Understanding Hypersensitivity Reactions and Treatment Options
School
MCPHS University**We aren't endorsed by this school
Course
PSB 451
Subject
Biology
Date
Dec 12, 2024
Pages
9
Uploaded by redgir
Drugs that interfere with the hypersensitivity reaction Anti-IgE therapy - Xolair + MAB+ Binds to the antibodies that are produced in response to the first exposure of an antigen( IGE molecules)+ It prevents the IgE from binding to the mast cell — can’t be sensitized – second exposure won’t cause hypersensitivity+ Injections periodically, not the first line+ Useful for other hypersensitivity reactions like asthma and othersMast cell stabilizers - cromolyn - nedocromil+ Stabilize the mast cell, unknown MOA+ The antibodies can still insert themselves in the mast cell and the antigen can bind to the antibodies but this binding doesn’t release as much of the inflammatory mediators+ nasal spray, eye drops, OTC, RX+ Not a lot of ADRLeukotriene inhibitors - LT receptor antagonists - block the LT receptor activation- 5-lipoxygenase inhibitors - inhibit the formation of the cysteinyl LTHistamine receptor antagonists - we do not have drugs that can stop the formation of histamine- First generation antihistamines - Second generation antihistamines + Effect of this is not that great because there is so many inflammatory mediators that have the same effectEpinephrine- Useful in treating anaphylaxis- If you give H-1 drugs for anaphylaxis, they won't do anything- Is a physiological antagonist, that reverses the shock occurring in allergic rxn by activating alpha-1- Activates B-2 - bronchodilation- Reverses the effects created by inflammatory mediatorsHypersensitivity reactionPeople exposed to any allergens like pollen, animal dander, some medications1. On first exposure - antibody is produced and insert themselves into the membrane of mast cells, basophils, and eosinophils( prominent in the airways)2. The cell is then sensitized3. On a second exposure- the allergens will bind to the antibodies that are instructed into the mast cells — a single allergen binds to two antibodies simultaneously( crosslinks the antibodies) — now any of those cells are going to be activated and release inflammatory mediators ( like histamine, leukotrienes, platelet-activating factor, kinins)
4. The inflammatory mediators are mostly released in the airways but if a lot is released, they might get into the blood and affect other parts of our bodyHistamine works by activating 4 d/t subtypes of receptors (H-1 to H-4)H-1 is responsible for hypersensitivity, found in CNS- leads to wakefulnessBronchial smooth muscle-bronchoconstriction( wheezing, SOB)Blood vessels( large and capillaries)- in the nasal mucosa there are capillaries – lead to vasodilation of BV – leads to swelling of the nasal mucosa— reduce the amount of space for exchange( congestion)When there is a lot of histamine released during anaphylaxis— the effects of histamine are magnified- The effects might go out of the airway and go the BV causing vasodilation—drop in BP — hypotension and shockNerve endings- itchingLeukotrienes- Cause bronchosontriction- They are products of arachidonic acid( cleaved by phospholipase A2) metabolism — and can be a substrate for COX and 5-lipoxygenase ( forms leukotrienes)+ Luckotriene A-4 – very unstable but is converted to B-4 and C-4 by leukotriene C-4 synthase+ They are released to extracellular cells — C-4 can be converted to D-4 and E-4 non-enzymatically+ These three are referred to as cysteinyl leukotrienes and they can activate the cysteinyl leukotriene receptor+ This receptor is found in bronchial smooth muscle and leads to bronchoconstrictionWhen we inhibit COX- we have more arachidonic acid available for the 5-lipoxygenase pathway- This is why people who take NSAIDs report wheezing and SOB- Many patients have higher levels of 5-lipoxygenase or leukotriene C-4 synthase( both are polymorphic) which makes them more susceptible to bronchoconstriction and suchLeukotriene modulators Leukotriene receptor antagonists- montelukast - zafirlukast + Antagonists for the cysteinyl receptor – compete with LT—block effects of activation+ Taken PO+ Associated with an increase in URTI, CNS effects like bad dreams and nightmares, suicidal thoughts( debatable)+ More favored approach5-lipoxygenase inhibitor - zileuton+ This means we produce less cysteinyl LT+ Less used b/c associated with severe GI effects like diarrhea
+ This enzyme is polymorphic( some people have more) – so when this drug is used at a certain dose- most people do not respond — not very effectiveH-1 Receptor Antagonists (antihistamines) - competitiveThe difference b/n the first and the second is lipophilicity and selectivityFirst generation They are more lipophilic, can go to CNS and bind to H-1, cause sedation( an ADE)They are nonselective, block muscarinic receptors- blurred vision urinary retention, dry mouthThe anti-muscarinic effect can be helpful b/c it has a drying effect- reduces nasal secretions, bronchodilation● Also has a benefit for people who have motion sickness- diphenhydramine (Benadryl) - clemastine - dimenhydrinate (Dramamine) - chlorpheniramine (ChlorTrimeton) - brompheniramine - hydroxyzine (Atarax/Vistaril) - cyclizine – meclizine (Antivert) - promethazine (Phenergan) - cyproheptadine - blocks SR receptors, a good H-1 antagonist- Doxepin - TCA, can block muscarinic and histamine receptors, there is a topical cream to reduce itchingSecond generationThey are more hydrophilic and do not cross BBB much, are non-sedatingMore selective to H-1 receptors so not much anti-muscarinic activity- loratadine (Claritin) - desloratidine (Clarinex) - cetirizine (Zyrtec) - azelastine (Astelin) - fexofenadine (Allegra) Indications- seasonal allergies- Hypersensitivity rxnsMost are OTCMost effective if taken before an allergic rxn starts, take it regularly
Anti-emetics D2 receptor antagonists - prochlorperazine (Compazine) - trimethobenzamide (Tigan) - promethazine (Phenergan) - amisulpride (Barhemsys) - used for post-operative N/V+ There is a blockage in the chemo trigger zone which reduces N/V+ There is D-2 rectors in the GI tract – inhibition of the D2 receptors ( Prokinetic movement)- strengthens the contractions of gastric smooth muscles in the downward directions+ Also constricts the lower esophageal sphincter( LES) muscle – found at the end of the esophagus – prevents upward movement of substances+ Useful to administer this drug in a non-oral route – given as ODT, rectal suppositories+ Low selectivity, blocks muscarinic and histamine receptors– and can be used for motion sickness by affecting histamine receptors in the earADR-slowed or abnormal movements ( parkinsonian symptoms, dystonia, tardive dyskinesia) - these drugs are not taken chemically so these effects are not much of a concern 5-HT3 receptor antagonists - ondansetron (Zofran) - granisetron - dolasetron - palonosetron + Found in chemo trigger zone - activation leads to N/V - blocking reduces N/V centrally+ In the GI activation leads to increased movement of the tract (pro-kinetic and anti-kinetic)- which means there is upward and downward movement+ Blocking in the GI leads to less upward and downward movement of substances+ They have fewer ADRs+ Useful in chemotherapy-induced N/V ( CINV) - preferred more than D-2 antagonist+ 90% of SR in the body is found in the GI - chemotherapy damages these receptors that release SR which leads to increased release of SR in the GI causing N/VDrawbacks- not useful for N/V associated with motion sicknessMetoclopramide (Reglan) - Blocks D-2 receptors and 5-HT3 receptors- Not superior to others, doesn’t do a good job- Used as antiemeticNK-1 receptor antagonist - aprepitant/fosaprepitant (Emend) -phosphorylated the drug to make it more lipophilic ???- netupitant/fosnetupitant (Akynzeo : with palonosetron) - combo with 5-HT3 antagonist+ Neurokinin 1 - receptor for substance P( released in the dorsal horn of the spinal cord to painful stimulus and binds to NK-1 receptors in the ascending neurons to transport pain impulses) — but has no analgesic effect
+ Substance P is an emetogenic substance- if you inject it SC- it will cause N/V+ More effective if given before the emetogenic event+ Used to prevent chemotherapy-induced B/V+ Not a lot of ADRCB-1 receptor agonists - dronabinol (Marinol) - nabilone+ Cannabinoid receptors - can be activated by endogenous things+ CB-1 is found in the chemo trigger zone and activation leads to reduced N/V+ Taken PO+ Schedule 2 drugs because of the abuse potentialADR- activation in the brain leads to tachycardia, HTN, sedation, increased appetiteNone of these drugs are available OTC,There is an area in the brain called the chemo trigger zone - not well protected by BBB- Works as a sensor to monitor things in the blood like harmful things- If it senses something harmful – leads to vomiting and expel substances from GI- It is a protective mechanismThere are Mu opioid receptors in the chemo trigger zone – opioids cause N/VAlso DA receptors PregnancySpoiled foodsGeneral anesthetics - emergence syndromeSmelling somethingMotion sickness - like carsIn the GI tract- substances are moving in the opposite direction to expel stuffDrugs to treat Irritable Bowel SyndromeIBS-C - with constipationlubiprostone (Amitiza)- At the lumen of the intestine, there are receptors for an endogenous substance called uroguanylin( URog) - a membrane-bound receptor that is a form of guanylate cyclase- C ( converts GTP into cGMP – activates PKG —PKG phosphorylates two transporters found on the luminal surface of the cells that line the intestine ( CLC2 and CFTR) — they are responsible to transport Cl and bicarb into the lumen- Increased chloride in the lumen draws more water into the lumenAmitiza directly activates the CLC2 transporter – more chloride is released from the cells into the lumen- Draws more water into the lumen- Easier for fecal mass that was in the lumen to be softer and pass quicklylinaclotide (Linzess) plecanatide (Trulance) - Peptides, work by activating the URoG receptor that is linked to GC - they mimic URoG
- PKG is activated, transporters are phosphorylated, and increased CL in the lumen— more water in the lumen- They are peptides so they have to be taken on an empty stomach( far fewer acids in the stomach) tegaserod (Zelnorm) - partialprucalopride (Motegrity) - full- Agonists at the 5HT-4 receptors, prevalent in the GI tract, they activate it- Activation of 5HT-4 receptors leads to increased contraction of GIT, increased secretions( like a muscarinic agonist, and 5HT-3)- Zelnorm- was originally on the market 25 years ago and taken off the market 2 years later b/c of increased strokes, and MI ( CV events)---because of effects on platelets( there are SR receptors on the plts)+ Came back to the market 5 years ago, there is a limited distribution system, for people with no risk of CV events (it is a CI)tenapanor (Ibsrela) - Works by inhibiting the Na/H antiporter ( NHE3-like the one in the proximal tubule of the nephron) found in the GI tract – responsible for absorbing Na taken in from the diet - It inhibits the transporter which leads to more Na in the GIT — which leads to more water in the GI and that will loosen up fecal matter and pass quickly- Inhibiting NHE3 in the PCT is not the best diuretic but it can still cause a little bit of dehydration- ADR-can cause severe dehydration mostly in childrenIBS-D - with diarrheaalosetron (Lotronex) - 5HT-3 antagonist, not used as an anti-emetic- Activation of 5HT-3 increases secretions in the GI and motility in both directions, so blocking it reduces secretions and motility- Was taken off the market a while ago because it caused death by ischemic colitis and toxic megacolon) – b/c it leads to constipation ( stops GI tract so bad) and the colon folding on itself- It is available now but there is limited distribution only by specialistseluxadoline (Viberzi) - Activates Mu and kappa receptors in the GI ( like loperamide and diphenoxylate which are Mu agonists in the GI)- This leads to stopping the GIT- It is also a delta opioid antagonist – not known what blocking it actually does- Does not cross BBB so no CNS effectsIBS- spasms of the GI tract, pain, constipation, or diarrhea- Primarily affects women- Not tests for it- We could use drugs like muscarinic receptor antagonists -dicyclomine, and hyoscyamine( these are available as SL tablets for rapid onset of action) - to reduce spasms of the GI tract- We could also use laxatives for constipation- Imodium OTC, lamotil ( diphenoxylate) RX for diarrhea
- We may see antidepressants being used to treat IBS+ SSRIs in low doses for IBS-C - b/c their ADR is N/V, diarrhea by activating SR receptors+ TCAs can block muscarinic receptors which slows down GI movement so low doses seen used in IBS-D+ In the GI tract- it doesn't take 2-4 weeks to work- works quicklyGERD- acid and stomach content is moving up into the esophagus( throat and mouth), has a bad taste and discomfort- The lower esophageal sphincter is weak when people age, it is easier for content to move up the esophagus- Overtime can lead to erosive esophagitis and Barret’s carcinomaUlcers- There is an imbalance between the amount of acid being produced VS protection of the stomach lining- That protection is due to mucus- Some patients can produce too much acid due to diet reasons, and some drugs- H.Pylori - leads to the release of acid and ulcer because it can damage D cells+ D cells are activated by stomach acid and release somatostatin onto a somatostatin receptor on the G cells+ This activation leads to reduced release of gastrin ( when there is enough acid in the stomach –like negative feedback)+ The presence of H.pylori will stop this feedback and lead to over production of stomach acid+ Use antibiotics like metronidazole, clarithromycin, amoxicillin- When people eat with an ulcer- it leads to pain because the nerves in the GI are exposed- If the hole is bigger, there might be bleeding the more the acid affects it- Too little mucus can cause gastric and duodenal ulcers+ NSAIDs are known to reduce mucus+ PGE-2 is associated with increasing production of stomach mucusWe need acid to be secreted into the stomach along with enzymes to break down food- Dietary peptides can activate G cells that line the stomach - they are called G cells because they secrete a peptide called Gastrin( CCK) into the bloodstream- The gastrin will activate its receptor on ECL cells and parietal cells- Activation on ECL- leads to the secretion of histamine onto its receptor on the parietal cell which is the H-2 receptor- Activation of H-2 or CCK on the parietal cell leads to activation of the K+/H ATPase pump – which releases H+ions into the stomach in exchange for K+- There are also M-3 receptors found on the ECL cells( ACH is released from the vagus nerve of PNS) – which leads to histamine being released- Activation of M-3 on parietal cells increases the activity of the transporter — increases stomach acid- The stretching of the stomach also increases the acid release
Anti-ulcer drugs PGE2 receptor agonist- activation increases mucus ( protects the lining) and Bicarb( helps to neutralize acid)- misoprostol (Cytotec) + Increase mucus and bicarb, protect the stomach+ Doesn't do anything to acid levels+ PGE-2 receptors are found in the uterus so it is also used in medical abortions+ CI- pregnancy+ ADR- causes diarrheaSucralfate - A drug activated by acid, in the presence of stomach acid it produces a repeating sugar unit substance that will adhere to exposed proteins in an ulceration—prevent further ulceration and help it heal over time- A repeating sugar unit requires stomach acid- They should not take an antacid within an hour or 2- It has the potential to bind to certain drugs in the stomach – so take it separately from other drugsThe ones below reduce stomach acidH2 receptor antagonists - have minimal affinity for H-1 receptorsActivation leads to increased activity of the proton pump – so blocking reduces activity— and decreases stomach acidUsed for GERD, ulcersAll are OTC70% reduction in stomach acid- cimetidine (Tagamet) - first one, not used much, known for inhibiting P450- nizatidine (Axid) - famotidine (Pepcid)ADR- tolerance develops over time — when H-2 is blocked for a long time – the body tries to respond by increasing stomach acid - people get hypergastrinemia ( too much gastrin) b/c of the body's response – this reduces the effect of the drugs- Hypergastrinemia- when people stop taking the H-2 antagonists abruptly- there will be rebound hyperacidity - so taper down
Proton pump inhibitors Directly inhibit the H/K+ ATPase, more effective than H-2 blockage90% decrease in stomach acidMany are available OTCThey are prodrugs that need to be activated by acid - after activation, they bind irreversibly to the PP from inside the parietal cellsThe drug has to pass to the stomach, get into the intestine to be absorbed then reach the parietal cells – then the acid there will activate to bind to the proton pumpWe need the formulation to be able to resist the stomach acid - enteric coated tablet, acid-resistant capsules- omeprazole (Prilosec/Zegerid) + Zegerid- combo with Na bicarb to neutralize acid and be absorbed+ Can inhibit CYP450 so DI- esomeprazole (Nexium) - lansoprazole (Prevacid) - dexlansoprazole (Kapidex) - rabeprazole (Aciphex) - pantoprazole (Protonix) These drugs do not have a fast onset of actionBinds irreversibly so when it is stopped- effects will persist, so no worries about rebound – takes time for new PP to be synthesizedProblems- stomach acid also helps kill bacteria, so more susceptible to bacterial infections- Certain drugs require an acidic environment to be absorbed so this class might affect the absorption of certain drugs+ Vitamin D is affected — leading to a higher risk of osteoporosis