Elsaid - pharmacology of antihistamines (copy)

HL

what is a histamine?

• an endogenous mediator as a member of the group “Autacoids”

• key aspects of histamine:

  • bioactive amine synthesized from histidine

  • release to produce local effects (both centrally and peripherally)

  • role of histamine:

    • immediate allergic response

    • regulation of basal acid secretion in the stomach

    • neurotransmitter and modulator of neurotransmitter release

      • neurons release histamines as NTs —> block histamine signaling in the brain —> drowsiness

type I immune reaction

IgE-mediated — histamine plays an important role

mechanism:

• drug-IgE complex binding to mast cells with release of histamine, inflammatory mediators

  • mast cells are immune cells with histamines and mediators inside

  • located in mucous membranes like skin and pulmonary

clinical manifestations:

• urticaria (hives), angioedema, bronchospasm, pruritis, vomiting, diarrhea, anaphylaxis

timing of reactions:

• minutes to hours after drug exposure

type II immune reaction

cytotoxic

mechanism:

• specific IgG or IgM antibodies directed at drug-hapten coated cells in the blood

clinical manifestations:

• hemolytic anemia, neutropenia, thrombocytopenia

  • hemolytic anemia — drug bound to RBC —> antibodies directed against RBC

timing of reactions:

• variable

type III immune reaction

immune complex

mechanism:

• tissue deposition of drug-antibody complexes with complement activation and inflammation —> tissue damage

clinical manifestations:

• serum sickness, fever, rash, arthralgia, lymphadenopathy, urticaria, glomerulonephritis, vasculitis

• antibodies in the renal tissue (glomerulus) —> inflammation and destruction of glomerulus

timing of reactions:

• 1 to 3 weeks after drug exposure

type IV immune reaction

delayed, cell-mediated

mechanism:

• MHC presentation of drug molecules to T cells with cytokine and inflammatory mediator release

• lot more significant than type 1

clinical manifestations:

• allergic contact dermatitis, maculopapular drug rash

timing of reactions:

• 2 to 7 days after cutaneous drug exposure

histamine: triple response of Lewis

intradermal injection of histamine causes:

• red spot: appears within few seconds and maximal at 1 min (direct vasodilator effect of H1 receptor mediated by NO production)

  • vasodilation of capillaries in the skin —> increased blood flow —> redness

• flare or red flush: develops more slowly due to histamine induced stimulation of neuronal reflex causing vasodilation (indirect effect)

  • stimulation of neural endings —> itching

• wheal: swelling at 1-2 min at injection site: histamine effect on blood capillaries increasing permeability

  • increased permeability —> fluid going into eh tissue —> swelling

mild/cutaneous histamine release symptoms

erythema, urticaria, and/or itching

mild to moderate histamine release symptoms

• skin reactions

• tachycardia (reflex of vasodilation)

• dysrhythmias

• moderate hypotension (bc of vasodilation)

• mild respiratory distress (histamine causes bronchoconstriction)

severe/anaphylactic histamine release symptoms

• severe hypotension (bc of vasodilation)

• ventricular fibrillations (heart trying tot pump more blood to make up for vasodilation)

• cardiac arrest

• bronchospasm (direct bronchoconstriction)

• respiratory arrest

histamine receptors

4 subtypes:

• H1, H2, H3, and H4

all four receptors are G-protein coupled receptors

activation of H1 receptors causes:

• itching, stimulates secretion from nasal mucosa

• contraction of bronchial smooth muscles —> respiratory distress

• CNS: H1 receptors inhibit appetite and increase wakefulness

• H1 and H2: cooperate to induce vascular capillary dilation

• H1: increased vascular permeability —> swelling

activation of H2 receptors causes:

gastric acid secretion and H2 receptors may work with H1 receptors in certain types of hypersensitivity reactions

activation of H3 receptors causes:

• presynaptic H3 receptors function as auto receptors for histaminergic neurons

  • autoreceptors = pre-synaptic receptor —> regulates histamine release (stops histamine release once it senses there is enough)

• H3 receptor antagonists promote wakefulness

activation of H4 receptors causes:

chemotaxis of immune cells and secretion of pro inflammatory cytokines

H1 receptors

G protein coupling (second messengers):

• Gq — increased systolic Ca2+, increase NO and cGMP

distribution:

• smooth muscle

• endothelial cells

• CNS

drugs that are inhibitors of receptor activation:

• antihistamines (1st and 2nd generation)

H2 receptors

G protein coupling (second messengers):

• Gs — increased cAMP

distribution:

• gastric parietal cells

• cardiac muscles

• mast cells

• CNS

drugs that are inhibitors of receptor activation:

• ranitidine — NOT on the market anymore

H3 receptors

G protein coupling (second messengers):

• Gi — eduction in cAMP

distribution:

• CNS

• pre and postsynaptic

drugs that are inhibitors of receptor activation:

• Pitolisant (indicated for narcolepsy)

H4 receptors

G protein coupling (second messengers):

• Gi — reduction in cAMP, increase in Ca2+

distribution:

• cells of hematopoietic systems

drugs that are inhibitors of receptor activation:

• N/A

epinephrine

physiologic antagonist —> physiological effect (does NOT act on the same pathway)

antagonizes the effect of H1 mediated bronchial smooth muscle contraction and vasodilation —> DOC for anaphylaxis

• 𝜶1 receptor agonism: vasoconstriction leading to increases SVR (systemic vascular resistance) and reduction in mucosal edema

• β1 receptor agonism: increased inotropy and HR (increases CO)

• β2 receptor agonism: bronchodilator and inhibition of further mediator release from mast cells

  • Norepinephrine does NTO effect bronchial smooth muscle —> NOT DOC

cromolyn sodium and nedocromil

mast cell stabilizers —> histamine antagonism —> reduce histamine release

MOA: prevent mast cell degranulation and release of histamine and other mediators

H1-Antihistamines (H1 inverse agonists)

• an inverse agonist —> does NOT compete with histamine for the same receptor

  • NOT receptor antagonist

• histamine (agonist) binds to active receptor and stabilizes the active conformation —> shifts the equilibrium to more active state

• antihistamine (inverse agonist) binds to inactive receptor conformation —> shifts the equilibrium to more inactive state (less active state available)

1st vs 2nd generation antihistamines side effects

1st generation:

• lipophilic —> goes into CNS —> drowsiness

• lots of targets —> more side effects

2nd generation:

• acts in PNS and can NOT get into CNS —> less drowsiness

• more specific for H1

1st generation antihistamines

• Alkylamines:

  • Chlorpheniramine

• Piperazines:

  • Hydroxyzine, Meclizine, Cyclizine

• Piperidines:

  • Cyproheptadine (has serotonin antagonists properties: used as appetite stimulant and in management of serotonin syndrome)

• Ethanolamines:

  • diphenhydramine, dimenhydrinate, doxylamine

• Phenothiazine:

  • promethazine

• Other:

  • Doxepin (also classified as TCA)

2nd generation antihistamines

Piperazines:

• Cetirizine, Levocetirizine

Piperidines:

• Loratidien, Desloratidine, Fexofenadine

Other:

• Azelastine, Olopatadine (available as nasal spray and eye drops)

pharmacological uses of antihistamines

• allergic rhintiis

• allergic conjuctivitis

• urticaria (hives)

• management of cold ysmtpoms

• eczema

• pruritus (itching) associated with atopic dermatitis

1st generation antihistamines ADEs

CNS H1 receptors:

• ↓ alertness, cognition, learning, memory, and psychomotor performance

• ↑ impairment with or without sedation

Muscarinic receptors (cholinergic):

• ↑ dry mouth

• ↑ urinary retention

• ↑ sinus tachycardia

serotonin receptors:

• ↑ appetite

• ↑ weight gain

𝜶-adrenergic receptors:

• ↑ dizziness

• ↑ postural hypotension

• ↑ reflex tachycardia

cardiac ion channels (IKr, INa, and others):

• ↑ QT interval

• ↑ ventricular arrhythmias

how do anticholinergic drugs increase heart rate?

by increasing SA node firing rate

sympathetic nerves

norepinephrine binds to β receptor and stimulates sympathetic nerves —> increases HR

• Ca2+ also going into the cell through the channel ICa

parasympathetic (vagal) nerves

ACh binds to m2 receptor —> decreases HR

• K+ also going out of the cell through the channel IKACh

β-blocker effect on HR

β-blockers block β1 receptor —> sympathetic pathway not active and only parasympathetic pathway active —> decrease HR

anticholinergic effect on HR

anticholinergics like Atropine and Benadryl blocks ACh from binding to m2 receptor. —> parasympathetic pathway not active and only sympathetic pathway active —> increase HR

other uses for 1st generation antihistamines

• motion sickness: nausea & vomting, dizziness caused by motion

• management of acute dystonia associated with central D2 receptor blockade

pathophysiology of antihistamines used for motion sickness

mediated by the inner ear vestibular system) and increased cholinergic/histaminergic neurotransmission

• cholinergic and histaminergic neurons (H1 and M receptors) in the inner ear (vestibular system) release ACh and histamines to the cerebellum to the emetic center (medulla) —> causes nausea and vomiting

examples of drugs used to prevent motion sickness

• Scopolamine (muscarinic receptor antagonist)

• meclizine and dimenhydrinate (1st generation antihistamine)

  • 2nd generation can NOT be used bc they cannot get into the CNS

1st generation antihistamines used for management of acute dystonia

management of acute dystonia associated with central D2 receptor blockade

e.g. diphenydramine

1. Degeneration of DA cells in Parkinson’s disease removes the inhibitory influence on the ACh neuron so ti fires more often, causing the movement disorder

2. Dopamine binds to DA receptors normally inhbitors the cholinergic cell. Blocking these receptors lead to the same motor effects as degeneration of the cells in Parkinson’s disease

3. Anticholinergic drugs block ACh receptors and reduce Parkinsonian symptoms