Pharmacodynamics of Drugs Acting on Respiratory System
Session 9: Pharmacodynamics of Drugs Acting on Respiratory System
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of Drugs acting on Respiratory System
Describe drug interactions associated with Drugs acting on Respiratory System
Describe side effects of Drugs acting on Respiratory System
Describe contraindications of Drugs acting on Respiratory System
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD projector
Handout 9.1: Pharmacodynamics of drugs for cough, cold and allegy
PST 05104 Pharmacology & Therapeutics 68 NTA Level 5 Semester 1 Facilitator Guide
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
40 minutes
40 minutes
Presentation/
Mechanism of Action of Drugs acting on
Mechanism of Action of Drugs acting on
2
2
40 minutes
40 minutes
Buzzing
Respiratory System
Respiratory System
Buzzing
Respiratory System
Respiratory System
3
3
25 minutes
25 minutes
Presentation/
Drug Interactions Associated With Drugs
Drug Interactions Associated With Drugs
3
3
25 minutes
25 minutes
brainstorming
acting on Respiratory System
acting on Respiratory System
brainstorming
acting on Respiratory System
acting on Respiratory System
4
4
20 minutes
20 minutes
Presentation
Side Effects of Drugs acting on Respiratory
Side Effects of Drugs acting on Respiratory
4
4
20 minutes
20 minutes
Presentation
System
System
System
System
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Drugs acting on
Contraindications of Drugs acting on
5
5
20 minutes
20 minutes
Brainstorming
Respiratory System
Respiratory System
Brainstorming
Respiratory System
Respiratory System
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 69 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Drugs acting on Respiratory System (40 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
What are the mechanisms of action of Drugs acting on respiratory system?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
The following are the mechanisms of drugs used to treat Asthma and chronic obstructive pulmonary disease (COPD);
Beta 2 (β2)-Agonists
o Intravenous salbutamol is also used in obstetric practice to inhibit premature labour). o Agonists occupying β2-adrenoceptors increase cyclic adenosine monophosphate
(cAMP) by stimulating adenylyl cyclase via stimulatory G-proteins. o Cyclic AMP phosphorylates a cascade of enzymes.
o This causes a wide variety of effects including:
Relaxation of smooth muscle including bronchial, uterine and vascular;
inhibition of release of inflammatory mediators;
increased mucociliary clearance;
increase in heart rate, force of myocardial
Muscarinic Receptor Antagonists
o There is increased parasympathetic activity in patients with reversible airways obstruction, resulting in bronchoconstriction through the effects of acetylcholine on the muscarinic (M2, M3) receptors in the bronchi.
PST 05104 Pharmacology & Therapeutics 70 NTA Level 5 Semester 1 Facilitator Guide
The final common pathway is via a membrane-bound G-protein which when stimulated leads to a fall in cAMP and increased intracellular calcium, with consequent bronchoconstriction.
Antimuscarinic drugs block muscarinic receptors in the airways leading to bronchodilation.
Methylxanthines
It is not clear exactly how theophylline produces bronchodilation.
Its pharmacological actions include the following:
Relaxation of airway smooth muscle and inhibition of mediator release (e.g. from
mast cells).
Theophylline raises intracellular cAMP by inhibiting phosphodiesterase.
However, phosphodiesterase inhibition is modest at therapeutic concentrations of theophylline
Antagonism of adenosine (a potent bronchoconstrictor) at A2-receptors;
Anti-inflammatory activity on T-lymphocytes by reducing release of platelet-activating factor (PAF).
Glucocorticosteroids
Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations
of COPD because of their potent anti-inflammatory effect.
This involves interaction with an intracellular glucocorticosteroids receptor that in
turn interacts with nuclear DNA, altering the transcription of many genes and thus the synthesis of pro-inflammatory cytokines, β2-adrenoceptors, tachykinin-degrading enzymes and lipocortin (an inhibitor of phospholipase A2, reducing free arachidonic acid and thus leukotriene synthesis).
They are used both in maintenance therapy (prophylaxis) and in the treatment of the acute severe attack.
Mast Cell Stabilizers (Cromoglicate and Nedocromil)
The degranulation of mast cells and eosinophils is an important step in the response to an allergen.
Degranulation leads to release of a variety of proinflammatory factors, including histamine, leukotrienes, and various cytokines.
These factors then act on tissues to elicit the classic signs of an allergic reaction.
Mast cell stabilizers work by preventing this degranulation from occurring.
The mechanism by which they accomplish this is still not confirmed.
Mast cell stabilizers have a variety of other actions that may contribute to their efficacy.
They suppress the actions of chemotactic factors on eosinophils, neutrophils, and monocytes, and they may reduce movement of leukocytes in asthmatic airways.
PST 05104 Pharmacology & Therapeutics 71 NTA Level 5 Semester 1 Facilitator Guide
Leukotriene Modulators
o Leukotriene B4 is a powerful chemo-attractant (eosinophils and neutrophils) and increases vascular permeability producing mucosal oedema.
o Leukotrienes C4, D4 and E4 (cysteinyl leukotrienes) are potent spasmogens and pro-inflammatory substances (‗SRS-A‘).
o Leukotriene modulators fall into two classes, namely leukotriene receptor antagonists and 5-lipoxygenase inhibitors.
o Leukotriene C4 and D4 antagonists: Montelukast is a competitive inhibitor of LTD4 and LTC4 receptor.
5-Lipoxygenase Inhibitors:
o 5-Lipoxygenase is the enzyme required for the synthesis of LTA4, which is an unstable epoxide precursor of LTB4 is which is a potent pro-inflammatory chemo-attractant and cysteinyl leukotrienes (LTC4, LTD4 and LTE4).
o Zileuton which is a competitive inhibitor of 5-lipoxygenase enzyme results decreased synthesis of the above leukotrienes.
Anti-IgE Monoclonal Antibody
o Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody.
o It is used as additional therapy in patients with severe persistent allergic asthma due to IgE-mediated sensitivity to inhaled allergens and inadequately controlled by glucocorticosteroids plus long-acting β2-agonists.
o It binds to IgE at the same epitope on the Fc region that binds FcεRI, this means it cannot react with IgE already bound to the mast cell or basophils and is not anaphylactogenic.
For mechanism of actions of drugs for cough, cold and allergy
REFER Students to Handout 9.1: Pharmacodynamics of drugs for cough, cold and allegy
PST 05104 Pharmacology & Therapeutics 72 NTA Level 5 Semester 1 Facilitator Guide
STEP 3: Drug Interactions Associated with Drugs Acting on Respiratory System (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with drugs acting on respiratory system?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
The following are drug interactions for drugs used to treat Asthma and Chronic Obstructive Pulmonary Disease
Methylxanthines
o Although synergism between β2-adrenergic agonists and theophylline has been demonstrated in vitro, clinically the effect of this combination is at best additive.
o Theophylline metabolism is induced in the presence of hepatic CYP450-inducing agents, such as rifampicin.
Mast Cell Stabilizers (Cromoglicate and Nedocromil) o None of major significance
Leukotriene Modulators
o No clinically important drug–drug interactions are currently recognized
STEP 4: Side Effects of Drugs acting on Respiratory System (20 minutes)
The following are the side effects of drugs used ro treat asthma
Anticholinergic side effects (first-generation agents): dry mouth, urinary retention
Muscarinic Receptor Antagonists
o Adverse effects of muscarinic receptor antagonists include dry mouth, mydriasis (causes blurred vision), tachycardia, hot and flushed skin, agitation, urinary retention, constipation, and delirium.
o A mnemonic to remember these side effects is ―red as a beet, dry as a bone, blind as a bat, and mad as a hatter.‖
o These effects are due to blockade of muscarinic receptors at different organs.
Glucocorticosteroids
o Hyperglycemia and steroid induced diabetes
PST 05104 Pharmacology & Therapeutics 73 NTA Level 5 Semester 1 Facilitator Guide
Weight gain and severe swelling, particularly in the face; caused, in part, by the mineralocorticoid effects
Psychiatric symptoms including depression, mania, and psychosis; other types of
cognitive dysfunction can also occur, including euphoria, insomnia, mental confusion
Gastric and duodenal bleeding secondary to inflammation or ulceration
Infections resulting from immunosuppression
Skin effects: thin skin, violaceous striae (stretch marks), acne
Eyes: cataracts and glaucoma
Muscular effects: muscle wasting, myopathy
Adipose distribution: buffalo hump, central obesity
Osteoporosis may occur.
Cushing‘s syndrome: Moon facies, buffalo hump (cervical fat pad), central obesity, supraclavicular fat collection, acne
Adrenal suppression: Because of negative feedback loops, exogenous glucocorticoids will suppress CRH and ACTH.
One significant side effect of glucocorticoids is an increased white blood count (driven by an increase in neutrophils).
Mast Cell Stabilizers (Cromoglicate and Nedocromil)
Generally well tolerated
Side effects generally related to topical application o Cough from irritation of the throat
o Nasal irritation—local irritation from sprays
STEP 5: Contraindications of Drugs acting on Respiratory System (10 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
The following are the contraindications for drug used to treat asthma and COPD;
Muscarinic Receptor Antagonists
Narrow angle glaucoma, GIT &UT obstruction
Glucocorticosteroids
o Active serious infection due to immunosuppressive effect
PST 05104 Pharmacology & Therapeutics 74 NTA Level 5 Semester 1 Facilitator Guide
Diabetic patients, refer side effects.
STEP 6: Key Points (5 minutes)
Leukotriene antagonists (e.g. montelukast) are effective as oral maintenance therapy in chronic persistent asthma.
Glucocorticosteroids are associated with many adverse effects
Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations of COPD because of their potent anti-inflammatory effect.
STEP 7: Evaluation (5 minutes)
What are the groups of drugs used in management of asthma?
What are contraindications of drugs for asthma?
What is the mechanism of action of codein (antitussive)?
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 75 NTA Level 5 Semester 1 Facilitator Guide
Handout 9.1 Pharmacodynamics of drugs for cough, cold and allergy
Antitussives
o Antitussives constitute a heterogeneous class of compounds that inhibit cough through either a central or a peripheral mechanism, or a mixture of the two.
o Centrally acting agents such as dextromethorphan work by inhibiting the cough center in the brain, elevating the threshold for coughing.
o The exact mechanism by which they do this is still poorly understood.
o Dextromethorphan, for example, is an N-methyl-d-aspartate (NMDA) antagonist, although it is not known what contribution this has to its antitussive effects.
o Opiates such as codeine and hydrocodone also work through a central mechanism.
o Peripheral-acting agents work either by anesthetizing the local nerve endings or acting as demulcents. Demulcents have a soothing effect on the throat.
o Older-generation antihistamines (dexbrompheniramine, diphenhydramine) have also been used as antitussives with some success.
o The mechanism behind their use is not well understood.
Expectorants (guaifenesin, ammonium chloride, terpin hydrate, potassium iodide, iodinated glycerol)
o Expectorants comprise a heterogeneous collection of compounds that facilitate the removal of mucous from the respiratory tract.
o Mucus serves as an airway lubricant and functions as a first level of immune defense. o When mucus becomes thickened and/or dried out by infections, the functions of the
mucus, including the clearing of infections, becomes impaired.
o Expectorants typically work by increasing the amount of fluid in the respiratory tract, which increases flow and clearance of local irritants as well as reducing the viscosity of mucus.
o It is not clear exactly how guaifenesin increases respiratory fluid, but it may be through a local irritant effect.
Decongestants (phenylephrine, oxymetazoline, xylometazoline, naphazoline pseudoephedrine, ephedrine, phenylpropanolamine )
o Nasal congestion occurs when the nasal passages become edematous, usually a result of an inflammatory response to an upper respiratory tract infection, an allergic response, or a response to chemical irritant
o All decongestants are vasoconstrictors.
PST 05104 Pharmacology & Therapeutics 76 NTA Level 5 Semester 1 Facilitator Guide
The main mechanism by which they reduce nasal congestion is by constricting precapillary blood vessels, which reduces capillary hydrostatic pressure, blood flow, and volume.
Hydrostatic pressure is one of the forces that pushes plasma out of a blood vessel into the tissues, causing edema.
Capillary permeability and oncotic pressure are the two other factors that influence the formation of tissue edema.
By reducing hydrostatic pressure, the outward force that pushes fluid out of the vessel becomes an inward force that drives fluid into the vessel.
The net effect is to reduce leakage in blood vessels, therefore reducing congestion.
Through reduction of blood flow and volume, a smaller amount of fluid is made
available to the leaky capillaries, and thus edema formation decreases as well.
The vasoconstriction is mediated by stimulation of α1 receptors.
These receptors are stimulated either by direct agonists or indirectly.
Direct agonists tend to be analogs of norepinephrine, although with greater selectivity
for the α1 receptor.
Indirect agonists (pseudoephedrine, ephedrine, and phenylpropanolamine) work by increasing levels of endogenous norepinephrine.
H1 antagonists
H1 antagonists are agents that antagonize the allergic responses and other effects mediated by histamine. These are also known as antihistamines.
Histamine plays a key role in allergic reactions, also known as immunoglobulin E
(IgE)–mediated hypersensitivity reactions.
The role of histamine in the immune response is largely mediated by H1 receptors.
H1-receptor antagonists competitively antagonize histamine at these receptors, mitigating the immune response to an allergen.
Mast cell stabilizers
Mast cell stabilizers are used in conditions with an allergic component such as
The details on mechanism of action will be discussed in asthma
Drug interactions:
Expectorants (guaifenesin, ammonium chloride, terpin hydrate, potassium iodide, iodinated glycerol)
o Guaifenesin: none of major significance
Decongestants (phenylephrine, oxymetazoline, xylometazoline, naphazoline pseudoephedrine, ephedrine, phenylpropanolamine )
None of major significance
Side effects
PST 05104 Pharmacology & Therapeutics 77 NTA Level 5 Semester 1 Facilitator Guide
Antitussives
Opiates main side effects are sedation and constipation at the lower doses used to suppress cough.
Expectorants (guaifenesin, ammonium chloride, terpin hydrate and others) Guaifenesin: Generally well tolerated; side effects occur infrequently which include Nausea, Drowsiness and Vomiting which are typically only seen at high doses.
Decongestants (phenylephrine, oxymetazoline, xylometazoline, naphazoline pseudoephedrine, ephedrine, phenylpropanolamine )
o CNS stimulation: The phenylamines (phenylephrine, ephedrine, pseudoephedrine) share common structural features with amphetamine, and therefore they also stimulate the CNS. This manifests as: agitation, anxiety and insomnia
o Rebound congestion is typically only seen with topical agents
H1 antagonists
o Sedation: H1 receptors in the CNS mediate wakefulness, so antagonism of these receptors leads to drowsiness.
o Some antihistamines also antagonize serotonin receptors, and this might also contribute to sedation.
Contraindications
Antitussive
None of major significance
Expectorants (guaifenesin, ammonium chloride, terpin hydrate, potassium iodide, iodinated glycerol)
None of major significance
Decongestants (phenylephrine, oxymetazoline, xylometazoline, naphazoline pseudoephedrine, ephedrine, phenylpropanolamine )
o Concomitant use with monoamine oxidase inhibitors (MAOIsmay lead to an increase in norepinephrine levels which may result into hypertensive crisis..
o All Decongestants cause vasoconstriction, which may lead to rise in blood pressure in patients with hypertension
H1 antagonists
o Fexofenadine and hydroxyzine are contraindicated in pregnancy due to teratogenic effects in animals
o First-generation antihistamines are contraindicated to breastfeeding mothers because they are more likely to cross into breast milk, and this may lead to excess sedation in the nursing infant
PST 05104 Pharmacology & Therapeutics 78 NTA Level 5 Semester 1 Facilitator Guide
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