State of Medical and Pharmaceutical

University
“N. Testemiţanu”
Department of Pharmacology and clinical
pharmacology
 1. Respiratory stimulants
(Analeptics)
2. Antitussives
3. Expectorants
4. Medication of bronchial asthma
5. Medication of pulmonary edema

2
Drugs that directly or reflexly
stimulate the respiratory and
cardiovascular center

3
A. With central action
◦ Caffeine sodium
benzoate
◦ Pentetrazol
(PENTYLENETETRAZOLE )
◦ Bemegride
◦ Aethimizolum
◦ Camphor
◦ Sulfocamphocainum

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With peripheral
action

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 Respiratory stimulants
(analeptics)
 Excite CNS on subcortical and bulbar levels (do not have selective action
on CNS's centers);
 Decrease latent period of reflexes;
 Decrease threshold excitation of nervous centers;
 Intensify the exchange of substances, energy consumption and oxygen in
the brain;
 Narrow therapeutic index
 Short duration of action - 2-3 hours (2-5 minutes – N-cholinomimetics (IV);

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 Increase the frequency and minute-volume
breath;
 Intensely excite the respiratory center when it is
inhibited and increase physiological reactivity to
stimuli (CO2, H +, reflexes from CR);
 Effect - short and unstable;
 Repeated administration - exhaustion of the
respiratory center, convulsions and mitigate of
the effect.
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 Stimulate N-cholinoreceptors of the
sinocarotid area and reflexly increase the
activity of respiratory center;

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 Newborn asphyxia;
 Respiratory arrest caused by trauma or surgery.
 After general anesthesia (speed up awakening and
stimulates breathing);
 Slight poisonings with barbiturates and opioids.
 Hypoventilation after drowning;
 Collapse of central origin;
 Syncope;
 Obstructive chronic bronchitis;
 The elderly:
◦ Heart failure in the elderly after infectious
diseases, pneumonia;
◦ Hypotension.
 Neuro circulatory dystonia
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 Side effects
Cough;
Nausea,vomiting, restlessness;
Hypertension, tachycardia, arrhythmias;
Headache, feeling hot, tremor;
Muscular hypertonus;
Convulsions.

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 Contraindications
 Brain traumas, coma, hypoxia;
 In poisonings:
 with convulsive toxins (strychnine);
 drugs that excite the CNS and / or may cause
convulsions (antidepressants, antihistamines,
opioids, penicillins, fluoroquinolones, etc..)
 with barbiturates and opioids (medium and severe
gravity)
 Meningitis, tetanus;
 Epilepsy history.
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Are plant alkaloids, synthetic
derivatives and other compounds
able to calm or remove the cough.

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 A. With central action
13

1.Opioid 2.Non-opioid
 Dextromethorphan  Glaucine
 Ethylmorphine  Noscapine
 Codeine phosphate  Oxeladin
 Levo-propoxyphene  Butamirate
 Morphine
B.With peripheral action
- Prenoxdiazine (libexin)
- Pronilid
- Pentoxyverine

C.With mixed action

(central and peripheral)
- Tipepidine citrate
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Opioids
◦ Suppress the cough reflex by direct
stimulation of mu-OR on the cough
centre in the medulla

Nonopioids
◦ Suppress the cough reflex by numbing
the stretch receptors in the respiratory
tract and preventing the cough reflex
from being stimulated 15
Opioid drugs:
◦ are used only when cough is
dangerous.

Indications:
◦ cough after surgery,
◦ cough that can produce emphysema,
◦ TBS,
◦ Cough that facilitate penetration of
various infection,
◦ cancer with cough ,
◦ pneumatorax, myocardial infarction,
aortal aneurysm
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 Constipation,
 Nausea,
 Dizziness, dysphoria, drowsiness,
 Bronchospasm,
 In children, convulsions (doses>

0.3 mg / kg),
 Tolerance, physical and

psychological dependence.
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 Non opioid drugs with central and
peripheral action are indicated in:
◦ Acute and chronic bronchitis,
◦ Bronchopneumonia,
◦ Bronchial asthma,
◦ emphysema,
◦ before and after bronchoscopy,
bronchography.

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Prenoxdyazine.
◦ Has antitussive action, but it doesn’t
inhibit cough center and doesn’t
produce any dependence.
◦ It has local anesthetics and
spasmolitic action.
Side effects:
◦ allergy
◦ dyspeptic symptoms,
◦ angioneurotic edema.
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 EXPECTORANTS
A medication that helps bring up mucus and other
material from the lungs, bronchi, and trachea.
1. Secretostimulants
a) With reflex action: b) Direct acting:
– Infusion or extract of – iodine: potassium and sodium
thermopsis, iodide;
marshmallow, ipecac, – ammonium salts (chloride,
acetate and ammonium
– Licorice hydrochloride,
carbonate);
– Mucaltine – Extractum – sodium salts (sodium benzoate,
folium Althaeae siccum ; sodium carbonates);
– essential oils (anise, eucalyptus)
– guaifenezin,
– Miscellaneous (pertusine,
terpinhidrat etc).
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 2. Secretolitics (mucolytic agents)
a) Proteolytic enzymes c) Stimulants of surfactant
– Trypsine secretion
– Chymotrypsine • Bromhexine
– Chymopsine • Ambroxol
– Dezoxyribonuclease d) Surfactants
b) Thyolic derivatives • Alveofact
– Acetylcysteine (ACC)
– Carbocysteine
– Mesna

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SECRETOSTIMULANTS
WITH REFLEX ACTION
 Are administered orally;
 In small doses irritate gastric mucosa and reflexly
increase bronchial secretion;
 T1/2- of short duration;

 High doses - Excite vomiting center → nausea,

vomiting;
 Are administered in low doses and often (every 2-4
hours).
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SECRETOSTIMULANTS
WITH DIRECT ACTION
 Are administered orally;
 Are absorbed from the digestive tract and are
excreted in airway mucosa;
 Direct action on secretory cells – secretion
increases;
 Stimulate motility of cilia of the mucosa and
bronchial peristalsis favoring the elimination of
secretions.
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SECRETOLITICS
PROTEOLYTIC ENZYMES
 Are applied locally in aerosol or
instillation;
 Can fluidize bronchial secretions,
purulent, viscous;
 They work by splitting pus, necrotic
material, deoxyribonucleic acid fibers,
which thickens the mucus and makes it
difficult expectoration.
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SECRETOLITICS
THYOLIC DERIVATIVES
 Break off S-S groups and bind with them. In this way
decrease viscosity of the bronchi mucus.
 Acc is used also in intoxication with paracetamol as a
liver protector
 Side effects: bronchospasm, nausea, vomiting,
diarrhea, anaphylactic reaction

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 Bromhexine:
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 Break off mucopolysaharide and

mucoproteic groups..
 Alo it stimulates secretion of surfactant.

 Side effects:

 rarely nausea,
 vomiting,
 allergy.
 Indications for
27 secretolitics:
 Acute and chronic bronchitis,
 bronchopneumonia, pneumonia,

 mucoviscedoses,

 tracheitis, pleurisies,

 Before and after surgery

 Asthma is characterised by:
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 inflammation of the
airways
 bronchial hyper-

reactivity
 reversible airways

obstruction
 I. Adrenomimetics
A. Non selective:
▪ Alfa-beta-adrenomimetics : epinephrine ,
ephedrine
▪ Beta-adrenomimetics: β1; β2-adrenomimetics:
isoprenaline, orciprenaline;
B. Selective
▪ β2-adrenomimetics: salbutamol, hexoprenaline,
terbutaline, fenoterol, clenbuterol, salmeterol,
formoterol

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 II. Methylxanthines
 aminophylline, theophylline
III. M-cholinoblockers:
 atropine, platyphylline , ipratropium bromide,
oxitropium bromide, troventol
IV. Glucocorticoids:
 systemic: prednisone, prednisolone,
methylprednisolone, triamcinolone,
dexamethasone;
 inhaled: beclomethasone, budesonide, flunisolide,
fluticasone
V. Inhibitors of mast cells degranulation:
 Sodium cromoglycate, nedocromil, ketotifen ;
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 VI. H1- Antihistamines :
 Diphenhydramine, clemastine, terfenadine,
astemizole, loratadine, cetirizine ,.
VII. Antileucotriens:
1. Inhibitors 5-LOX:
▪ zileuton
2. Antagonists of LT receptors:
▪ zafirlukast, montelukast
VIII. Thromboxane synthetase inhibitors :
 ozagrel
IX. Combined drugs:
 berodual (ipratropium bromidum + fenoterol),
 intal plus,
 ditec (fenoterol + sodium cromoglicat),
 redol, solutan 31
 Adrenergic agonists
 General characteristics
 Adrenergic agonists stimulate β2-
adrenoceptors, resulting in:
relaxation of bronchial smooth muscle
inhibit the release of mediators
stimulate mucociliary clearance.
 Adrenergic agonists are useful for the

treatment of the acute bronchoconstriction

(exacerbations) of asthma.
 These agents are used both for quick relief

and for long-term control, depending on

biologic half-life.
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 Adrenergic -Agonists
Three types
 Nonselective adrenergics
 Stimulate alpha-, beta1- (cardiac), and beta2-
(respiratory) receptors
 Example: epinephrine
 Nonselective beta-adrenergics
 Stimulate both beta1- and beta2-receptors
 Example: isoproterenol
 Selective beta2 drugs
 Stimulate only beta2-receptors
 Example: salbutamol

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Epinephrine

 administered as an inhalant or
subcutaneously
 onset of action occurs within 5—10
minutes
 duration is 60—90 minutes.

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Ephedrine
 Ephedrine is an indirect,
nonselective β- and α1-
adrenoceptor agonist
 rarely used in the treatment of
asthma.
 Some preparations combine
ephedrine with a methylxanthine.

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Isoprenaline

 nonselective β-receptor agonist

 a potent bronchodilator.
 It is most effective in asthmatic
patients when administered as an
inhalant.
 During an acute attack, dosing every
1—2 hours is typically required
 oral preparations are administered 4
times daily (qid).
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Short-acting β2-adrenoceptor agonists

Salbutamol, fenoterol
administered by:
 Inhalation, onset of action is 1—5 minutes.
 available for oral administration.

Long-term use of these agents for the

treatment of chronic asthma has been
associated with diminished control,
perhaps due to β-receptor down-
regulation.

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Long-acting β2-adrenoceptor agonists
 Salmeterol, formoterol
administered as inhalants
have a slower onset of action
a longer duration of
These agents are very effective for
prophylaxis of asthma but should not
be used to treat an acute attack.

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Beta-Agonists: Indications
 Relief of bronchospasm related to
asthma, bronchitis, and other
pulmonary diseases
 Useful in treatment of acute attacks
as well as prevention

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Beta-Agonists: Side Effects
Beta2 (salbutamol)
 Hypotension OR hypertension
 Vascular headaches
 Tremor
 Contraindicated: allergies, tachyarythmias,
severe cardiac disease

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Adverse effects of adrenergic agonists
 based on receptor occupancy.
 These adverse effects are minimized by inhalant

delivery of the adrenergic agonists directly to the

airways.
 Epinephrine, ephedrine, and isoproterenol have
significant β1-receptor activity and can cause cardiac
effects, including tachycardia and arrhythmias, and the
exacerbation of angina.
 The most common adverse effect of β -adrenoreceptor
2
agonists is skeletal muscle tremor, anxiety.
 The adverse effects of α-adrenoceptor agonists include
vasoconstriction and hypertension.
 Tachyphylaxis, a blunting in the response to adrenergic
agonists on repeated use, can be countered by switching
to a different agonist or by adding a methylxanthine or
corticosteroid to the regimen.

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Methylxanthines
 For
asthma, the most frequently administered
methylxanthine is theophylline (1,3-dimethylxanthine).

 Mechanism of action
 Methylxanthines cause bronchodilation by action on the
smooth muscles in the airways.
 The exact mechanism remains controversial;
 adenosine-receptor antagonist (adenosine causes
bronchoconstriction and promotes the release of histamine
from mast cells).
 may decrease the entry and mobilization of cellular Ca2+
stores.
 Theophylline inhibits phosphodiesterase (leading to
increased cAMP), but this effect requires very high doses,
and its contribution to bronchodilation remains to be
established.

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Theophylline
 Theophylline is available in a microcrystalline
form for inhalation and as a sustained-release
preparation; it can be administered
intravenously.
 Theophylline has a very narrow therapeutic
index; blood levels should be monitored upon
the initiation of therapy.
 Theophylline has a variable half-life; t 1/2 is
approximately 8—9 hours in adults, but it is
shorter in children.
 Clearance of theophylline is affected by diet,
drugs, and hepatic disease.

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 Therapeutic uses
Methylxanthines are used to treat acute or
chronic asthma that is unresponsive to β-
adrenoceptor agonists; they can be
administered prophylactically.
These agents are used to treat chronic
obstructive lung disease and emphysema.
Methylxanthines are used to treat apnea in
preterm infants (based on stimulation of the
central respiratory center); usually, caffeine
is the agent of choice for this therapy.

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 Adverse effects
 Arrhythmias (Sinus tachycardia,
extrasystole, palpitations, ventricular
dysrhythmias),
 nervousness, vomiting, and
gastrointestinal bleeding.
 Gastroesophageal reflux during sleep
 Methylxanthines may cause behavioral
problems in children.

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Anticholinergics:
Mechanism of Action
 Acetylcholine (ACh) causes
bronchial constriction and
narrowing of the airways
 Anticholinergics bind to the ACh
receptors, preventing ACh from
binding
 Result: bronchoconstriction is
prevented, airways dilate

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Anticholinergics
 Ipratropium bromide (Atrovent)
 Slow and prolonged action
 Used to prevent
bronchoconstriction
 Combined
(salbutamol/ipratroprium)

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Anticholinergics
Side effects:
Dry mouth or throat
Gastrointestinal distress
Headache
Coughing
Anxiety

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Corticosteroids
 Anti-inflammatory
 Used for chronic asthma
 Do not relieve symptoms of acute
asthmatic attacks
 Oral or inhaled forms
 Inhaled forms reduce systemic
effects
 May take several weeks before full
effects are seen
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Corticosteroids:
Mechanism of Action
• Glucocorticoids produce a significant
increase in airway diameter, probably
by:
• attenuating prostaglandin and
leukotriene synthesis via inhibition
of the phospholipase A2 reaction
• inhibiting the immune response.

 They increase responsiveness to

sympathomimetics and decrease mucus
production.
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• Available as oral, topical, and inhaled
agents.
A. Use of inhaled glucocorticoids is
recommended for the initial
treatment of asthma, with additional
agents added as needed. They are
used prophylactically rather than to
reverse an acute attack.
B. Inhaled glucocorticoids are partially
absorbed.

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Inhaled Corticosteroids:
Side Effects
 Pharyngeal irritation
 Coughing
 Dry mouth
 Oral fungal infections
 Systemic effects are rare
because of the low doses used
for inhalation therapy
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A. Because of their systemic
adverse effects, oral
glucocorticoids are usually
reserved for patients with
severe persistent asthma.

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Mast Cell Stabilizers
 Cromoglycate (Intal®)
 Nedocromil (Tilade®)
 Ketotifen fumarate (Zaditen®)

54
Mast Cell Stabilizers:
Indications
 Adjuncts to the overall management of
asthma
 Used solely for prophylaxis, NOT for
acute asthma attacks
 Used to prevent exercise-induced
bronchospasm
 Used to prevent bronchospasm
associated with exposure to known
precipitating factors, such as cold, dry
air or allergens
55
Mast Cell Stabilizers:
Side Effects
-Coughing -Taste changes
-Sore throat -Dizziness
-Rhinitis -Headache
-Bronchospasm

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Antihistamines
Drugs that directly compete with
histamine for specific receptor sites

57
 Antihistamines
H1 histamine receptor- found on smooth muscle,
endothelium, and central nervous system tissue;
causes vasodilation, bronchoconstriction, smooth
muscle activation, and separation of endothelia
cellss (responsible for hives), and pain and itching
due to insect stings
H1 antagonists are commonly referred to as
antihistamines
 Antihistamines have several properties
 Antihistaminic
 Anticholinergic
 Sedative
 Antivomitive

58
 Antihistamines:
Mechanism of Action

 Block action of histamine at the H1 receptor

sites
 Compete with histamine for binding at
unoccupied receptors
 Cannot push histamine off the receptor if
already bound

59
 Antihistamines:
Mechanism of Action
 The binding of H1 blockers to the histamine
receptors prevents the adverse
consequences of histamine stimulation
 Bonchospasm

 Vasodilation

 Increased GI and respiratory secretions

 Increased capillary permeability

60
 Antihistamines:
Mechanism of Action
 More effective in preventing the actions of
histamine rather than reversing them
 Should be given early in treatment, before
all the histamine binds to the receptors

61
Indications
Management of:
Bronchial asthma
Allergic reactions
Nasal allergies
Seasonal or perennial allergic rhinitis
(hay fever)
Motion sickness
Sleep disorders

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 Antihistamines: Side effects

 Anticholinergic (drying) effects,

most common
Dry mouth
Difficulty urinating
Constipation
Changes in vision (M-cb)
 Drowsiness
Mild drowsiness to deep sleep

63
Antileukotrienes
 Also called leukotriene receptor
antagonists (LRTAs)
 Newer class of asthma
medications

64
Antileukotrienes:
Mechanism of Action
 Leukotrienes are substances released
when a trigger, such as cat hair or
dust, starts a series of chemical
reactions in the body
 Leukotrienes cause inflammation,
bronchoconstriction, and mucus
production
 Result: coughing, wheezing,
shortness of breath

65
Antileukotrienes:
Mechanism of Action
 Antileukotriene agents prevent
leukotrienes from attaching to
receptors on cells in the lungs and
in circulation
 Inflammation in the lungs is
blocked, and asthma symptoms
are relieved

66
Antileukotrienes: Drug Effects
By blocking leukotrienes:
 Prevent smooth muscle contraction of
the bronchial airways
 Decrease mucus secretion
 Prevent vascular permeability
 Decrease neutrophil and leukocyte
infiltration to the lungs, preventing
inflammation

67
Antileukotrienes: Indications
 Prophylaxis and chronic treatment
of asthma in adults and children
older than age 12
 NOT meant for management of
acute asthmatic attacks
 Montelukast is approved for use in
children ages 6 and older

68
Antileukotrienes: Side Effects
zafirlukast montelukast
 Headache  has fewer side
 Nausea effects
 Diarrhea
 Liver dysfunction

69
 Drugs used in pulmonary edema
• Pulmonary edema is a condition in which fluid
accumulates in the lungs, usually (but not
always) because the heart's left ventricle does
not pump adequately.

70
1. Antispume remedies;
– ethanol 30-40% through mask and 70-80% through catheter
– antiphosmilan- alcoholic sol. 10%0,6 or 1 ml (inhalations).
2. Antidyspnoea:
– narcotic analgesics: morphine 1%-1ml
• phentanyl 0,005-1-2ml
• talamonal 2-3 ml
• promedol 1%-1-2 ml
3. Antiarrhythmics:
– Lidocaine sol. 10%-2 ml
– Procainamide sol 10%-5 ml
– Verapamil sol.0,25%-2-4 ml

71
4. Oxygen therapy
5. Bronchodilators: Aminophylline
6. Increase of heart contractility:
– Cardiac glycosides: strophanthine 0,05% or corglycon
0,06% 0,3-0,5 ml i/v
7. Pulmonary dehydration:
– Diuretics: frusemide or ethacrynic acid 20-120 and 50-
150 mg i/v
8. Decrease of alveolar-capillary permeability
– Antihistamines (diphenhydramine, cloropiramine i/v
or i/m)
– Glucocorticoids (hydrocortisone, prednesolone 150-
300 and 50-150mg i/v or perfussion) 72
9. Decrease of hypoxia and acid-base disturbances:
– O2 ,
– Sodium hydrocarbonate 5%
10. Decrease of arterial pressure:
– ganglion-blocking drugs: hexamethonium,
– α-adrenoblockers: phentolamine 0,5%-0,5 ml
– Sodium nitroprusside 50mg
– Blood effusion
11. Antihypotension:
– phenylephrine 1%-0,5 mli/v with 40 ml glucose 40 ml
– dopamine 0,5% - 5 ml with 125 ml NaCl 0,9%
– norepinephrine 0,2% - 2-4 ml
73