Derm/Otolar/Rheum: Week 4 (Exam 1)

_______

• Tretinoin or (all-trans-retinoic acid; ATRA) is the acid form of vitamin A (mimic at high concentrations)

• Used topically for Acne Vulgaris

• Targets: nuclear receptors RAR + RxR.

Retinoic Acid

_______

• 3rd Gen retinoid specific for RAR.

• Used as a cream for acne and is efficacious in mild forms of psoriasis

Tazarotene

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_______

• Used orally for severe cystic acne.

• Teratogenic

Isotretinoin

_______

• Accompanied by Sxs of hypervitaminosis A, including skin dryness, itching, lipid abnormalities (increased triglycerides + LDL

Isotretinoin

RA Ligand → _______

_______ → recruits the enzymes that express genes

Vitamin A/drug, Co-Activators

Retinoic Acid and Derivatives:

• _______

• _______

Acitretin, Etretinate

_______: Oral formulation → severe psoriasis

• A 2nd gen retinoid that is thought to work in psoriasis via inhibition of keratinocyte proliferation.

Acitretin (Soriatane)

_______

• An active acid metabolite of Etretinate

• Both are agonists on the retinoid receptors

Acitretin

_______

• Less lipophilic

• Elimination t_1/2: 2-4 days

• >98% eliminated 2 months → conception after treatment

Acitretin

_______

• Small amounts converted to Etretinate; accelerated by alcohol (C/I bc of the risk of acceleration of acid treatment = highly lipophilic = Etretinate = problems following conception)

Acitretin

_______ (came to the market 1st)

• Highly lipophilic

• Elimination t_1/2: >120 days

• >98% eliminated 2 or more years

Etretinate

_______

• Metabolized to Acitretin

• Drawback: Women cannot get pregnant

Etretinate

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_______ - Modulating Agents

• Coal tar → Activates TF

• This signaling is important to skin homeostasis.

• This responds to various endogenous + exogenous ligands → diverse biological effects.

Aryl Hydrocarbon Receptor

_______

• Tapinarof binds to this receptor + downregulates ____ production, oxidative stress + increases barrier protein production.

Aryl Hydrocarbon Receptor, IL-17

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_______

• A chronic inflammatory arthritis (joint inflammation) in association with skin psoriasis.

• Distinct from RA: usually RF and ACPA negative.

Psoriatic Arthritis

_______

• IL12/23-Th17 axis → important role of pathogenesis

• Th17 drives psoriasis → migrate into skin + joints → inflammation in both!

Psoriatic Arthritis

_______

• Inhibitors of this axis + anti-TNF-alpha drugs are commonly used to manage this.

Psoriatic Arthritis

_______ Pathophysiology

• The accepted model for pathogenesis involves a trigger e.g. UV light, bacteria or viral infections. 

• Cell apoptosis related to UV or viral/bacterial infections → nucleic-acid mediated immune response via activation of dendritic cells (DC) + B cells

Systemic Lupus Erythematosus

SLE

• Systemic: _______ + _______

• Mouth + Nose: _______

• Muscles: _______

• Face: _______

low-grade fever, photosensitivity, ulcers, aches, butterfly rash

• _______ → non-erosive arthritis involving 2 or more peripheral joints characterized by tenderness, swelling, or effusion

• _______ → Cellular casts may be red cell, hemoglobulin, granular tubular or mixed

Arthritis, Renal d/o

Drug-induced lupus Erythematosus (DILE): HPI

• Most commonly encountered with:

  • _______

  • _______

  • _______

Hydralazine, Procainamide, Isoniazid

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_______ is an endogenous mediator as a member of the group “Autacoids (very short half-life)”.

Histamine

Key aspects of histamine:

• Bioactive _______ synthesized from _______ (activated _______ → dump out _______).

• Released to produce local effects (both centrally/NT/dual roles + peripherally/allergic rxn)

• Role of Histamine:

  • _______

  • Regulation of _______ secretion in the stomach

  • _______ + _______ of NT release

amine, histidine, mast cells, histidine, immediate allergic response, basal acid, NT, modulator

What is the image showing?

Biosynthesis and Metabolism of Histamine

Gell-Coombs Classification of Hypersensitivity Reactions

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Type __ (__-Mediated) KNOW!

• Drug-__ complex binding to mast cells with release of histamine, inflammatory mediators

• Form __ + anchors itself on the mast cells → degranulation of mast cells → releases histamine → causes allergic reactions

• Can be mild (bronchoconstriction, itching, runny nose) or massive (can be fatal if not medically treated)

I, IgE, IgE, IgE

Type-__ (cytotoxic)

• Attaches itself to cell surfaces + immune cells come in to destroy antigens presented on the cells

• IgG or IgM

• Ex. Heparin-Induced Thrombocytopenia

II

Type-__

• Antigen with Ab → blood migrates to the tissue → tissue destruction

• Ex. SLE

III

Type-__ (poison ivy, contact dermatitis)

• T-cell mediated reaction confined to the skin, hypersensitivity

IV

Histamine: Triple Response of Lewis

• Intradermal injection of histamine causes:

  • _______: Appears within a few seconds and maximal at 1 min (Direct Vasodilator Effect of H1 receptor mediated by NO production).

  • _______: develops more slowly due to histamine-induced stimulation of neuronal reflex causing vasodilation (indirect effect).

  • _______: Swelling at 1-2 min at injection site: Histamine effect on blood capillaries increasing permeability.

Red spot, flare or red flush, wheal

Clinical Symptoms Associated With Histamine Release

• Mild/_______ → erythema, urticaria, and/or itching

• _______ → skin rxns, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress

• Severe/_______ → severe hypotension (peripheral vasodilation), ventricular fibrillations (high HR), cardiac arrest, bronchospasm, respiratory arrest

Cutaneous, Mild to Moderate, Anaphylactic

Histamine Receptors

• 4 subtypes, named H1, H2, H3, and H4.

• All four receptors are _______.

• Outcomes of receptor activation

  • Activation of _______ receptors causes:

    • Itching stimulates secretion from nasal mucosa

    • Contraction of bronchial smooth muscles

    • CNS: _______ receptors inhibit appetite + increase wakefulness

      • Increase in Appetite → weight gain

    • _______ + _______: Cooperate to induce vascular capillary dilation

    • _______: Increased vascular permeability

GPCRs, H1, H1, H1, H2, H1

Histamine Receptors

• Activation of _______ receptors causes:

  • Gastric acid secretion + receptors may work with _______ receptors in certain types of hypersensitivity reactions

H2, H1

Histamine Receptors

• Activation of _______ receptors causes:

  • Presynaptic receptors function as autoreceptors for histaminergic neurons

  • _______ receptor antagonists promote wakefulness.

H3, H3

Histamine Receptors

• Activation of _______ receptors causes:

  • Chemotaxis of immune cells and secretion of proinflammatory cytokines

H4

_______ KNOW!

• G Protein Coupling (2nd messengers): Gq (increased cytosolic Ca2+, NO + cGMP)

• Distribution: Smooth muscle, endothelial cells, CNS

• Drugs that are Inhibitors of Receptor Activation: Antihistamines (1st + 2nd gens)

H1

_______

• G Protein Coupling (2nd messengers): GS (increased cAMP

• Distribution: 

• Drugs that are Inhibitors of Receptor Activation: Ranitidine

H2

_______

• G Protein Coupling (2nd messengers):

• Distribution: 

• Drugs that are Inhibitors of Receptor Activation: Pitolisant (indicated for narcolepsy)

H3

_______

• G Protein Coupling (2nd messengers):

• Distribution: 

• Drugs that are Inhibitors of Receptor Activation: N/A

H4

Physiological Histamine Antagonist

• _______: Antagonizes the effect of H1 mediated bronchial smooth muscle contraction + vasodilation.

• _______ receptor agonism: Vasoconstriction leading to increased SVR and reduction in mucosal edema

• _______ receptor agonism: Increased inotropy + HR (increases CO)

• _______ receptor agonism: bronchodilation + inhibition of further mediator release from mast cells

Epinephrine, alpha-1, Beta-1, Beta-2

Histamine Antagonism: _______

• Cromolyn Sodium and Nedocromil.

• MOA: Prevent _______ degranulation and release of histamine + other mediators.

• Uses: Allergic rhinitis, allergic eye conditions e.g. conjunctivitis, keratitis

Mast Cell Stabilizers, mast cell

• _______ Agonist → drug that produces opposite effect of agonist

• _______ (Histamine) → active state preferred

• _______ Agonist (AH) → inactive state preferred

H1 Inverse, Agonist, Inverse,

2nd Gen AH (can be given _______ → minimal ability to get into CNS

• _______: Cetirizine, Levocetirizine

• _______: Loratidine, desloratidine, fexofenadine

• Other: _______, _______ (available as nasal spray + eye drops), Acrivastine + Pseudoephedrine

during the day, Piperazines, Piperidines, Azelastine, Olopatadine

Pharmacological Uses of Antihistamines

• Other uses include (Allergic Rhinitis, Allergic Conjunctivitis, Urticaria/_______):

  • Management of _______.

  • _______

  • _______ associated with atopic _______

Hives, Cold sxs, eczema, pruritus, dermatitis

Adverse Effects of 1st generation AHs

• _______ Recetors

  • Decreased → alertness, cognitions, learning, memory, and psychomotor performance

  • Increased → impairment with or w/o sedation

• _______ Receptors

  • Increased → Dry mouth, urinary retention, sinus tachycardia

• _______ Receptors

  • Increased → Appetite, Weight gain

• _______ receptors 

  • Increased → dizziness, postural hypotension

• _______ (IKr, INa)

  • Increased → QT interval, ventricular arrhythmias

CNS H1, Muscarinic, Serotonin, Alpha-Adrenergic, Cardiac Ion Channels

Anticholinergic drugs _______ HR by increasing _______ node firing rate

increase, SA

Other Uses for 1st Generation AHs

• _______: N/V, dizziness

• Pathophysiology: mediated by the _______ (vestibular system) and increased cholinergic/histaminergic neurotransmission

motion sickness, inner ear

• Examples of drugs used to prevent motion sickness:

  • _______ (Muscarinic Receptor antagonist)

  • Meclizine, Dimenhydrinate (_______)

• Mechanism: 

  • _______ (vestibular system) → cholinergic + histaminergic neurons (H1 + M receptors [Histamins + ACh]) → _______ → _______ (Medulla) → _______

Scopolamine, 1st gen AH, inner ear, cerebullum, emetic center, N/V

Other Uses for 1st Generation AH (Due to anticholinergic properties)

• Management of acute dystonia associated with central _______

  • e.g. _______ (AH + ACh drug)

D2 receptor blockade, Diphenhydramine

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Non-Specific Immunosuppressants for SLE (MHA)

• _______ → oral DMOD, immunosuppressant effect

• _______ → DMOD  for RA

• _______ → immunosuppressive drug, prevent organ rejection

Methotrexate, Hydroxychloroquine, Azathioprine

1st Gen AH → _______ increase

Ciproheptidine → _______ stimulant

• _______ = allergic reaction of allergies + itching, increasing sedation + appetitive

HR, appetite, H1