L21- Antihistamines

define a local hormone

a chemical messenger formed in many tissues

what is histamine

autocoid (self remedy)

• local hormone

how is histamine synthesised

the amino acid histidine combines with enzyme histidine decarboxylase to form histamine the amine

if histamine is not stored, what happens to it

rapidly inactivated by amine oxidase

where is histamine released

• C3a and C5a receptors (acute inflammatory response)

• pathogen pattern receptors (acute inflammatory response)

• immunoglobulin (Ig)E - cell fixed antibody (hypersensitivity)

how do histaminergic neurones in TMN work in the arousal pathway

spontaneously active and release histamine during wakefulness

how do histaminergic neurones in TMN work in the emetic centre

receive input from vestibular centre in the inner ear (spatial orientation)

what are H₁ G-protein coupled receptors coupled to

phospholipase C

what are H₂ G-protein coupled receptors coupled to

adenyl cyclase

what do H₁ receptors do

increase intracellular calcium:

• myosin phosphorylation

• vascular permeability

• NFkB activation

what do H₂ receptors do

increase cAMP:

• proton pump function

• gastric acid secretion

what do H₃ and H₄ receptors do

decrease cAMP

what are the functions of H₁ receptors

• CNS neural activation

• nasal and bronchial mucus secretion

• smooth muscle contraction

• sensory nerve endings

• capillary permeability and dilation

• proinflammatory cytokine secretion

• increase in force of heart contraction (inotropic)

what are the functions of H₂ receptors

• increase in force heart contraction (inotropic)

• chronotropic (time change) - increase in heart rate

• stimulation of gastric acid secretion in stomach

• capillary permeability

describe allergic rhinitis as a localised histamine response

inflammation inside the nose in response to allergen (e.g. dust)

• sensory nerve stimulation

• increase nasal secretions

• capillary permeability and dilation

describe urticaria (hives) as a localised histamine response

skin rash in response to allergen e.g. nettle sting

• itchy, raised bump

• sensory nerve ending stimulation

• capillary permeability and dilation

what happens if the histamine is not localised

• enters bloodstream

• release is faster than inactivation

describe how tummy pain occurs

intestinal muscle contractions in response to histamine

describe how wheezing, chest tightness occurs

bronchiole contraction in response to histamine

what happens if there is mismatch between sensory input and spatial orientation

activates the histaminergic neurons in the tuberomammillary nucleus which release histamine in the emetic centre causing sickness

where is the emetic centre

medulla

what are advantages of 1st generation antihistamines

• inexpensive and effective

• cross the BBB so prevent motion sickness

• cross the BBB so can cause sedation

• not very H₁ selective- extra wanted effects

what are disadvantages of 1st generation antihistamines

• cross the BBB- unwanted sedation (e.g. drowsy)

• not very H₁ selective - unwanted adverse effects

what can 1st generation antihistamines also be, giving an unwanted effect

muscarinic cholinergic receptor antagonists

• particularly diphenhydramine and promethazine

what is a wanted effect for muscarinic receptor antagonism

antiemetic effects

what does diphenhydramine also affect

5-HT neurotransmission

give examples of 2nd generation antihistamines

• cetirizine (sedating)

• loratidine (non-sedating)

• fexofenadine (non-sedating)

what are the functions of 2nd generation antihistamines

• add COOH

• do not cross BBB as easily

• less unwanted secretion

• less anticholinergic effects

describe the absorption of H₁

Oral Cmax: 1-2 hours

describe the distribution of H₁

• 1st gen- all tissues

• 2nd gen- all tissues except CNS

describe the metabolism of H₁

• 1st gen- cytochrome P450s

• 2nd gen- most cytochrome P450s (not cetirizine)

describe the elimination of H₁

half life: 4-6 hours

when shouldn’t H₁ receptor antagonists be used

• to treat asthma

• to treat anaphylaxis

where is the function of H₂ receptors

gastric acid secretion

define peptic ulcer

perforation in the lining of the small intestine or stomach

how do peptic ulcers form

• infection with gram-ve Helicobacter pylori

• use of NSAIDs

where are H₂ receptor antagonists used

• promote peptic ulcer healing

• reduce gastroesophageal reflux disease (heartburn)

how do H₂ antagonists block binding of histamine

competitively - fully reversible

what percentage can H₂ antagonists reduce gastric acid secretion by

70%

what are the advantages of using H₂ receptor antagonists

• effective for peptic ulcers

• effective for heartburn

• inexpensive

• relatively safe

what are the disadvantages of using H₂ receptor antagonists

• peptic ulcer reoccurrence is common

• not as effective when treating NSAID induced peptic ulcers

• takes 45 minute for heartburn action

• reduce efficacy of drugs requiring acidic environments

• cimetidine affects metabolism of other drugs

what are alternatives to H₂ receptor antagonists

proton pump inhibitors (PPIs)

how do proton pump inhibitors work

• decrease H+ secretion

• proton pump H+/K+/ATPase

• prodrug- acid resistant coating removed in duodenum

• absorbed and transported to parietal cell

• 18 hours to be resynthesised- irreversible/long acting

give examples of proton pump inhibitors

• dexlansoprazole

• omeprazole

what are the advantages of using proton pump inhibitors

• highly effective

• long duration

what are the disadvantages of using proton pump inhibitors

• delayed onset of action

• increased risk of gut infection

• gut pH substantially above physiological level