Pharmacology-3

Dr. Mamdouh Oraby

AUTACOIDS
 Autacoids

 Compounds with hormonal like-effects.

 Unlike hormones, autacoids:
 Isn’t stored, released from glands, or
circulate in the blood to the site of action.
 Act locally at / near the site of synthesis
 Have a short duration of action.
 Therefore, autacoids are termed "local
hormones“
 Classification of Autacoids

1. Amines autacoids
 Ex: Histamine & Serotonin
2. Eicosanoids (lipids)
 Ex: Prostaglandins & leukotrienes
& Thromboxanes
3. Peptides autacoids
 Ex: Renin & Angiotensin
4. Endothelin derived
 Ex: Nitric oxide (NO)
 1- Histamine

 A chemical messenger mostly generated in mast cells.

 Mediates various cellular responses, including:
 Allergic and inflammatory reactions
 Gastric acid secretion
 Neurotransmission in parts of the brain.
 Histamine has no clinical applications.
 Antihistamines or histamine receptor blockers have
important therapeutic uses.
 1- Histamine
 Distribution:
 Plants & animal tissues (Venoms & secretions of insect stings).
 In human, it is sequestered in granules in mast cells & basophils
(which are distributed in nose, mouth, blood vessels, and skin).
 Non-mast cell histamine is found in:
Brain (acts as an endogenous neurotransmitter).
Enterochromaffin-like (ECL) cells in the stomach (↑ gastric
acid secretion)
Synthesis of histamine
 Histamine release
a. Immunologic release:
 Antigen-mediated allergic reactions induce IgE antibodies that bind
to mast cell surfaces → degranulation & release of histamine (This
mechanism requires energy (ATP) and Ca+2).
 Histamine release

b. Chemical or Mechanical release:

i. Drugs: Morphine & tubocurarine can
displace histamine from the mast cells.
ii. Trauma and tissue injury
iii. Destruction of histamine cells (by
organisms' toxins and cold (cold-induced
urticaria).
 Histamine receptors and its location:

 Four types of histamine receptors (GPCRs);

Receptor
Distribution Post-receptor mechanism
type
Smooth muscle, Gq-protein coupled to inositol
H1 Endothelium, Brain, trisphosphate (↑ IP3) & DAG & ↑
Exocrine glands Ca+2

Gastric mucosa, Heart Gs-protein coupled to adenyl cyclase

H2 muscle, Mast cells, Brain. (AC) & ↑ cAMP
 Histamine receptors and its location:

Receptor type Distribution Post-receptor mechanism

Presynaptic: Brain, Myenteric

H3 plexus, other neurons Gi, ↓ cAMP

White blood cells

(eosinophils, neutrophils, T-
H4 Gi, ↓ cAMP
cells)
 Histamine
 Physiological effects of histamine:
i. CVS:
 Vasodilatation of blood vessels (H1) (↑
NO → ↑ capillary permeability & edema).
 ↓ blood pressure.
 Reflex tachycardia (due to ↓ B.P).
ii. Bronchial smooth muscles:
 Contraction (H1) (bronchoconstriction &
severe bronchial spasm)
 Histamine

iii. GIT:
 Contraction of intestinal muscles
 ↑ Gastric acid secretion (H2R)
iv. Skin (Local effects):
 Injection of histamine causes:
 Redness (vasodilatation).
 Edematous wheel
 Flare (pain & itching)
 Histamine

vi. Other effects of histamine:

a) Responsible for allergic conditions (Ex: allergic rhinitis,
conjunctivitis, urticaria, asthma, and anaphylaxis; H1R)
b) ↓ Appetite (↑ satiety): antipsychotics & antihistamines ↑
appetite & weight gain; (↓ H1 & H3).
c) ↓ Ach & peptide transmitters & amines release from the brain
& peripheral nerves (H3 R, Gi, ↓ cAMP)
d) ↑ Inflammatory conditions.
 Histamine Antagonist
I. Physiological antagonists:
Ex; Epinephrine is lifesaving in systemic anaphylaxis.
II. Release inhibitors:
Ex: Cromolyn & Nedocromil & Corticosteroids: ↓
degranulation of mast cells (used for treatment of asthma).
III. Receptor antagonist
a. H1 receptor antagonist
b. H2 receptor antagonist
 Histamine receptor antagonists

A. H1 receptors antagonists:
 Tow main classes of H1 antagonist: (some are invert agonists)
First generation Second generation
 Non-specific H1 blocker  Specific blocker for peripheral H1
 Cross BBB.  Don’t penetrate BBB
 Causes sedation  Less CNS sedating effect
 Less polar drugs (more lipid  More polar drugs (less lipid
soluble) soluble)
 Less expensive  More expensive
 Atropine-like effect.  Less atropine-like effect.
 Histamine receptor antagonists

 First generation antihistamines:

Ethanolamines: Diphenhydramine & Carbinoxamine
Piperazine derivatives: Cyclizine & Meclizine
Alkylamines: Chlorpheniramine
Phenothiazine: Promethazine
Miscellaneous: Cyproheptadine
 Histamine receptor antagonists
Second generation antihistamines:
Piperidine: Fexofenadine
Miscellaneous: Loratadine & Desloratadine & Cetirizine &
Azelastine & Astemizole.
First generation antihistamines
 Histamine receptor antagonists

Pharmacokinetics:
 Well absorbed from GIT
 Peak occurs in 1-2 hr.
 Duration of action of 4–6 hours.
 Meclizine and several second-generation agents are longer-acting,
with a duration of action of 12–24 hours.
 Biotransformation occurs the liver via enzymatic CYP3A4
 Drug interaction occurs with certain drugs (e.g. Ketoconazole is
an inhibitor to CYP3A4).
 Histamine receptor antagonists

 Effects of 1st generation H1 antagonists:

1. Sedation & dizziness:
Inhibition of neuronal transmission (↓ H1 in CNS)
2. Antimuscarinic (anticholinergic) action:
 Atropine-like effect: ex; ethanolamine derivatives
3. α-receptor-blocking effects:
Can cause orthostatic hypotension & reflex tachycardia: ex;
phenothiazine (promethazine)
 Histamine receptor antagonists

4. Serotonin-blocking actions:
Ex; Cyproheptadine )used to stimulate appetite(.
5. Local anesthetic effects:
 Ex; Diphenhydramine & Promethazine: block
Na+ channels in neuronal membranes.
6. Antiemetic effects:
 Ex; Promethazine has anti-motion sickness effect
(protective rather than treatment).
 Histamine receptor antagonists

Clinical uses of H1 receptor antihistamines:

a. Treatment of allergic reaction:
 Allergic rhinitis (hay fever) & urticaria (2nd
generation).
 As adjunct therapy for anaphylaxis (2nd line therapy
after epinephrine & corticosteroids).
b. Motion sickness
 Prevention of motion sickness & vertigo
 EX: Diphenhydramine, Promethazine, Meclizine
 Histamine receptor antagonists
c. Local anesthetic:
 Diphenhydramine & promethazine are more potent than
procaine (can be used in patients allergic to procaine).
Adverse effects of 1st generation H1 blockers:
A. Sedation & drowsiness
B. Antimuscarinic effects: Dry mouth & blurred vision & urinary
retention & constipation (atropine-like effect).
C. Hypotension & tachycardia (α-blocking effect)
D. At very toxic dose levels: stimulation &agitation & seizures
Histamine receptor antagonists
 Histamine receptor antagonists

Adverse effects of 2nd generation H1 blockers:

 Astemizole and terfenadine induces cardiac arrhythmias
(blocking K+ channels & prolongation of action potential).
Drug interaction:
a) Liver CYP3A4 inhibitors: ketoconazole & macrolide
antibiotics (e.g. erythromycin) + 2nd generation astemizole or
terfenadine → lethal ventricular arrythmias.
 Histamine receptor antagonists

c) Sedating antihistamines (1st generation blockers) + CNS

depressants → additive sedating effect (contraindicated while
driving or operating machinery).
d) MAOIs + Antihistamines → ↑ the anticholinergic effect of
antihistamines (this combination should be avoided).
e) 1st generation antihistamines + cholinesterase inhibitors (e.g.
donepezil & rivastigmine) → ↓ the effect of the later
compounds in treatment of Alzheimer's disease.
Histamine receptor antagonists
 Histamine receptor antagonists

B. H2 receptor antagonists:
 These agents are used for the treatment of
peptic ulcer by inhibiting gastric acid secretion
through blocking H2 receptors in parietal cells.
 Ex: Cimetidine, Ranitidine, Famotidine.
 Cimetidine is an inhibitor of cytochrome
P450 pathway and thus reduces metabolism
of many drugs.
 2- Serotonin (5-HT)
A neurotransmitter that is synthesized
from the amino acid L-tryptophan by
hydroxylation followed by
decarboxylation of the amino acid.
Location:
Synthesized mainly in:
 Enterochromaffin cells in GIT (90 %)
 Serotonergic neurons in CNS.
 Blood platelets
 2- Serotonin
 Pharmacokinetics:
 Serotonin is stored in the nerve endings.
 Free-circulated serotonin is metabolized by monoamine
oxidase enzyme (MAO) to 5-hydroxyindoleacetic acid (5-
HIAA) which is excreted in urine.
 Urinary 5-HIAA is a measure of serotonin synthesis and
can be a diagnostic test for tumors-producing excessive
serotonin (carcinoid tumors = tumors of enterochromaffin
cells).
 2- Serotonin

Foods such as bananas (contain large serotonin amounts) must

be avoided during the carcinoid tumor diagnostic test.
Mechanism of action:
 5-HT has 7 families of receptors subtype (5-HT1-7).
 All 5-HT receptors are G-protein except 5-HT3 which are
ligand-gated ion channel (Na+/K+ channel).
 The second messenger coupled to 5-HT G-proteins is either
cAMP or IP3.
 Serotonin

Physiological effects:
I. CVS:
 Vasoconstriction (renal & cerebral & pulmonary).
 Vasodilatation to skeletal muscle & heart blood vessel
II. GIT:
 Prokinetic effect: ↑ ACh release → ↑ peristalsis & motility →
Contraction of GIT smooth muscle (5-HT4 & 5-HT2).
 ↑ vomiting reflex from medulla (Activation of 5-HT3 in GIT)
 Serotonin

III. CNS:
 Precursor of melatonin (circadian
rhythm regulation)
 Appetite suppressant.
 Mood elevation.
 Modulating anxiety & migraine
 Serotonin Agonists
a) Buspirone (5-HT1 agonist):
 Used for treatment of anxiety
b) Lorcaserin (5-HT2 agonist):
 Used for appetite suppression.
c) Triptans: Sumatriptan, almotriptan:
 5-HT1 agonist: treatment of migraine
(vasoconstricting effect)
d) Cisapride (5-HT4 agonist):
 Used for gastroesophageal reflux and GIT
motility disorders.
 Serotonin Agonists

e) Fluoxetine:
 SSRIs (block serotonin
reuptake).
 Used for management of
depression.
f) Tegaserod:
 A 5-HT4 partial agonist
 Used for constipation
associated irritable bowel
syndrome
 Serotonin antagonists
1) Cyproheptadine (5-HT2 & H1 blocker):
 Used for serotonin syndrome & carcinoid
tumor
 Used as an appetite stimulant.
2) Ondansetron: 5-HT3 antagonist
 Approved for the prevention of nausea &
vomiting
3) Pizotifen (5-HT2 & H1 blocker):
 Used for migraine prevention & appetite
stimulant.
 Serotonin antagonists

4) Metoclopramide:
 5-HT3 & D2 R. antagonist in
CTZ in brain.
 Used as antiemetic.
 5-HT4 agonist (Prokinetic
drug) → ↑ motility of GIT →
↓ nausea and vomiting.
 Serotonin syndrome
Cause:
Concomitant administration of MAOIs (e.g. selegiline) +
serotonin agonist (SSRIs; e.g. fluoxetine) or tyramine rich
food such as milk, yogurt, eggs and red meat.
Clinical features: Muscle rigidity & hyperthymia &
hyperreflexia & seizures & tachycardia & hypertension &
mental changes & coma.
Treatment is supportive together with serotonin inhibitors.
 Eicosanoids
 Eicosanoids are oxygenation products of
polyunsaturated 20-carbon fatty acids.
Eicosanoids include
 Prostaglandins (PGs): PGI2 and PGE2
Thromboxanes (TXAs)
 Leukotrienes (LTs)
 Eicosanoids
Synthesis of eicosanoids:
 Eicosanoids

Pharmacodynamics:
 Eicosanoids act in an autocrine and a paracrine fashion, (i.e,
limited to the site or near site of their synthesis)
 Prostaglandins receptors are G-protein which may be:
Gs: ↑ AC & ↑ cAMP (↓ intracellular Ca+2)
Gi: ↓ AC & ↓ cAMP
 TXA2 and LTs: ↑ PLC & ↑ intracellular Ca+2
 Eicosanoids
Physiological effects:
I. Vascular smooth muscles:
 TXA2 is a potent vasoconstrictor.
 PGs are vasodilators (↑ cAMP & ↓ intracellular Ca+2(.
II. Bronchial smooth muscles:
 PGs → relaxation of bronchial muscles (bronchodilatation).
 LTs: potent bronchoconstrictors (↑ mucous secretion →
mucosal edema (contributed to allergic reactions and asthma).
 N.B: Bronchospasm induced by NSAIDs is due to decrease PGs
synthesis by inhibition of COX pathway → ↑ LTs synthesis
(NSAIDs is not recommended in asthmatic patients)
 Eicosanoids

III. Uterine smooth muscles:

 PGs cause contraction of the uterus.
IV. GIT:
 PGs ↓ gastric acid & pepsinogen in the
stomach (cytoprotective).
V. Platelets:
 PGs inhibit platelet aggregation
 TXA2 is a potent platelet aggregator.
 Eicosanoids
VI. Inflammation and Immunity:
 PGs ↑ vascular permeability → edema
 LTs → ↑ inflammation & immunity (↑ T-lymphocytes,
neutrophils & monocytes & mast cells).
Prostaglandin analogs and their clinical uses:
a. Abortion:
1. Dinoprostone (20-mg suppository): synthetic PGE
Has oxytocic action (induce abortion- abortifacient).
2. Misoprostol: synthetic PGE1
Combined with mifepristone produce early abortion
 Eicosanoids
3. Carboprost tromethamine: a synthetic PGF
Used for second trimester abortion
Control postpartum hemorrhage.
b. Induction of labor:
 Dinoprostone:
 Facilitate the labor & softening of the cervix before labor
c. Peptic ulcer:
 Misoprostol: ↓ gastric acid & ↑ mucous & bicarbonate
secretion (cytoprotective effect)
 Eicosanoids
d. Glaucoma:
 Latanoprost & Travoprost (eye drops).
 Treatment of open-angle glaucoma (↓ intraocular
pressure.
e. Pulmonary hypertension:
 Epoprostenol & Treprostinil (spray &
injection)
 Treatment of pulmonary hypertension (↓
vascular resistance in the pulmonary blood
vessels).
 Eicosanoid inhibitors
i. Corticosteroids & NSAIDs:
Inhibit eicosanoid synthesis
ii. Leukotriene-receptor inhibitors:
 Zafirlukast & Montelukast: used in
asthma.
iii. Lipoxygenase inhibitors
 Zileuton: used for asthma (↓
leukotrienes synthesis).