Autocoids: Histamine, Serotonin, and Receptors

Autocoids Overview

• Autocoids are the focus
• Histamine, serotonin, eicosanoids, and autonomic nervous system drugs are discussed

Histamine

• Histamine is also known as beta imidazole ethyl amine
• It's produced by basophils, transforming into mast cells extracellularly, which produce histamines
• Histidine is the major source
• There are two main receptors: histamine 1 and histamine 2 antagonists

Histamine Antagonists

• Prototype histamine 1 antagonist: Diphenhydramine is present as an immune response
• Prototype histamine 2 antagonist: Cimetidine is present in the gastrointestinal tract, mostly in acid

Serotonin

• Serotonin, the happy hormone, regulates mood
• Tryptophan is a major source; it undergoes decarboxylation acted upon by hydrolase to produce 5-hydroxytryptamine

5-Hydroxytryptamine Receptors

• 5-Hydroxytryptamine 1A (5HT1A) is located presynaptically and inhibits the release of certain neurotransmitters
• 5-Hydroxytryptamine 1D (5HT1D) is located in peripheral blood vessels and causes vasoconstriction
• 5-Hydroxytryptamine 2A (5HT2A) is located in smooth muscles, particularly in vascular and uterine smooth muscle and causes contraction
• 5-Hydroxytryptamine 3 (5HT3) is located in the CTC (chemo receptor trigger zone) and causes emesis
• 5-Hydroxytryptamine 4 (5HT4) is located in the GIT and promotes peristalsis

Other Components

• Bradykinin, if present, causes caffeine-like effects

Eicosanoids

• Prostaglandins include prostaglandin E1, E2, and F2
• Leukotrienes mainly cause inflammation and bronchoconstriction
• Prostacyclin PG12 and thromboxane TXA2 are present
• Prostaglandin, prostacyclin, and thromboxane are products of eicosanoids through the action of the enzyme "cyclooxygenase" pathway

Anti-Histamines

• Anti-histamines block or affect histamine receptors
• Histamine 1 antagonists block histamine receptors, especially in mast cells, acting against allergy
• There are two generations of antihistamines

First Generation Anti-Histamines

• The main action is to compete pharmacologically to block peripheral and CNS histamine 1 receptors, including some muscarinic receptors; they are used for allergic reactions, but also cause anti-motion sickness effects
• Examples include hay fever, allergic rhinitis, angioedema, motion sickness, and dystonia
• Classified as ethanolamines which are the most sedating, with significant anticholinergic effect, and are mostly used as sleeping pills and management to EPS (extra pyramidal syndrome)
• Diphenhydramine is also topical with calamine
• Doxylamine (generic: unisom) and diphenhydramine (generic: Benadryl) are included
• Ethlenediamine has piperosin, emedazoline, and pinotiacin
• Pyrilamine is a drug
• Piperazine acts as anti-motion sickness
• Hydroxyzine (Iterax), Meclizine (bonamine), and Cyclizine are drugs
• Alkyl Amine can also be used as an adjunct to cold medication
• Brompheniramine, phenylephrine, chlorpheniramine (brand: antamine), and Bioflu are drugs
• Phenothiazine acts as an anesthetic
• Promethazine (Phenergan) is a drug
• Cyproheptadine is used for serotonin syndrome and has a 5HT receptor blocking capacity

Second Generation Anti-Histamines

• Unlike 1st generation antihistamines, they competitively block to histamine receptors to CNS and peripheral
• 2nd generation antihistamines only affect the periphery, with most losing the sedating property leading to a loss of the anti-motion sickness effect

Categories of Second Generation Anti-Histamines

• Less sedating: Cetirizine (Zyrtec), Acrivastine (if you have benadryl allergy)
• True non-sedating antihistamines: Loratadine (alerta,claritin)- antihistamine allowed to pilots, Fexofenadine (telfast) - also recommended to pilots, Desloratadine (airius), Levocetirizine (xyza)

Histamine 2 Anti-Histamines

• They Known in practice as H2RA (Histamine 2 receptor antagonist)
• Location: Parietal cells that have acid regulation capacity
• Potency (most to least): Famotidine (H2Bloc) and Nizatidine (axid)
• Oral drugs that have high bioavailability, Ranitidine (zantac/ulcin), & Cimetidine (tagamet)
• Prototypes of cimetidine is first but potency cimetidine is the least

Serotonin Drugs

• 5HT1A PA (partial agonist)
• Buspirone (buspar) is an anxiolytic to treat anxiety
• 5HT1D FA (full agonist)
• Sumatriptan can treat migraines or cluster headaches, as well as Naratriptan, zolmitriptan, and rizatriptan
• 5HT2A A (agonist): Ergotamine methylergometrine / methergine / ergonovine will provide treatment for birth
• 5HT2A AT (antagonist): Ketanserin treats hypertension or carcinoid tumors
• 5HT3 antagonist: Granisetron(kytril), Ondansetron (Zofran) treats Chemotherapy or post operative vomiting. Higher forms of anti emetic medicine
• 5HT4 agonist: Tegaserod (Zelnorm) a partial agonist, that helps cell norm medication, and treats constipation-dominant IBS

Prostaglandins & Other Eicosanoids

• Leukotrienes: are antagonists that consist of lipooxygenase inhibitors
• Zileutin treats asthma propylaxis
• Montelukast and Zafirlukast treat asthma propylaxis
• A side effect is Churg Strauss syndrome (eosinophilic vasculitis)

Other Drugs

• Thrombaxane: platelet aggregation or vasoconstriction
• Prostacyclin PG12: Epoprosterol acts as a vasodilator in pulmonary hypertension. Also has anti-platelet activity
• Prostaglandins PGE1: Alprostadil treats (erectile dysfunction), & Misoprostol (cytotec) is a cytoprotectran that treats severe ulcer disease & will aid your production of mucus to protect the gastrointestinal wall
  • Abortifacient effect (pampalaglag) associates with uterine cramping activity
• PGE2: Dinoprostone will terminate a pregnancy to 12 weeks of life to the 2nd trimester or cervical ripening. Drug use: evening primerose oil that is inserted in vaginal and used for cervical ripening with operation with cervix
• Oral capsule drug used for excessive menstruation: Tranexamic acid
• PGF2: Latanoprost used to treat glaucoma, increases outflow of AQUEOUS humor

ANS (Anatomy and Physiology) and AntiNicotinic

• ANS: Consist of 2 neuron system & a presence of a ganglio outside of the ANS
• Nervous System Divide: 2 neuron system
  • Central Nervous System: Brain & Spinal cord
  • Peripheral Nervous System: Other neurons that is placed outside / side of the brain and spinal cord
    • Division of PNS: Afferent & Efferent
      • Afferent: path of signal direction of the information will come from the periphery to the CNS
      • Efferent: the signal in direction comes from the CNS to the periphery
        • Types of Efferent: Somatic & Autonomic
          • Somatic: Involves voluntary movement (skeletal muscles)
          • Autonomic: Involuntary Function (Muscles or Organs)
        • Autonomic Divided Into: Enteric, Sympathetic, & Parasympathetic
          • Enteric: control gastric secretion ( Increase Gastric Secretions)
          • Sympathetic: information transform is from CNS to the ganglia closer to the spinal cord
          • Parasympathetic: Information coming from CNS that goes through lower portion of spinal cord
            • Ganglia is farther from the sympathetic

Parts of the Synapse

• How the neurotransmitter synthesizes & transfers from the presynapse to the postsynaspe
  • Presynapse: synthesizes, releases, and stores neurotransmitters [pre-synaptic receptors (Receptor intention to modulate)]
    • Circle with activity use as storage are called Vesicles: Calcium the neurotransmitter will go out from vesicles
  • Synaptic Cleft: Presence of enzymes modulates to convert with component source that is Acetylcholinesterase
  • Post Synapse: neurotransmtter binds to receptors and renders an activity of effect
• Cranial Nerves: Nerves affected in periphery
  • Olfactory , Optic , Oculomotor, Trochlear, Trigeminal, Abducens, Facial, Vestibulocochlear/Auditory, Glossopharyngeal
  • Also includes: Vagus Nerve, Accessory Nerve, & Hypoglossal Nerve

Autonomic Nervous. System Characteristics

• Sympathetic: Flight & Flight System
  • Target organ/neuroeffector: Alpha 1, Alpha 2, Beta 1, Beta 2
• Parasympathetic (Cholinergic): Rest and Digest
  • Autonomic Nervous System: Parasympathetic Division
    • Pupils constrict
    • Salivation
    • Airways constrict
    • Heart rate slows
    • Stomach digests
    • Intestines digest
    • Bladder constricts
    • Reproductive system increases blood flow

Autonomic Nervous System

    - Symptoms to Anticholinergic Poisoning: 
         - Red as a Beet
         - Blind as a Bat
         - Dry as a Bone
         - Full as a Flask
         - Hot as Hades
         - Tachy as a Train
         - Mad as a Hatter
    - Signs of Cholinergic Crisis: DUMBELLS
         - Diarrhea (and Diaphoresis) and abdominal cramping
         - Urination
         - Miosis (pinpoint pupils)
         - Bradycardia (muscarinic) or Tachycardia(nicotinic
         - Emesis (Nausea and Vomiting)
         - Lacrimation
         - Lethargy
         - Salivation

Adrenoceptor (ANS receptor)

• Cholinoceptors & Adrenoceptors & Dopamine Receptors
• Adrenoceptors: Binds neurotransmitters to sympathetic
• Adrenergic Receptors:
  • Alpha: located in vascular smooth muscles (Presynaptic Nerve Terminals, blood platelets, fat cells, & neurons in the brain)
    • Ex. prostate, eyes, pilomotor (hair cells)
      • (pilomotor: with alpha agonist there is goosebumps)
  • Beta: mostly found in smooth muscles which control involuntary movement [cardiac muscle (pre synaptic nerves, fat cells)] -Beta 1: Kidneys ( Increase in Renin) -Beta 2: Smooth Muscles (like organs) -Beta 3: Adipose
• Dopamine (1,4): Renal, Splanchnic Nerve, Presynaptic Nerve Terminals

Cholinoceptors location to the ANS

• Parasympathetic (Muscarinic): - location: nerve impulse nerve ending (nerve 1) & heart (nerve 2) - M1 Location: Nerve ending, M2: Heart, M3: smooth(Eyes/Lungs/Exocrine Glands) -Muscarinic location controls eyes, lungs, & exocrine glands
• Nicotinic location Ganglia & Skeletal Muscles: - Ganglia ANS & CNS (NN) - Skeletal Muscles (NM)

Autonomic Drugs

• Sympathetic Drugs (right of Flight) -All the intrisic activity of the sympathetic are being manifested by the sympathomimetics
• Adrenergic Agonist (Sympathomemtrics): Direct Acting Adrenergic Agonist
  • Types (Selective & Non-Selective)
• Mimics activity to the sympathetic receptors
• Binds Alpha, Beta, Dopamine
• Natural Catecholamines: If affinities that is low to the usual dose prefer beta receptors other than alpha receptors. -Epinephrine (Cardiac Stimulant) - used for cardiac life support anaphylaxis -Epi & Lidocaine controls local vasoconstriction effect -Norepinephrine (inotropic effects) - controls septic shock (shock with related in sepsis /infection in blood) -Dopamine (bronchodilator): controls acute asthma attacks -Selective Agonist has preferred receptors (Beta1 and beta 2)

Types Selective Agonists

• Beta 1 Selective Agonist: Dobutamine (controls Cardiogenic Shock/Acute Heart failure)
• Beta 2 Selective Agonist: Isosxuprine (to delay premature labor in the uterus) Terbulatine ( for asthma + COPD) Short term Beta 2 Agonists / for Asthma

Non selective Agonists

• Beta- Beta Selective Agonsist
• Isoproterenol (for shock and acute heard Failure)
• ALPHA1- selectively controls -decontaminants & management hypotention, local vasoconstrictors
• Alpha 1- nasal, Phenylephrine, management arrhythmia (methoxamine)

Types Alpha Agonsist

• Alpha Selective agonsist (Clonadine) for management of hypertension
• Methyl dopa -for hypertensive pregnant women with tests for hemolytic anemia
• Guanfacine for emergency Hypertentsion
• Dopamine Selective Agonsist Adjuncts -Phentolodopine , adj treatment alt for hypotensive criss and vasodilatros
• Indirect Acting ANDRinergic Agonists and Angtagonists of Norepinephrine with overuse from hypertentsitns to tochycorida

Centrally Action

• Ampetamine is used for ADHD
• Treatment- Methylphenidate with high dose of ADHD
• Phentermine: with components that increase in slimming by -Suppresses appetite and PPA
• Adrenergic Antag & Agonist

Classification Alpha Blockers (Selective)

• Prazosin - vasodilator; hypertension
• Doxazosin - for hypertension
• Tamsulosin - urinary retention related to BPH

Selective and Non-Selective Alpha Blockers

• Selective: Yohimbine - for erectile dysfunction
• Non-Selective: -Phenoxybenzamine -Irreversibly non-selective -Phentolamie- For hypertenssion/reversible

Beta Blockers

• Selective: Beta 1 selective and acts on heart & Bisoprolol for hypertension and Acebutolol
• Non-Selective: Beta1&2 acts on Acebutolol
• Intrinsic sympathomimetic agonist (ISA) effect drugs = Carteolol , Labetalol, AcebutololPindolo
• Intrisnc stabilizing Membrane activity relating to arrhythMia drugs = Pindolol Propranolol Acebutolol Labetalol & Metoprolol

Mixed Alpha/Beta Blocking Activies

• Labetalol and Carvedilol
• Autonomic Drugs with ParaSympathetic is to Rest and digest

Cholinergic Agonist

• stimulate receptors

• Neurotransmitter 0 Acetylchoine

• Choline Ester

• enzyme that degrades with the Acetylcholinesterase A-cetylvhokune prototype of C esters

• Drug resist: Acetylchoninsterase with Methaonline the diagnosis the drug treatment / Carbacnal is topical for glaucoma treatment

Cholinergic Alkaloids Uses

• Pilocarbine- Motic & constrict and saliva by sjogren programming treatment with Arecholine (betal nut, filipino and muscarine
• comes from mushroom with Nicrtone treatment for covulusion

Actions for Cholinergic Agonist

• Short acting- Diagnosis with edrophoinum for mysthenia gravis
• Intermediate to long acting drugs: Neostigmine / Phisostigmine (antidotes for atroopine poisining for myasthenia gravis and reversal with Pyridostigmine for mysthenia gravis as well

Long Acting action for Cholinergic Agonist

• Used for: long acting with Organophosphates -used as scabicides with echophiate for open glaucoma and malathon fro insecticide and parabon

Indirect action

• 1st line treat
  • used for Alzhimers
  • and for Revastigmine.tcrine ,
  • 2nd line treat
  • is to know synthezing Tyrosine for actetachonne that builds by acetyle choline

Cholinergic Agonist and ParaSympatholytics

• Antimusclarinic Based Use for Cnd
• Used motion sickness by scopolamine and for parkinsons disease
• Drug of choice in parkinson, use Biperden, etc and for Levodopa treatment for Parkinson's w

Mydriatic-Cyclopeic Drugs affect ciliary muscle = dilation of pupils

Atropine or cholestetric and the anti- muscariic and will treatment for tachycardia for patient with bradycardia and Homoatropie

• Brochodialotors will increase the effects of the lungs (ipratropium +tiotrooprium treatment with hydroacciditiy
• Antinicotnic
• Mucleular blockers
• Successcinholat

•  main effetc maligant hyper with danrtolie is antidote and ISauquinl derivatives
  

• ( Atracrirum, vMicavium, StendiolDeratives.Pancurcnium, .veconiuim +Ganglonic Bloccckers Hexamrthoiium Nuecamul amine to toxin
• Cholinergic regenerator
• Praldiome : is for organs poison