OTC Drugs Flashcards
T or F. OTC drugs include supplements, minerals, etc.
F! Very little regulation; hard to be certain of concentration, buyer beware!
Primary afferents
neurons that detect sensory info in the periphery (skin, GI tract, etc.)
- they synapse onto secondary afferents in SC which pass sensory info to brain
Polymodal Nociceptors
- pain detected by primary afferents called nociceptors
- polymodal nociceptors: detect many types of painful stimuli (thermal, mechanical, chemical, electrical)
- different types of painful stimuli are detected by specific receptors expressed on polymodal nociceptors
TRP channels
- transient receptor potential channels
- temperature sensitive ligand-gated ion channels
- TRPM8 = activated at temps below 10 edgress C (cold)
- TRPV1 = activated at temps above 43 degrees C (hot)
TRPV1 and TRPM8 receptors can also be activated by ligands
- TRPV1 by capsaicin
- TRPM8 by menthol
Why is inflammation associated with pain?
- bc our innate immune system release substances that bind to nociceptors that cause pain
- receptors respond to inflammatory molecules (bradykinin, cytokines, prostaglandins)
Arachidonic acid
- fatty acid present in phospholipids of cell membranes
- freed from the phospholipid molecule by the enzyme phospholipase A2
- key inflammatory mediator
- what guides non-specific inflammation that happens in response to an infection
- metabolized by COX1 and COX2
(Cyclooxygenase) COX1 and COX2 metabolize arachidonic acid into …
prostaglandins, prostacyclin, and thromboxane
5-lipoxygenase (LOX) metabolized arachidonic acid into …
various leukotrienes (another inflammatory mediator
These drive inflammation because (3)
prostaglandins and leukotrienes
- they are potent vasodilators
- they are pyrogenic (fever)
- they attract immune cells (leukotactic) and coordinate the immune response
These are the enzymes that convert arachidonic acid into precursors of prostaglandins
COX1 and COX2
COX1 is primary expressed in …
non-inflammatory cells (blood vessels, platelets, gastric mucosa)
COX2 is primarily expressed in …
inflammatory cells
What do Aspirin and other NSAIDs inhibit? What’s the result?
both COX isoforms
- this decreases prostaglandin production that inhibits inflammation and reduces pain
- inhibitors also suppress prostaglandin synthesis in the brain that is stimulated by pyrogens and reduce fever (antipyretic action)
Why are non-selective NSAIDs associated with gastric toxicity?
due to inhibition of COX1 enzymes in gastric mucosa
- inhibition of COX1 decrease bicarbonate secretion – more H+
- chronic use = gastric ulceration, upper GI bleeding, renal failure
What was developed to bypass gastric toxicity?
specific COX2 inhibitors (ex: celecoxib)
- effective at reducing inflammation in chronic inflammatory disease (less so for acute pain)
- suggests that mechanisms beyond blocking inflammation drives analgesic effect
- associated with higher risk of cardiovascular toxicity (not available OTC)
This drug is a weak COX1 and COX2 inhibitor … what was later found about it?
Acetaminophen
- inhibits a third COX isoform (COX3); found most abundantly in cerebral cortex
- an analgesic and antipyretic agent; lacks anti-inflammatory effects (unlike NSAIDs)
Acetaminophen
- negligible toxicity at therapeutic doses
- overdose or patients with liver damage = liver damage and death
- preferred drug primarily in children
- if enzymes become overwhelmed by high doses, liver engages secondary pathways that involve SIP enzymes (class 1 metabolism) that leads to reactive intermediates that can eventually lead to toxic compounds leading to liver cell death
Albert Niemann
- German chemist who isolated cocaine from coca leaves
- numbed his tongue
- introduced cocaine as a topical anesthetic for ophthalmological surgery
Due to the addictive and toxicity issues with cocaine, synthetic substitutes were developed:
procain, lidocaine, and bupivicaine = most widely used topical anesthetics
- most contain a hydrophobic (Aromatic) moiety, a linker region, and a substituted amine
- linker region determines its pharmacological properties; how long it works, how well, how fast
**having both properties important!! Amphiphilic! Dissolve equally in water and fat
Procain
there is an ester link (none of the others have this) - leave this susceptible to plasma esterase which can hydrolyze this link, bc of this, duration of action is much shorter than other drugs ; positive side: sometimes you need short term anaesthetic (dentist numbing gums prior to injection of longer anaesthetic like bupivacaine)
Local anaesthetic binding
- bind reversible to a specific site within pore of Na+ channels
- block ion movement through this pore
- site in which anaesthetics bind is only accessible intracellularly (anesthetics must cross cell membrane)
- hydrophobicity increases both potency and duration of the action bc the more hydrophobic they are, they more able they are to cross fatty plasma membrane and enter cell which is now more hydrophilic to then get access to pore binding site intracellularly
T or F. Local anesthetics have higher affinity for the open conformation of the sodium channel s they preferentially block neurons that are active
T! so in other words, nociceptors when there’s pain! even they block all sensation and can cause motor paralysis (depending on where applied and conct’n); this is why they don’t!
Capsaicin
- agonist for the TRPV1 receptor
- active ingredient in chilli peppers
- initial application = moderate burning pain (less pain overtime)
- chronic activation of TRPV1 receptors leads to desensitization and loss of TRPV1+ nociceptors (analgesia)
OTC cough and cold medications are used to treat symptoms of
upper respiratory infections (runny nose, congestion, cough, and fever)
A common symptom of upper respiratory tract viral infections
Cough
- reflex = clear the breathing passage of irritants, microbes, fluids, and mucus
The coughing reflex is initiated by …
stimulation of sensory nerves innervating the throat and lungs
How does the cough reflex work?
- sensory neurons in throat/lungs detect irritation via receptors (ex: TRPV1)
- send info to cough center in medulla oblongata (also controls breathing reflex)
- efferent nerves via parasympathetic and motor nerves stimulate the diaphragm, intercostal muscles and lungs to initiate “noisy expiration”
Antitussives
- OTC drugs that inhibit cough reflex (do mostly by inhibiting neurons in medulla oblongata
- dextromethorphan, diphenhydramine, codeine
- moderately effective at best!
Codeine
- mu opioid receptor agonist
- mu receptors in medulla and peripheral nerves innervating respiratory tract
- receptors are inhibitory GPCR
- > inhibit Ca channels, activate K+ channels and inhibit adenylyl cyclase
- > neuronal inactivation and reduced transmitter release
- also have an effect on inhibiting respiration
- not very potent, not a full agonist; wide TI
- at high enough doses = death
- not recommended for under 18 (addiction, overdose)
- moving to prescription status
Dextromethorphan
- active NMDA receptor antagonist
- inhibits neurons in medulla
NMDA receptor
- ligand gated ion channel that’s gated by glutamate
- leads to rapid excitation of neurons and dex, acting as an antagonist, will block ability of glutamate to activate receptors
Diphenhydramine
- antihistamine H1 inverse agonist
- inhibits histamine action at these receptors
- crosses BBBt o suppress medullary cough center
H1 receptors
Gq GPCR
- located on respiratory smooth muscles, stimulates sensory nerves producing cough
Decongestants
Pseudoephedrine, Phenylephrine
Pseudoephedrine
- agonist at the alpha and beta adrenergic receptors
- sympathomimetic drug (structure structurally related and tend to act at same receptors)
- activates alpha adrenergic receptors in mucosa of resp tract = vasoconstriction of blood vessels
- activity at beta adrenergic receptors cause smooth muscle relaxation leading to dilation of the bronchi
- shrinks swollen nasal mucous membranes, reduces edema, etc, and increases nasal airway latency (easier to breathe)
Structurally related to amphetamine
Pseudoephedrine
- stimulant properties
- technically OTC but still have to talk to pharmacist to avoid abuse and illegal use
Phenylephrine
- specific alpha adrenergic receptor agonist
- vasoconstriction in nasal mucosa (like pseudoephedrine, but no smooth muscle relaxation, nor does it impact heart)
- no stimulant properties
- less effective decongestant
Oral drugs that enhance the clearance of mucus
Guaifenesin (Mucinex)
Guaifenesin
- bark from Guaic tree (Caribbean)
- increases output of bronchial secretions by decreasing the adhesiveness and surface tension
- expulsion via cough reflex
- mechanism of action unknown; may act as an irritant of gastric vagal receptors
- THEORY: at much higher doses, all expectorants are emetic drugs (cause nausea and vomiting) ; at lower doses, may provide secretions to expel drugs easier
Allergies - how does it occur
- B cells react inappropritately to an allergen
- produces IgE antibodies
- antibodies bind to receptor on mast cells or basophils
- subsequent exposure = inflamatory chemicals (histmaine)
Where are H1 receptors located?
smooth muscles on vascular endothelial cells, heart, and the CNS
Activation of the H1 receptor causes
- increase vascular permeability
- vasodilation
- stimulation of sensory neurons to produce cough
- smooth muscle contraction of bronchi
- eosinophilic chemotaxis
Histamine receptors occur throughout the brain, with particularly high density in …
regions involved in arousal and waking (thalamus, cortex, noradrenergic, serotonergic, and dopaminergic nuclei)
T or F. Diphenhydramine readily crosses the BBB
T! it inversely agonized the H1 CNS receptors, resulting in drowsiness
OTC Diphenhydramine products for allergies and sleep-aid
Benadryl and Nytol
Inhibitory constant (Ki)
how well an antagonist (or inverse agonist) binds to a receptor (aka affinity)
- conctn of drug that displaces 50% of the labeled ligand
- low Ki = high affinity
First generation antihistamines (like Diphenhydrmaine) bind with relatively high affinity to
muscarinic cholinergic receptors
-> they have anticholinergic effects
Side effects of dIphenhydramine due to its anticholinergic effects:
dry mouth, constipation, and confusion
Who are cautioned against using first gen antihistamines and why?
older people; inhibiting the cholinergic system long term can lead to dementia, Alzheimer’s
Issues with Diphenhydramine: (3)
- tolerance develops rapidly to sedative effects
- use of sedatives decrease quality of sleep (less time in REM - less restorative)
- dementia, Alzheimer’s risk
Second/Third generation antihistamines (compared to first)
- higher selectivity for H1 receptors
- poor blood-brain barrier permeability (no drowsy effects)
- longer duration of action (fewer doses)
- not good at treating cough either (cough centre)
Cetirizine
- second generation antihistamine
- H1 receptor antagonist
- poor BBB permeability; minimal sedation
- duration of action = ~24h
Loratadine
- H1 inverse agonist
- almost entirely bound to plasma proteins (eg. albumin); bound proteins NOT active
- prodrug (desloratidine - unbound)
- 8h halflife compared to desloratidine’s 27h
- poor BBB penetration
