Antihistamines and Antimuscarinics Flashcards
The histaminergic system and antihistamines.
What are autacoids?
- local hormones
- short acting endogenous mediators
- act as part of an inflammatory response
define pleitropic?
having more than one effect
what cells synthesise, store and release histamine?
- mast cells (in skin, GI, respiratory tract
- Basophils (in blood)
- Some neurons (in CNS and peripheral NS)
What is the effect of histamine secretion?
- acid secretion
- mucosal protection
- Fluid transport
- Neurotransmission
- Visceral sensitivity
- Motility
- Inflammation
- Allergy
- Tumour growth
How is histamine synthesised?
by decarboxylation from an amino acid precursor, histadine. Uses histidine decarboxylase
Where is histamine stored?
in granules in mast cells, basophils and enterocytes
Why is histamine released?
in response to a stimuli which is a Ca dependent exocytosis
how is histamine eliminated?
by oxidative deamination and/or transmethylation
what is produced when histamine undergoes deamination?
a ribose conjugate
what is produced when histamine undergoes transmethylation?
monoamine oxidase
Where are H1 receptors found and what do they control?
- found in smooth muscle, in endothelium cells and the CNS.
- control bronchoconstriction, vasodilation, pain itching, motion sickness, rhinitis, separation of epithelial cells
Where are H2 receptors found and what do they control?
- in gastric parietal cells, vascular smooth muscle cells, basophils
- regulate GA secretion, vasodilation, inhibition of IgE-dependent degranulation
Where are H3 receptors found and what do they control?
- in CNS cells and peripheral NS
- control release of DA, GABA, ACh, 5-HT and NE. Also controls presynaptic feedback, inhibiting histamine synthesis and release
Where are H4 receptors found and what do they control?
- in bone marrow and white blood cells
- mediate mast cell chemotaxis
What are H1 receptors coupled to?
Gq proteins which are coupled to phospholipase C (PLC)
What are H2 receptors coupled to?
Gs proteins which are coupled to adenylyl cyclase (AC) increasing cAMP.
What are H3 receptors coupled to?
Gi/o proteins which are coupled to AC as well as K-channels
What is the effect of H3 receptors on calcium influx and presynaptic neurotransmitter release?
reduces Ca influx and inhibits the neurotransmitter release.
What are H4 receptors coupled to?
Gi/o in mast cells and eosinophils
What is the effect of H4 receptors, coupled to eosinophils, on calcium?
it triggers calcium mobilisation causing mast cell chemotaxis.
What is the ‘triple response of Lewis’?
a cutaneous reponse that occurs from firm stroking of the skin producing:
- an initial red line
- a flare around the line
- a wheal
What happens when histamine is injected transdermally?
- a red spot appears
- flare
- wheal (oedema)
what is the effect of histamine on the heart?
- forces contraction of atrial and ventricular muscles by promoting Ca2+ influx.
- speeds heart rate by hastening diastolic depolarisation in SAN
- slows AV conduction to increase automaticity and elicit arrhythmias
Which receptor controls the majority of the effect of histamine on the heart?
H2 receptors and cAMP accumulation.
H1 only controls the slowing down of AV conduction
Effect of H1 and H2 on the lungs?
H1- bronchodilation, increased mucus viscosity, stimulates vagal sensory nerve endings causing cough
H2- slight bronchodilation and increased mucus secretion
What are the effects of histamine on H1 receptors?
- decreased peripheral vascular resistance
- Increased vascular permeability
- Increased GI motility
What are the effects of histamine on H2 receptors?
- decreased peripheral vascular resistance
- Tachycardia (increased heart rate)
- Increased gastric acid and pepsin secretion
- Increased mucus production
What are the effects of histamine on H3 receptors?
stimulate nerve endings (pain)
What are the pathophysiological actions of histamine?
- mediates immediate hypersensitivity reactions and acute inflammatory responses
- causes anaphylaxis
- causes allergic reaction
- causes duodenal ulcers
- causes systemic mastocytosis
- causes gastrinoma
What is anaphylaxis?
- a type I allergic response mediated by IgE antibodies
- IgE binds to receptors on mast cells and basophils
- Antobody binds to antigen causing release of histamine, leukotrienes, prostaglandins etc
What are the effects pf anaphylaxis?
- decreased blood pressure
- decreased cardiac output
- bronchoconstriction 4. increased pulmonary secretions
- pruritis
How is anaphylaxis treated?
give epinephrine (a physiological antagonist of histamine, not a pharmacological one)
Three mechanistically different approaches
to minimize histamine reactions are…?
- physiological antagonism
- inhibit histamine release
- pharmacological antagonism
What drugs are given as mast cell stabilisers?
cromolyn
What drug is given as an H1 receptor antagonist?
diphenhydramine or cetirizine
What drug is given as an H2 receptor antagonist?
ranitidine or cimetidine
Properties of 1st generation H1 antihistamines?
- antiallergy
- sedative
- antimimetic (prevent motion sickness)
- antitussive
- given to treat anaphylaxis
- lipid soluble - good CNS penetration
- well absorbed
- metabolised in liver
adverse reactions of 1st generation H1 antihistamines?
- sedation
- drowsiness
- headache
- nausea
- vomit
- cough
- constipation
- diarrhoea
- dry mouth
- blurred vision
- urinary retention
Properties of 2nd generation H1 antihistamines?
- lipid soluble
- highly ionised functional group so less CNS penetration
- well absorbed
- metabolised in liver
adverse effects of 2nd generation H1 antihistamines?
- terfenadine and astemizole prolong QT interval in cardiac cycle and they affected the K+ channels. However they are no longer supplied.
How are 2nd generation antihistamines excreted?
in their unmetabolised form in urine.
