Anti-Histamine Drugs

What are examples of biogenic amine NTs?

3 catecholamines:

• Dopamine

• Norepinephrine (noradrenaline)

• Epinephrine (adrenaline)

Other biogenic amines include: histamine and serotonin

What is histamine?

Histamine is a biogenic amine that acts as a signaling molecule in the periphery but also as a NT in the CNS

How is histamine produced? How is it metabolized/inactivated?

Decarboxylation of a.a. histidine by a histidine decarboxylase

Histamine methyltransferase and DAO

What class does histamine belong to?

Biogenic amine *test question

What produces histamine?

Produced by mast cells via allergic reactions or histaminergic neurons

What are histamine’s functions?

IgE mediated allergic reactions

Regulation of gastric acid secretion

Vasodilator

Where is histamine stored?

Secretory granules in mast cells

Enterochromaffin-like (ECL) cells in the stomach: released from ECL cells to activate parietal cells (secrete gastric acid)

Presynaptic vesicles in neurons (neurotransmitter)

Histamine role in normal physiology

Released during injury: (wound healing)

• Vasodilation leakage of inflammatory mediators

• Recruitment of immune cells

Stimulate gastric acid secretion

Neurotransmitter

• Controls neuroendocrine functions: body temperature, arousal, and cardiovascular regulation

Histamine receptors location and types

Endogenous ligand for family of 4 GPCRs

• H1 and H2 mediate most peripheral functions

  • H3 is in the brain, H4 in immune cells (mast cells)

H1 receptor activation can lead to:

Type I hypersensitivities

• Release of histamine from mast cells via H1

Histamine release in response to IgE mediated allergic reactions that is found in seasonal rhinitis (hay fever), urticaria (HIVES), angioedema

• excessive gastric acid secretion

  • mechanism: H2 receptor activation

When do mast cells release histamine?

During injury

Immunologic stimulated release

• antigen binds to mast cell

• complement cascade activation

Release by displacement

• bound to heparin, displaced by morphine

Histamine binds to what kind of receptors

All are coupled to G-proteins

Allergic Inflammation: H1 → Allergic Inflammation

Gastric Acid Secretion: H2 → gastric acid secretion

Neurotransmission: H3 → Neurotransmission

Immunomodulation: H4 → Immunomodulation

H1 receptor characteristics

H1 is a Gq coupled to PLC → Girk Inhibition

Expression: smooth muscle cells of airways, GI tract, cardiovascular system, endothelial cells

Responses: vasodilation, bronchoconstriction, endothelial cell, contraction, permeability, pain/itching nerve stimulation

epinephrine used to treat severe allergic rxns

histamine effect on endothelial cells vs smooth muscle cells

H1 is expressed in endothelial and smooth muscle cells

Histamine stimulates endothelial cell contraction

• cells separate, open gaps

• leakage of fluid and small molecules

• edema and hives (urticaria)

• this creates gaps so that inflammatory mediators can be released into the blood to recruit immune cells

Histamine mediates vasodilation in the smooth muscle

• via nitric oxide (NO) release by the endothelial cells

• flushing, headache

• decrease in blood pressure

Why is a pt experiencing stimulation of pain and itchiness?

• urticaria

• Gq-mediated post-synaptic response (GIRK inhibition)

h1 receptor effects on respiratory system

bronchoconstriction

usually insignificant except: allergy induced asthma and anaphylaxis

H1 immunity/inflammation

leakage of inflammation mediators and antibodies

H1 receptor effects Gi tract smooth muscle

contraction (large histamine doses may cause diarrhea)

h1 receptor effects uterus

contraction (anaphylaxis: miscarriage)

Describe

ON THE LEVEL OF ENDOTHELIAL CELLS

When histamine bind to receptors in the endothelial cells (closest layer to systemic circulation)

The endothelial cells will contract

Allows for the leakage for the inflammatory mediators (Like Nitric Oxide) to recruit more immune cells into the smooth muscle cells

Histamine stimulates endothelial cell contraction

and

Mediates Vasodilation

H2 receptor

effector; second messenger

expression

and function

Gs coupled to Adenylyl Cyclase

Expression: Gastric mucosa and parietal cells, cardiac muscle, mast cells, brain (post-synaptic)

Functions: gastric acid secretion, cardiac stimulation, negative feedback regulation of histamine release from mast cells

Cardiovascular H2 receptor effects

increase heart rate

contributes to anaphylaxis

direct stimulation, increased contractility, increased rate

Secretory tissue H2 receptor effects

secretion of gastric acid (enterochromaffin-like ECL cells —> parietal cells —> acid secretion)

H3

effector and second messenger

expression

functions

Gi coupled to AC

Also to N-type voltage gated Ca channels and reduce Ca influx

Expression: Brain (presynaptic)

Functions: Feedback inhibition of histamine synthesis and release; inhibits release of other neurotransmitters'; regulates food intake, body weight

h4

effector and second messenger

expression

function

Gi coupled to AC

expression: leukocytes

Function: chemotactic to immune cells

H1 antagonists would be used for

immediate allergic responses

h2 antagonists would be used for

gastro-intestinal disorders such as

Ulcers, heartburn, GERD

1st generation antihistamines are:

sedating or non-sedating

sedating

These cross the BBB and get into the brain

*exception is alkylamines; minimal sedation alongside 2nd gen

examples of ethanolamines

These are 1st generation (sedating histamines)

diphenhydramine, doxylamine, Dimenhydrinate, Carbinoxamine

examples of alkylamines

1st generation sedating histamines

Chlorpheniramine, brompheniramine

Alkylamines have the lowest BBB penetration

examples of piperazines in 1st generation

1st generation sedating histamines

meclizine, cyclizine, hydroxyzine

phenothiazines example

1st generation antihistamine (sedating)

promethazine

What is special about cyproheptadine

blocks H1 and 5HT receptors

2nd generation (non-sedating) examples

Piperazines: Cetirizine (different from the other 1st generations); cannot cross the BBB

Piperidines: Loratadine, Desloratadine, Fexofenadine

physiologic antagonist of histamine action

epinephrine for anaphylactic shock

Release inhibitors

Cromolyn, nedocromil: block activation of mast cells

Mast cell stabilizers

Selective competitive antagonists of histamine receptor H1 receptor

H1> > H3> H2

at a low dose of h1 antagonist, the drug will bind to H1 receptors

At a higher concentration, the drug will bind to h3 (brain) and H2 (GI)

What other effects do H1 receptors have

Antagonist effects at other receptors:

Anticholinergic Actions: Can block muscarinic (cholinoceptors) and a-adrenergic (adrenoreceptor) receptors

• Decrease secretions, relaxation of smooth muscles

Some can cross BBB: CNS depression, antimigraine, antivertigo, anti-motion sickness actions

5-HT receptor blockers: some antihistamines have additional anti-5-HT actions and can produce sedation, increase appetite, decrease itching

indications for H1 antagonist

Allergic reactions, immediate, IgE-mediated

• Inhibit H1 receptors on endothelial cells, nerves (pain/itch)

• Blocks response of various cells to histamine

drugs for

For allergic rhinitis (hay fever), urticaria (HIVES)

Alkylamines (chlorpheniramine, brompheniramine; lowest of the 1st)

and 2nd generation non-sedative drugs

2nd generation are just as effective with less side effects

Diphenhydramine is common even with sedation

can you use an h1 antagonist for angioedema?

Not effective when swelling is established; preventative only

h1 antagonist use for atopic dermatitis (eczema)

diphenhydramine, blocks itching

t/f h1 antagonists can be used for bronchial asthama

false; only allergic asthma

off-target effects from H1 antagonists are predominately mediated by

muscarinic blockade

Sedation is a signifiant side effect that is mediated in the CNS

sedation effects of diphenhydramine, dimenhydrinate, hydroxyzine, doxylamine, promethazine

++ sedation potential

sedation effects of carbinoxamine, cyproheptadine

+

sedation effects of cyclizine, meclizine

+-

sedation effects of brompheniramine, chlorpheniramine, all second generation

- -

H1 antagonists that can be used as sleep aids

doxylamine, diphenhydramine, promethazine

what h1 antagonists can you use for as anti-nausea medications

2nd generations are not useful due to limited CNS penetration

can be used for motion sickness, nausea with pregnancy/anti-emetic, chemotherapy nausea

medications used for motion sickness

Can use these for motion sickness:

dimenhydrinate, diphenhydramine, cyclizine, meclizine, promethazine

Not alkylamines

medications used for nausea with pregnancy

promethazine

NOT piperazines (teratogenic): cyclizine and meclizine

contraindication of cyclizine and meclizine

pregnancy; these are teratogenic

what are atropine-like effects on peripheral muscarinic receptors from H1 antagonists

Dry mouth, blurred vision

Greatest anti-cholinergic activity (M1 blockers)": carbinoxamine, dimenhydrinate, diphenhydramine, promethazine

what drug has adrenoceptor a inibition

promethazine ++

can cause orthostatic hypotension

what can cause serotonin receptor inhibition

cyproheptadine

what h1 antagonist can cause sodium channel inhibition

local anesthesia

diphenhydramine and promethazine are useful local anesthetics if ppts have allergy to lidocaine drugs

Adverse effects of H1 antagonists

excitation and convulsions in children (rare)

Drug allergies

Overdose: similar to atropine overdose: stimulation, agitation, convulsions, coma

CNS depression, drowsiness, sleep

• synergism/additive effect seen with other CNS depressants

Anticholinergic adverse effects (muscarinic blockade)

• Dry mouth, eyes, and respiratory tract, blurring vision, increase IOP, urinary retention, constipation

  • *less common with 2nd generation antihistamines

Histamine receptors are all

A. Ligand gated ion channels

B. G-protein coupled receptors

C. Expressed only in the periphery

D. Expressed only in the central nervous system

E. Activated by allergy drugs

B) G-Protein Coupled Receptors

Activation of beta-adrenergic receptors cause...?

A. Sedation

B. Vascular smooth muscle contraction

C. Heart muscle contraction

D. Bronchiolar smooth muscle contraction

E. Gastric acid secretion

A. Sedation

B. Vascular smooth muscle contraction

C. Heart muscle contraction (BETA)

D. Bronchiolar smooth muscle contraction

E. Gastric acid secretion

Which is not a normal physiologic function of histamine?

A. Wound healing

B. Control of gastric acid secretion

C. Neurotransmitter

D. Control immune response

E. Mood stabilization

E) Mood stabilization is NOT a function of histamine; it is a function of serotonin

The mechanism of anti-histamine overdose is....

A. Activation of H1 receptors

B. Inhibition of H1 receptors

C. Inhibition of H2 receptors

D. Inhibition of muscarinic receptors

E. Inhibition of adrenergic receptors

D. Inhibition of muscarinic receptors

Physiologic responses to H1 receptor activation following an injury include:

A. Vasoconstriction

B. Bronchodilation

C. Secretion of gastric acid

D. Activation of pain and itch sensory nerves

E. All of the above

D. Activation of pain and itch sensory nerves

C) Gastric acid is H2

Which of the following H1 antagonists has the lowest level of CNS distribution?

A. Diphenhydramine

B. Doxylamine

C. Promethazine

D. Fexofenadine

E. Dimenhydrinate

D. Fexofenadine

2nd generation