Minor Ailments Pharmacology Flashcards
Decongestants: Used for? What receptor does it bind to? Mechanism of Action?
Topical (nasal, ophthalmic) and systemic decongestants are widely used in cough-cold preparations and in anti-allergy medications
Decongestants are α1 adrenergic receptor agonists that act in the nasal mucosa to produce vasoconstriction
Vasoconstriction decreases resistance to airflow and improves ventilation by decreasing the volume of the nasal mucosa and reduced delivery and secretion of fluids to the nasal mucosa
Ephedrine. What class does it belong to? What receptors does it bind to? What does it cause the release of?
Decongestant: Natural product, mixed-acting sympathomimetic drug
Directly stimulates α1-adrenergic receptors of respiratory mucosa causing vasoconstriction
Directly stimulates β-adrenergic receptors causing bronchial relaxation, increased heart rate and contractility
Enhances release of NE from sympathetic neurons
Pseudoephedrine: What receptors does it bind to? How does it compare to ephedrine?
Stereoisomer of ephedrine, but less potent than ephedrine in producing tachycardia, increasing blood pressure, and CNS stimulation
Directly stimulates α1-adrenergic receptors of nasal mucosa causing vasoconstriction;
Directly stimulates β-adrenergic receptors causing bronchial relaxation, increased heart rate and contractility
Phenylephrine: Class? Receptor?
Decongestant, and is a selective a1 adrenergic agonist
What is the onset of action for oral decongestants? And the adverse effects depends on?
Onset of action ~ 30 minutes
Adverse effects depend on the degree of α1 receptor selectivity
insomnia, tremor, irritability, nervousness, restlessness, dizziness, headache, tachycardia, palpitation, increased blood pressure (particularly in hypertensive patients
Topical nasal decongestants onset of action?
Onset of action – 5-10 minutes
Xylometazoline (Otrivin) 0.1%
Oxymetazoline (Dristan) 0.5%
What are these? Dosing? And are these short or long acting ?
Topical nasal decongestants, long-acting, and dosing is 2-3 sprays in each nostril q10-12 up to BID.
Phenylephrine Nasal. Dosing? Type of medication?
Short acting topical nasal decongestant.
Dose will be 2-3 sprays in each nostril q4h
Antitussives: Examples, MOA
Codeine and dextromethorphan
MOA: act centrally on medulla to increase cough threshold
Image: See the different parts of the medulla?
Opioid Antitussives
Codeine is both an opiate and an opioid
Acts on opioid receptors in the medullary cough centre
May also have additional peripheral action on cough receptors in proximal airways
Note – codeine itself has antitussive properties (does not require metabolism to morphine, which is needed for its full analgesic action)
Little evidence for effectiveness at OTC doses ADRs: sedation, constipation
Dextromethorphan. Does it have analgesic or euphoric properties? Where does it Act? Side effects compared to codeine?
No analgesic or euphoric properties
Does not act through opioid receptors
Acts centrally to elevate threshold for coughing
Produces fewer subjective and GI side effects compared to codeine
Dextromethorphan Metabolism: What happens if its taken in poor metabolizers or with 2D6 inhibitors?
What happens if you take it with MAOIs?
Metabolized by CYP 2D6, increased CNS effects in poor metabolizers/drug interactions with 2D6 inhibitors
Occasional dizziness, drowsiness, nausea
Risk of serotonin syndrome with MAOIs (contraindicated, blocks serotonin reuptake)
Expectorants
- Compounds that helps bring mucous and other materials from the bronchi
- Guaifenesin is an expectorant found in many cough-cold products
- Thought to act as an expectorant by stimulating respiratory tract secretions, thereby increasing respiratory fluid volumes and decreasing mucous viscosity
- May also promote mucociliary activity
- Evidence for efficacy is very limited, but so is the evidence for adverse effects, no known drug interactions
Histamine
Stored in which cells, tissues?
Physiological roles?
Primary storage site in tissues is in mast cells
Tissues with large numbers of mast cells include skin, bronchial mucosa, intestinal mucosa, also stored in basophils
Physiological roles in early phases of allergic reactions, GI acid secretion, immune system function, and sleep-wake cycles
Histamine in Allergic Responses
Mast cells after interacting with antigen through IgE antibodies= Ip3 is increased= increases intracellular calcium, this calcium causes exocytosis of histamine from secretory granules .
Other allergic mediators like leukotrienes also secreted
Mast cell with signaling pathways. Physically stimulated, or antigens, or compliment pathway during immune response. Drugs can also promote or inhibit release.
Beta adrenergic agents )epinephrine, isoproterenol) can inhibit, as can prostaglandins, and Ach can promote the release (but can be blocked by atropine).
Once activated, Histamine can bind to:
H1, H2, H3, H4
All are GPCRs
H1 receptors:
H1 receptors:
Distributed widely in CNS** and **periphery, particularly on smooth muscle and endothelial cells
Many of the common effects of histamine are due to activation of H<u>1 </u>receptors (itching, stimulation of nasal secretion, sedation associated with antihistamines, etc.)
H2 receptors:
Distributed in gastric parietal cells (involved in gastric acid secretion), cardiac muscle, mast cells, CNS
H3 Receptors
Autoreceptors on histamine-containing neurons, activation inhibits further histamine release
H4 Receptors
Located on cells of hematopoietic origin, white blood cells
Involved in inflammation, allergy, less understood than H1 receptors
Vascular Effects of Histamine
Dilation of resistance vessels - involves H1 (and H2)
Constriction of veins
- Due to activation of H1 receptors on vascular smooth
- muscle, contributes to extravasation of fluid and edema
- Increased capillary permeability Also contributes to edema
Effect on the vasculature
- Large amounts of histamine (e.g. during anaphylaxis) cause profound reduction in blood pressure due to vasodilation and plasma escape from circulation
Other Effects of Histamine
- Altered cardiac contractility and electrical conductance (H1 and H2)
- Contraction of non-vascular smooth muscle (H1), contributes to bronchoconstriction in patients with asthma
- Wheal formation, itching, pain (H1)
Difference Between 1st gen and 2nd gen antihistamines?
First generation antihistamines:
- Cross the blood-brain barrier and cause sedation by blocking histamine
- Most are not selective for H1 receptors, and also block muscarinic receptors (i.e. have anticholinergic activity)
Second generation antihistamines:
- Non-sedating, do not cross BBB
- More selective for H1 receptors, not associated with significant anticholinergic activity
- Typically have longer half-lives, may only require one dose daily
Adverse Effects of Antihistamine Drugs
CNS effects:
Sedation, dizziness, tinnitus, incoordination, fatigue, blurred vision, sometimes euphoria, nervousness, insomnia, tremors
All significantly reduced with second-generation agents
Anticholinergic effects:
Dry mouth, urinary retention, dysuria, constipation, increased heart rate
Reduced with second-generation agents
Arachidonic Acid Metabolites. From where do you get them? and Structure?
From diet and/or membranes. Long chain carbon molecules with a carboxylic acid functional group
Pathway of Arachidonic Acid
Arachidonic acid is made from phospholipids by enzyme Phospholipase A2
AA is then broken down into 2 pathways by 2 different enzymes : LOX enzymes break them down into leukotrienes, while COX enzymes break them down into prostaglandins
Eicosanoids
They are all the lipid signaling molecules related to or derived from arachidonic acid.
Autacoids (definition and examples?)
Include eicosanoids and histamine, serotonin, kinins. DEFINITION: substances produced by neural and non neural tissues that act LOCALLY to modulate the activity of smooth muscles, nerves, glands, platelet, and other tissues.
Eicosanoids
Ligands for GPCR, have multiple functions on multiple different tissues
What is the net effect on a particular tissue with multiple eicosanoids and receptors?
The net effect involves both the NUMBER and TYPE of eicosanoid receptors, and….. THE TYPE and CONCENTRATION of eicosanoids
Prostanoids
derived via actions of COX enzymes. AA→ PGH2→ Other prostanoids
COX enzymes
2 types of COX enzymes.
COX1 → “housekeeping”, expressed in most tissues, responsible for carrying out most of the homeostatic activities
COX2 → ??
Leukotrienes
Derived from HPETE, produced from arachidonic acid by lipoxygenase
Local Inflammatory Hormones
Histamine, bradykinin, prostaglandins, leukotrienes, chemokines, cytokines, etc
What compounds stimulate sensory pain neurons?
HISTAMINE and BRADYKININ
What reduces the threshold at which neurons will fire?
HISTAMINE and PROSTAGLANDINS
Acetaminophen vs NSAIDs MOA
Acetaminophen inhibit the synethesis and release of PGE2 in the thermoregulatory center, while NSAIDs inhibit COX enzyme
Aspirin
inhibitor of COX-1 selective (1st gen)
COX-1 and COX-2 . Inhibiting which one causes the therapeutic effects, and which one causes the adverse effects?
COX-1 inhibition is the Adverse effects
COX-2 is the therapeutic effects
Ibuprofen binds to COX1 or COX2?
Ibuprofen is almost exactly equipotent for COX1 vs. COX2
Naproxen, what is it selective for? And what is the difference between Naproxen and Ibuprofen?
Naproxen is slightly selective for COX-1.
Major difference is that it has a longer half life ~14 hours… compared to 2-4 hours for ibuprofen
What does Corticosteroids target?
first enzyme of the process.. Phospholipase A2
Shut down all pathways: prostaglandins, bradykinins, leukotrienes
Additional functions of corticosteroids:
- Lysis and redistribution of lymphocytes
- Reduced circulating lymphocyte counts
- Activation of NF-kappaB to increase apoptosis white blood cells
- Down-regulation of IL-1 and IL-6
- Inhibition of IL-2 in T-cells
- Inhibition of cytotoxic T lymphocytes
- Reduced neutrophil chemotaxis
muscarinic receptors, gastrin receptors, histamine receptors all promote activity of the proton pump to cause the release of acid secretion from parietal cells.
PHE2 acts to STOP (turn down) this pathway. It inhibits acid secretion. NSAIDs, meanwhile, will block PGE2 formation, so acid secretion will go up
In addition, Prostaglandins also activate the superficial epithelial cell to make mucus and bicarbonate. Thus, by blocking this production, we damage the mucous layer
Loperamide
anti diarrhea agent
Mu opioid receptor agonist, but doesnt cross the BBB
Reduces tone of the GI smooth muscle to cause constipation (usually ADR, but this time its used as a therapeutic effect)
What promotes sleep?
GABA, Opioids, Melatonin, Leptin
Duration of Insomnia (DSM-V)
transient = 1 week
short term insomnia= 4 episodes within 3 months
Chronic = persistent for >3 months
Risk Factors: women, older adults, more severe cases
Antihistamines for sleep
1st generation. Cross the BBB and cause sedation by blocking the HISTAMINE receptor in brain. Most are not selective for H1 receptors, and also block muscarinic receptors (anticholinergic activity)
Melatonin
NT derived from aa tryptophan
rleeased during dark cycle 9pm to 4am
binds 1,2,3 receptors, has antioxidant properties, etc etc
Melatonin 1= Galphai= promote sleep when activated
Melatonin 2= Gq coupled= coordinating function in the light dark cycle
