Pharm PY Tutor Histamine and Bradykinin

Histamine

A vasoactive amine that plays a role in vasodilation, increased vascular permeability, pain, erythema, pruritus, and various other physiological processes.

Scombroid poisoning

A condition caused by ingestion of improperly canned/stored then spoiled fish or swiss cheese that contain high levels of heat-stable histamine due to bacterial decarboxylation.

Bradykinin

A peptide that promotes vasodilation and is synthesized from high molecular weight kininogen via plasma kallikrein.

Antihistamines

Drugs that act as H1 antagonists to inhibit the effects of histamine; divided into first and second generations.

Angioedema

Swelling that can occur as a result of increased bradykinin levels due to the use of ACE inhibitors and other drugs.

ACE inhibitors

Medications that block angiotensin-converting enzyme, increasing levels of bradykinin which can lead to angioedema.

What does histamine decarboxylase do?

Converts histidine to histamine, which contributes to scombroid poisoning

Dx: N/V/D, flushing, urticaria, burning sensation in mouth/throat, fever, sweating, palpitations, abdominal cramping

Scombroid poisoning

H1 signaling

Gq

• Increased IP3 → DAG → Ca2+ → NFkB

H1 distribution

Endothelial cells in vasculature, smooth muscle, CNS

H2 signaling

Gs

• Increased cAMP

H2 distribution

Parietal cells in GI tract, cardiomyocytes, mast cells, CNS

H3 signaling

Gi/o

• Decreased cAMP

H3 distribution

CNS, gastric mucosa

H4 signaling

Gi/o

• Decreased cAMP

H4 distribution

Hematopoietic cells

1st Gen Antihistamines

Diphenhydramine, Meclizine, Hydroxyzine

1st Gen Antihistamine ADEs

Sedation, weight gain, cognitive impairment, respiratory suppression, orthostatic hypotension, AMS/delirium in elderly

Antimuscarinic effects = mydriasis (bad in glaucoma), decreased secretions, tachycardia, urinary retention, decreased GI motility

1st Gen Antihistamine use

Vertigo, motion sickness, allergies

Avoid 1st gen antihistamines in pts with

Acute angle closure glaucoma due to mydriasis

Diphenhydramine antimuscarinic effects

an H1 antagonist which ALSO has antimuscarinic effects

→ anti-SLUD (decreased secretions, urinary retention, decreased GI motility), mydriasis, tachycardia

2nd Gen Antihistamines

Loratadine, Cetirizine, & Fexofenadine

2nd Gen Antihistamines ADEs

Prolonged QT interval → may precipitate torsade de pointes

2nd Gen Antihistamines use

Allergies (Loratadine & Fexofenadine are approved for pilots)

2nd Gen Antihistamines note

2nd gen. H1 blockers are ionized at physiologic pH, so they don’t penetrate CNS very well → less sedation/weight gain than 1st gen.

Bradykinin induced by

By direct endothelial damage, promotes vasodilation/edema

Bradykinin acts on

Vascular endothelial cells to promote prostacyclin (PGI2) & nitric oxide (NO) activity → increased relaxation of vascular endothelium

Bradykinin degraded by

angiotensin-converting enzyme (ACE)

ACE normally converts AT-1 to AT-2 → vasoconstriction

Bradykinin counterindication

ACE inhibitors (ex: Lisinopril), DPP-4 inhibitors (ex: Sitagliptin), & Neprilysin antagonists (ex: Sacubitril) all increase bradykinin & can cause angioedema (face swelling)

Drug-induced angioedema presentation: swelling of eyes, lips, tongue, & airway if severe enough (can be life-threatening!)