Autacoids

Autacoids

Definition

·         Autacoid is derived from two word Autos means “Self” and Akos means “healing substance”.

·     Autacoids are the biological substance that release from the cell is response to variety of stimuli to produce physiological and pathological responses locally.

·         A hormone called local hormone that are produced by specific cells, and transported through circulation to act on target tissue.

Classification of Autacoid

1.      Amine Autacoids

§  Histamine, 5HT (Serotonin)

2.      Lipid derivatives autacoids

§  Prostaglandin, leukotriene, platelet activating factor

3.      Peptide autacoids

§  Plasmakinins (Bradykinin), angiotensin

Histamine

·         Histamine is an organic nitrate compound (Formed from amino acid histidine), which is involved in:

o   Immune response (allergic and immune response)

o   Resulting physiological function

o   Acting as a neurotransmitter

·         It is a naturally occurring imidazole derivatives.

·         It is produced by endogenously by decarboxylation of amino acid histidine in the presence of enzyme histidine decarboxylase.

·         Histidine is stored in the granules of mast cells, basophils and histaminergic neuron of CNS.

·         The highest concentration of histamine is present in lungs, skin, mucosal layer of GIT and intestine, liver and placenta. Histamine is also present in blood, most body secretions, venoms and pathological fluids.

Synthesis of Histamine

·         It is synthesized locally from the amino acid histidine by the enzyme histidine decarboxylase. It is degraded by oxidation and methylation.

Release of histamine

·         Allergies and anaphylaxis trigger significant release of histamine

·         When allergies enter into the body that results trigger immune cells to produce large IgE.

·         Some IgE attaches to the surface of mast cell (sensitized). On any subsequent exposer to the same allergen, the allergen interact with the specific IgE on the surface of the mast cells.

·         In response, the activated mast cell rapidly release histamine.

Receptors of histamine

Receptors

Location

H1 receptor

CNS, Smooth muscle, Cell of airway, GIT, Cardio vascular system, Endothelial cell, Lymphocyte.

H2 receptor

Parietal cell, Vascular smooth muscle cells.

H3 receptor

CNS, PNS.

H4 receptor

Bone marrow, Immune cells.

 

Pharmacological or physiological effect of histamine

a)      Blood vessel

·         Histamine causes marked dilatation of smaller blood vessel including arterioles, capillaries and venules.

·         Large arteries and veins are constricted by histamine mediated by H1 receptor on vascular smooth muscles.

b)     Activation of H1 receptor

·         Decrease vital capacity

·         Bronchoconstriction

·         Spasmodic contraction of ileum

·         Contraction of uterus

c)      CVS

·         H1 and H2 receptor dilate the arterioles and post capillary venules, so BP decrease.

d)     Gastric HCL

·         Increase stimulation of gastric acid secretion by H2 receptor.

·         In large dose release of pepsin.

e)      Nervous system

·         Parenteral administration of histamine produce itching and pain.

f)       Mucous

·         Histamine increases the nasal secretion and respiratory tract mucous secretion.

g)      Skin

·         Histamine causes triple response (redness wheal flore).

h)     Autonomic ganglia and adrenal medulla

·         Stimulate and release of Adr, which can cause rise in BP.

i)       CNS

·         Intracerebroventricular administration produce rise in BP, cardiac stimulation, behavioral arousal, hypothermia, vomiting and anti-diuretic hormone (ADH) release.

·         There is no effect on administration i.v.

·         Histamine does not penetrate BBB.

Pathophysiological roles

1.      Gastric secretion

·         Histamine stimulate HCL secretion in the stomach.

·         Histamine is released locally under the influence of all stimuli that evoke gastric secretion and activate the proton pump (H+K+ ATPase). (Stimuli: Cholinergic drugs, Gastrin, vagal secretion, prostaglandin).

·         H2 blocker diminish the acid secretion and also suppress the action of Ach and gastrin.

2.      Allergic condition

·         Release of histamine from mast cell causes AG-AB reaction on their surface and immediate types of hypersensitivity reaction like urticarial, angioedema, bronchoconstriction and anaphylactic shock produce.

·         H1 receptor inhibit the action of hypersensitivity.

3.      As transmitter

·         Histamine is the afferent transmitter which initiate the secretion of itch and pain at sensory nerve ending.

4.      Inflammation

·         Histamine produce vasodilatation effect during inflammation.

5.      Tissue growth and repair

·         Histamine is present in high concentration at growing and regenerating tissue, hence it play an important role of growth and repair.

6.      Headache

·         Vascular headache but no convulsion occur.

Uses of histamine: the uses of histamine is not used recently, but some oldest techniques are used as below:

·         Test for acid secrete at stomach.

·         Bronchialhyperreactivity.

·         Pheochromocytoma.

Antihistamine

·         Histamine has less or no clinical effect, but agents that inhibit the action of action of histamine or blocks the histamine receptor called anti-histamine.

Classification H1 – anti-histamine

Highly sedative

Moderately sedative

Mild sedative

2nd generation

Diphenhydramine

Dimenhydrinate

Promethazine

Hydroxyzine 

Pheneramine

Cyproheptadine 

Meclizine (Meclizine)

Cinnarizine

Chlorpheniramine

Dexchlorpheneramine

Triprolidine

Clemastine 

Fexofenadine

Loratadine

Desloratadine

Cetirizine   

Levocetirizine

Azelastine

Mizolastine

Ebastine

Rupatadine   

 

  Action of anti-histamine

1.      Antagonism effect

·         Antihistamine blocks histamine, that induce;

§  Bronchoconstriction

§  Contraction of smooth muscle and intestinal muscle.

§  Triple response (a red line on the skin – swelling, itch, wheal, flare).

§  Blood pressure decrease (low dose)

·         Constriction of large arteries by histamine is blocked.

2.      Anti-allergic action

·         It suppress;

·         urticaria

·         Itching

·         Angioedema

·         Asthma (partially)

3.      CNS

Older

First generation

Second generation

1.       CNS depressant.

2.       Restlessness and insomnia.

3.       In high dose convulsant and excitement may produce.

Motion sickness

Sedative effect

Weak sedation

Non-sedating

Cyclizine

Diphenhydramine

Dimenhydrinate

Hydroxyzine

Meclizine

Promethazine 

Cyclizine

Diphenhydramine

Dimenhydrinate

Hydroxyzine

Meclizine

Promethazine 

Brompheniramine

Chlorpheniramine

Clemastine

Cyproheptadine

Doxylamine

Acrivastine

Cetirizine

Levocetirizine

 

 

Desloratadine

Fexofenadine

Loratadine

 

4.      Anticholinergic

·         Antagonize the muscarinic action of Ach.

5.      Local anesthetics

·         H1 – antihistamine is not clinically used as local anesthetic, due to irritation effect.

6.      BP

·         Most antihistaminic with i.v. injection cause fall blood pressure, but there is no evidence on oral administration.

Effect of H1 – antihistamine 


Second generation anti-histamine do not cross brain, so no or less CNS effect.

Pharmacokinetics

·        
H1
receptor blockers are well absorbed orally.

·        
Onset of action
1-3 hours.

·        
Most of the drugs
average plasm half-life i.e. about 4-6 hours, except Meclizine and second
generation anti-histamine, which shows 12-24 hours plasma half-life.

·        
Duration of action
almost 24 hours (basically 2nd generation).

Uses

o   Allergic

o   Common cold

o   Common cold is a viral disease caused by various types
of virus for example rhinovirus. It is a communicable disease which is spread
by direct contact, droplets, used clothes, utensil, etc.

o   2nd generation, but less effective

o   Motion sickness

o   When brain receive disturbed or conflict information
from visual and vestibular receptor.

o   Promethazine, diphenhydramine, Dimenhydrinate,
Cyproheptadine, meclizine.

o   Pruritides

o   Unpleasant sensation of the skin that provokes the
urge to scratch.

o   Diphenhydramine, Chlorpheniramine, Cyproheptadine.

o   Vertigo  

o   Sensation of spinning dizziness.

o   Cinnarizine, Dimenhydrinate.

o   Cough

o   Diphenhydramine, promethazine.

o   Sedative,
hypnotic, anxiolytic

o   Promethazine produce serious respiratory depression.

o   Pre-anesthetic
medication

o   Promethazine

o   Parkinsonism

o   It is a slow progressive neurological disorder characterized
tremor, rigidity, bradykinesia, and postural instability.

o   Promethazine

o   Acute muscle
dystonia

o   It is a movement disorder in which muscle contract
involuntarily, causing repetitive or twisting movement.

o   Parenteral administration of promethazine,
hydroxyzine, diphenhydramine.

5-hydroxytryptamine (5-HT, serotonin)

  • Serotonin and enteramine both are 5-hydroxytryptamine, a monoamine neurotransmitter, and are derived from tryptophan.
  • About 90% of the body contains 5-HT is localized in the intestine and the rest are in platelets and the brain.
  • It also found in other animals and plants;
  • Animals: invertebrates and mollusks, arthropods, snake and bee venom/sting.
  • Plants: plants: tomato, pear, banana & pineapple.

Synthesis storage and destruction

  • It is synthesized from the amino acid tryptophan.
  • Tryptophan converted to 5-hydroxytryptophan with the help of enzyme hydroxylase.
  • 5-HTP decarboxylase to produce 5-HT.
  • The decarboxylase is non-specific, acts on DOPA as well as 5-hydroxytryptophan (5-HTP) to produce DA and 5-HT respectively.
  • It is degraded primarily by MAO and to a small extent by dehydrogenase.
  • 5-HT is actively taken up by an amine pump serotonin transporter (SERT), with a Na+ dependent carrier, which operates at a membrane of platelet and serotonergic nerve ending s (therefore, 5-HT does not circulate in free form in plasma).
  • This pump is inhibited by selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).
  • Platelets do not synthesize 5-HT but acquire it by uptake during passage through intestinal blood vessels.
  • Again 5-HT is stored within storage vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2).
  • It is inhibited by
  • The enzyme MAO (especially MAO-A) metabolized 5-HT.

5-HT receptors

  • Musculotropic (D type) and Neurotropic (M type) – blockade by Dibenzyline (phenoxybenzamine) and Morphine.
  • 4 Families and 14 subtypes.
  • The present system of classifying 5-HT receptors is based on molecular characterization and cloning of the receptor cDNAs.
  • 5-HT receptor subtype-selective agonists or antagonists.
  • All are GPCRs except 5-HT3.
    • Decrease cAMP production
    • 5-HT1 – Increase cAMP production 5-HT4, 5-HT6, 5-HT7
    • Generating IP3/DAG – 5-HT2.
  • The 5-HT3 is a ligand-gated cation (Na+, K+) channel which on activation elicits fast depolarization.

 

 5-HT1 receptors

  • All subtypes of the 5-HT1 receptor couple with Gi/Go protein and inhibit adenylyl cyclase.
  • 5-HT1A activates the K+ channel and inhibits the Ca2+ channel resulting in hyperpolarization.
  • These receptors primarily act as an autoreceptor in the brain and inhibit the firing of 5-HT neurons or the release of 5-HT from nerve endings.
  • Location of 5-HT1A receptor: Somadendritic synapse in Raphe nucleus, Brainstem, and hippocampus (antianxiety – Buspirone).
  • 5-HT1D – Basal ganglia and substantia nigra (dopaminergic).
  • 5-HT1D/1B – Cranial Blood Vessels (for constriction – sumatriptan – agonist).
  • Also inhibits 5-HT release in the forebrain and NA release in sympathetic nerve endings.

5-HT2 Receptors

  • Mainly 3 subtypes (5-HT2A, B, C).
  • All are coupled to Gq protein – activate Phospholipase C – IP3/DAG.
    • 5-HT2A – – also inhibits K+ channels.
    • Location: – vascular, visceral, platelets and cerebral neurones (prefrontal cortex).
    • Mediates direct effects of 5-HT (D-type).
      • Vasoconstriction, intestinal, uterine, and bronchial constrictions, platelet aggregation, and activation of cerebral neurons.
    • Ketanserin, Cyproheptadine, Methysergide are antagonists.
    • 5-HT2B: contraction of Rat gastric fundus.
    • Location of 5-HT2C receptor: Vascular endothelium – EDRF release (Vasodilatation) and CSF formation in choroid plexus.

5-HT3 receptor

  • Neuronal receptors – depolarizes rapidly by acting on Na+, K+ channel, and also the Ca2+
  • Somatic and autonomic nerve endings – pain, itch, and coronary chemoreflex (bradycardia, fall in BP, respiratory stimulation/apnoea depending on stimulation of receptors in coronary bed).
  • Nerve endings in myenteric plexus: increased peristalsis and emetic reflex.
  • Area postrema and nucleus tractus solitarious (NTS): vomiting and nausea.
  • Ondansetron is a specific antagonist which inhibits vomiting by blocking these receptors in the brainstem as well as in the gut wall.

5-HT4-7 Receptors

  • Gs: activates the adenylate cyclase.
  • Present in the mucosa, plexuses, and smooth muscle of the gut.
  • Increase Intestinal secretion and peristalsis.
  • In the Brain: the hippocampus area and the colliculi cause slow depolarization by decreasing K+ conductance.
  • Cisapride and renzapride are selective 5-HT4
  • Clozapine (atypical antipsychotic) has a high affinity for 5-HT6 and 5-HT7

Action of 5 – HT

  • 5-HT is a potent depolarizer of nerve endings. It thus exerts direct as well as reflex and indirect effects.
  • Tachyphylaxis is common with repeated doses of 5-HT.

CVS

  • Large arteries and veins are constricted but in microcirculation arterioles are dilated.
  • Release of 5 – HT from adrenal medulla that evokes cardiovascular reflexes.
  • Also releases Adrenaline, affects ganglionic transmission and reflex CVS action.
  • The net effect on CVS is complex
  • BP:
    • Early sharp fall: Coronary chemoreflex.
    • Brief rise in BP: vasoconstriction and increased cardiac output – also due to vasoconstriction.
    • Prolonged fall in BP: arteriolar dilatation and extravasation of fluid – skeletal muscle.

GIT

  • Potent stimulator of GIT
    • partly through enteric plexuses direct effect on the smooth muscle cells (5-HT2 receptor)
    • partly as a result of indirect excitatory effect on enteric neurons (5- HT3 & 4 receptors)
    • Diarrhoea
  • 5-HT inhibit gastric acid and pepsin, secretion however increase mucus production thus it has ulcer protective property.
  • Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally) on 5-HT receptors.

Respiration

  • Brief stimulation of smooth muscles of Bronchi via reflex stimulation of bronchial afferents- hyperventilation.
  • Large doses can cause transient apnoea through coronary chemoreflex.

Platelets

  • Responsible physiologically for Haemostasis by promoting platelet aggregation and clot formation, thereby preventing leakage.
  • Works in conjunction with collagen and other mediators.
  • Exogenous 5-HT also changes shape of platelets in injury and promote aggregation (via 5-HT2A).

CNS

  • Does not produce CNS effects because poor penetration across BBB.

5-HT agonist  

Cisapride

  • Cisapride shows peripheral 5-HT4 agonist action.
  • Useful in GERD, diabetic gastroparesis.
  • Oral bioavailability ~ 30%
  • t ½ 10 hours.
  • Adverse effect: serious ventricular arrhythmias.

Sumatriptan

  • Selective agonist for 5-HT1B, 1D
  • Useful in acute migraine attack
  • Bioavailability ~ 15%
  • Half-life 2-3 hours
  • Administered as oral, nasal or s.c.
  • In case 5% of patients shows chest pain.
  • Zolmitriptan, naratriptan can be given orally, longer acting, and safer.

Buspirone

  • Partial agonist at presynaptic 5-HT1A
  • Weak D2
  • Used as anxiolytic.
  • Rapid absorbed, undergoes extensive first pass metabolism.
  • t ½ 2-4 hours.
  • Excreted in urine and faeces.

5-HT antagonist

  1. Cyproheptadine
  • It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties.
  • Used as antipruritic.
  • It increases appetite, so used in children for weight gain.
  • Adverse effects: drowsiness, dry mouth, confusion, ataxia, weight gain.
  1. Methysergide
  • It is chemically related to ergot alkaloids.
  • Antagonizes action of 5-HT on smooth muscles including that of blood vessels.
  • It does not interact with α adrenergic or dopamine receptors.
  • It is a potent 5-HT2A/2C
  • Used for migraine prophylaxis, carcinoid and post-gastrectomy dumping syndrome.
  1. Ketanserin
  • It has selective 5-HT2 receptor blocking property with very less action on 5-HT1, 5-HT3 and 5 HT4 receptors and no partial agonistic activity.
  • Stronger blockade of 5-HT2A.
  • It has additional weak α1, H1 and dopaminergic blocking activities.
  • Ritanserin is a relatively more 5-HT2A selective congener of ketanserin.
  1. Clozapine
  • This atypical antipsychotic is a 5-HT2A/2C
  • Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia.
  1. Risperidone
  • This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar to clozapine.
  1. Ondansetron
  • It is the prototype of the new class of selective 5-HT3 antagonists.
  • It control nausea and vomiting against anticancer drugs and radiology therapy.

Ergot alkaloid

  • Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other grains.

Classification of ergot alkaloids

  1. Natural – Derivatives of the tetra-cyclic compounds (lysergic acid)
  • Amine alkaloids – Ergometrine (ergonovine)
  • Amino acid alkaloids – Ergotamine, Ergotoxine (ergocristine, ergocornine, ergocryptine)
  1. Semi-synthetic
  • Dihydro-ergotamine (DHE), Dihydroergotoxine, Bromocriptine (2-Bromoα-ergocryptine), Methysergide,
  1. Synthetic – (non lysergic acid derivative)
  • Metergotine

Ergotamine

  • 5-HT1 and 5-HT2
  • α-adrenergic antagonist.
  • Partial agonist activity at both types of receptor.
  • Used in acute migraine.
  • Action:
    • Sustained vasoconstriction, visceral smooth muscle contraction and vasomotor center depression.
    • Antagonizes action of NA and 5-HT in smooth muscles.
    • Potent emetic via CTZ and potent oxytocic.
    • Prolonged use – vasoconstriction and damage endothelium – thrombosis, gangrene.

Ergometrine

  • Amine ergot alkaloid.
  • Partial agonist of 5-HT receptor in uterus, placenta and umbilical blood vessels – but antagonist of 5-HT2 in GIT.
  • Weak partial agonist but no antagonistic effect of α-receptor – less vasoconstriction.
  • Moderately potent antagonist of 5-HT2 in intestine.
  • Weak DA agonist in lactotropes and CTZ – low vomiting.
  • Uterine myometrium.

Dihydroergotamine (DHE)

  • Hydrogenated ergotamine
  • Less serotonergic action than ergotamine and α-adrenergic action
  • Better blocker of α-adrenergic receptor
  • Less potent vasoconstrictor and so less intimal damage
  • Lesser oxytocic and emetic.

Dihydroergotoxine and Bromocriptine

  • Dihydroergotoxine: Hydrogenated mixture of ergotoxine groups – potent α-blocker
    • Variety of agonist/antagonist action in Brain on 5- HT, metabolic, vascular effects and Ach release.
    • Used for treatment of dementia.
  • Bromocriptine: selective D2 agonist in pituitary lactotropes (inhibits prolactin release), in striatum and in CTZ (emetic)
    • Used in Galactorrhoea, Parkinsonism etc.

Drug Therapy of Migraine

  • Migraine derived from the Greek word hemicrania, meaning “one side of head”.
  • Severe, throbbing, pulsating headache usually unilateral headache (few hours to a few days in duration).
  • Associated with nausea, vomiting, sensitivity to light and sound, flashes of light, loose motion and others.
  • Types:
    • Classical with aura: preceded by visual or other neurological symptoms – Without aura (common).

Pharmacotherapy of Migraine

  • Three types: Mild, Moderate and Severe
  • Mild: Less than one attack per month of throbbing but tolerable headache lasting up to 8 hours – no incapacitation
  • NSAIDS or combinations: codeine/diazepam/anhihistaminics/caffeine
    • Ibuprofen (400 mg 8 hrly)
    • Paracetamol (500 mg 8 hrly)
    • Naproxen (250 mg 8 hrly)
    • Mefenamic acid (500 mg 8 Hrly)
    • Diclofenac (50 mg 8 Hrly)
  • Useful in without aura – shoud be used till the attack only – no long term
  • Antiemetics: Gastric stasis
    • Metoclopramide (10 mg oral or IV)
    • Domperidone (10 mg oral)

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