Host Defense Flashcards
H1 Receptors
H1 receptors work through the phospholipase C pathway, hydrolyzing phosphoinosotol. It generates PIP3 and DAG. This pathway causes bronchial constriction, and these receptors are often found in the bronchial tree (more often/dense than H2). Calcium is often found in contraction. This is why we worry about airways in inflammatory responses, and is why we use antihistamines to target the H1 response. H1 is not a vasoconstrictor due to the fact that H1 receptors are not located on the smooth muscle, but on vascular endothelial cells. This activates machinery in endothelial cells that makes NO and arachadonic acid derivatives (especially PGI2, prostacyclin) via the increase in calcium. The endothelial cells also have some contractile elements, and the calcium causes constriction on a cell by cell basis. This leads to the leakiness associated with histamine, which is used to allow leukocytes to exit vasculature. Histamine is algesic, especially with H1 responses. Histamine is also useful for wakefulness in the CNS, which comes back as a side-effect of antihistamines, sedation. Retains amino group.
Histamine
involved in the inflammatory response and released following chemical, mechanical stimuli. It is found in mast cells, basophils, et c.
When released, it targets specific receptors, such as H1 and H2 (there are multiple other H receptors, but these are the most important.
Out of the two, H1 is most important)
The drugs of Host Defense are primarily H1 antagonists. H2 blockers are used more for GI effects.
H2 Receptors
H2 works through adenylate cyclase, generating cAMP, which can signal through a variety of pathways.
This response is more straightforward. The receptor is on the smooth muscle itself, and the adenylate cyclase causes muscle relaxation directly. Prominantly in the gut. In a big inflammatory response, we worry about excessive acid release in the gut leading to ulcer formation.
Retains imidazole ring.
Diphenhydramine
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Dimenhydrinate
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Clemastine
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Carbinoxamine
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Pyrilamine
First generation H1 antagonist
Ethylenediamines
Medium sedation, GI side effects
Tripelennamine
First generation H1 antagonist
Ethylenediamines
Medium sedation, GI side effects
Chlorpheniramine
First generation H1 antagonist
Alkylamines
Potent as H1 blockers, mild sedation
Brompheniramine
First generation H1 antagonist
Alkylamines
Potent as H1 blockers, mild sedation
Hydroxyzine
First generation H1 antagonist
Piperazines
Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic
Meclizine
First generation H1 antagonist
Piperazines
Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic
Cyclizine
First generation H1 antagonist
Piperazines
Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic
Promethazine
First generation H1 antagonist
phenothiazines
sedation, anti-cholinergic, used as anti-emetic; multiple CNS effects—dopaminergic and adrenergic receptors
Cyproheptadine
First generation H1 antagonist
Piperidines
used in temperature sensitive people, which leads to mast cell degranulation.
It may have something to do with the serotonin response, but its not well known.
Loratadine
A second generation H1 antagonist
The first of the second generation antihistamines were pro-drugs. They required metabolism by cytochrome p450. This made them more polar, which prevented them from crossing the blood brain barrier.
This class doesn’t have the drowsiness side effect, but also lacks the motion sickness treatment.
Terfenadine
Second generation H1 antagonist
toxicity: polymorphic ventricular tachycardia when taken at high dose or with certain P450 inhibitors like erythromycin, ketoconazole; unmetabolized parent drug blocks delayed rectifier potassium channels;
prolongs QT interval, torsades de pointes
Astemizole
Second generation H1 antagonist
toxicity: polymorphic ventricular tachycardia when taken at high dose or with certain P450 inhibitors like erythromycin, ketoconazole; unmetabolized parent drug blocks delayed rectifier potassium channels;
prolongs QT interval, torsades de pointes
Fexofenadine
Second generation H1 antagonist
Don’t cross into CNS, therefore don’t cause drowsiness active metabolite of Terfenadine
Cetirizine
Second generation H1 antagonist
Don’t cross into CNS, therefore don’t cause drowsiness
Active metabolite of hyrdroxyzine
Desloratadine
Second generation H1 antagonist
Don’t cross into CNS, therefore don’t cause drowsiness
Active metabolite of loratadine
B1 and B2 receptors
The receptors are named for bradykinin, B1 and B2 receptors.
They do very similar things to histamine. They constrict bronchial smooth muscle, dialate vascular smooth muscle, and have effects at nerve endings, especially as the source of pain during inflammation.
They are amplifiers of the inflammatory process
Bradykinin
Important algesic in inflammation
Made from high molecular weight kininogen by kallikrein
Broken down by Kininase I and II One amino acid (more) different from Kallidin
Aspirin
Irreversible inhibitor of the COXI and II.
All other NSAIDs are competitive.
It transfers an acetyl group in an active site.
This is a big deal with platelets, which don’t have nuclei. It can’t make thrombaxane until new platelets are produced. This leads to a much longer lived effect. If you knock out platelets, you can cause an increase in bleeding, especially in patients that are already susceptible.
SAIDS
SAIDS, steroidal anti-inflammatory drugs:
These are glucocorticoids, or steroids (anything derived from cholesterol). Glucocorticoids are produced by the adrenal cortex and have effects on metabolism and glucose.
They are very lipophilic, and can go through a membrane in absence of a cell surface receptor.
They tend to work as dimers with receptors that serve as transcription factors. It will bind to a hormone response element and increase transcription (or decrease in negative regulation).
Glucocorticoids work through gene-dependent actions
Sirolimus/Tacrolimus Pathway
HIV Plan of Attack
