Prostatic gland hyperplasia
 Hepatic or renal failure
 Age >60 ore children
 Anxiety, conscious disorders, cramps, vision
disorders, scotoma
 angina, arhhythmias, tachycardia, hypotension or
hypertension
 flu like syndrome, laryngitis and pharyngitis,
nasal obstruction
 xerostomia, anorexia, vomiting, nausea,
heartburn, exacerbation of cholecystitis, cholestatic
hepatitis, increase of ALAT ASAT ALcPH,
intestinal atony
 decrease of WBC, platelets, pancytopeny
 allergy
 Cimetidin, allopurinol, cyclosporin,
macrolides, oral contraceptives – decrease
clearance
 Phenobarbital, phentoin, xantines, smoking
increase biotransformation (induce microsomal
enzymes)
 Beta-blockers decrease broncholytic activity
 Adsorbents and antacides decrease
bioavailability
 Theophyllin increases effect of diuretics and
decrease – NSAIDS, probenecid, beta blockers
 200 and 350 mg
 After meals, 350 mg once daily (evening) – start
dose, then 350 mg 2 times daily
 Body mass <40 kg – 200 mg initially, then 200
mg 2 times daily
 Theophyllin blood levels should be 10–
20 mg/ml.
 Retard forte 375 mg
 Retard 250 mg
 Prolinged action 125 mg
 Prolonged action 500 mg
 2-3 capsels a day
 Decrease of platelets formation
 Dose dependent heart rate increase and QTc
increase
 Cmax 1 hr, H1/2 1,3 hrs
 Indications: high risk essential thrombocytemia
(age more than 60, platelets > 1000 х 109/l;
thrombotic and hemorrhagic complications in
history)
 Phosphodiestherase 4 inhibitor
 PDE4 is the enzyme which metabolises cAMP
located in inflammatory cells
 Mostly PDE4A, B,D
 Main metabolite – N-oxide – has same properties
 Increased cAMP due to PDE block leads to
decrease of excretion of LTB4, RPS, TNFalpha, IFN
gamma, granzymB
 In COPD decreases number of neutrophils in
sputum
 In healthy decreases neutrophils and Eos influx in
airways after endotoxin use
 Bioavailability 80%
 Cmax 1 hr; for N-oxide - 8 hrs ( 4 – 13 hrs).
 No influence of food intake
 P450 metabolism (CYP1A2 and 3A4)
 T1/2 17 for roflumilast, 30 hrs for N-oxide
 In aged – activity is increased
 No serious changes in kidneys failure
 In renal failure the inhibiting activity increases
20% for A class Clhild Peugh, 90% - in B class
 B,C class liver failure
 Systemic autoimmunities (not studied), tb,
cancer, HIV
 Use of biologics (no experience)
 Depression with suicide trend
 Galactose metabolism impairment
 Cytochrome
 Fluvoxamin treatment (CYP1A2 inhibitor)
 Enoxacin or cimetidin treatment ( CYP3A4/1A2)
 Class A liver failure
 Angioedema, gynecomastia, decreased body
masse, decreased appetite
 Insomnia, anxiety, several reports inluded
suicidal trend or suicide
 Headache, tremor, vertigo, dizziness
 Tachycardia
 GGTP increase, ASAT incrase, diarrhea, nausea,
GERD, gastritis
 Rash, urticaria
 Myalgia, weakness, rare – CK increase
 0,5 mg once daily
 No dose corrections for aged and mild liver
failure
 Inhibits cGMPdependent PDE-5
 This enzyme is present not only in male
reproductive system but in pulmonary vessels
also
 Small BP decrease (about 9 mm), less marked
in PH patients (2 mm)
 No influence on ECG
 Improves life expectancy in patients with
pulmonary hypertension
 Rapidely absorbed
 Cmax 30-120 min
 Р450: CYP3A4 and CYP2C9
 T1/2 – 4-5 hrs
 80% - intestinal excretion
 Venoocclusive pulmonary disease
 Use of nitric oxide donators
 Use of CYP3A4 inhibitors
 Anterior ishemic optic neuropathy with one eye
vision loss (not vasculitic nature)
 Pigment retinintis
 Liver failure >9 points
 MI or stroke in case history
 SBP<90, DBP<50
 Lactose intoleranse
 age <18
 III and IV classes of PH
 Lecukemia, sickle cell anemia
 Severe cardiac and pulmonary diseases
 20 mg 3 times daily
 Antagonist of ЕТА and ЕТВ receptors
 Decreases pulmonary and systemic vascular
resistance
 Prolonged treatment (12 and 16 weeks)
treatment III–IV functional class lead to
significant improvement
 62,5 mg и 125 mg
 62,5 mg 2 time daily – 4 wks, then 125 mg 2
times