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AUTACOIDS
1.
2.
3.
4.
Histamine
Bradykinin & Kallidin
5 Hydroxytryptamine (5HT)
Autacoids derived from membrane
phospholipid
a. Eicosanoids – arachidonic acid

(PG, PGI, TXA2, LT)
b. Modified phospholipids – PAF
HISTAMINES
Chemistry:
imidazole ring + amino group
connected by 2 methylene groups
Synthesis
 Decarboxylation of amino acid L-histidine
catalyzed by pyridoxal PO4-dependent Lhistidine decarboxylase.
 Ingested from food or formed by bacteria in the
GIT
 Storage sites:
 perivascular tissue – mast cell
 circulation – basophil (bound to chondroitin SO4)
 others – GIT, lungs, skin, heart, liver, neural tissue,
reproductive mucosa, rapidly growing tissues and
body fluids
Metabolism :
 Major pathways
 Deamination – small intestine, liver, kidney
and monocytes
 Methylation – small intestine, liver, skin,
kidney, thymus & leukocytes
 N-methylimidazole acetic acid principal urinary metabolite
Metabolism :
Functions:
1. Role in allergic responses – Ag + IgE (bound to mast
cells & basophils)
1. Preformed mediators
2. Most important mechanism of release/controlled by
H2 esp. in skin & blood
2. Release of other autacoids
3. Release by drugs (morphine, urase, amines), peptides,
venoms & other agents
4. Release by urticarias
5. Gastric secretagogue
6. Neurotransmitter  increased wakefulness,
thermoregulation
Selected Actions of Histamine in
Humans
Organ Tissue
CARDIOVASCULAR
Vascular
Facial cutaneous
Forearm
Gastric mucosa
Carotid artery
Pulmonary artery
Basilar artery
Coronary artery
Other pre & post cap
Arterioles
Postcapillary venules
Heart
Action
Receptor
 TPR
Vasodilatation
 Blood flow
H1, H2
H2
H1, H2
 Blood flow,relaxation
Constriction
Relaxation
Constriction
Constriction
Vasodilatation
 Permeability
 SA rate
 Force of contraction Atrial &
vent automaticity
H2 (?)
H1
H2
H2
H1
H1
H2
H2
Selected Actions of Histamine in
Humans
Organ Tissue
RESPIRATORY
Bronchiolar smooth muscle
Action
Receptor
Contraction (more prominent)
Relaxation
H1
H2
Acid and pepsin secretion, If
Relaxation & Contraction
(more prominent)
Relaxation (?)
H2
H1
CUTANEOUS NERVE
ENDINGS (Sensory)
Pain & itching
(esp to insect bites & needle
stings)
H1, H2 (?)
ADRENAL MEDULLA
Epinephrine release
H1
BASOPHILS
Inhibition of IgE – dependent
degranulation
H2
GASTROINTESTINAL
Oxyntic mucosa
GI smooth muscle
Gallbladder smooth muscle
H2 (?)
Selected Actions of Histamine in
Humans
 H1, H2 - located in post synaptic membrane
 H3 – presynaptic
 H1 - predominant in endotracheal & smooth
muscle
 H2 - facial veins, carotid a, pulm. a, heart
 gastric mucosa, heart, smooth muscle & some
immune cells
 H3 - several ares in CNS
 Triple response - wheal, flare & redness
H1 RECEPTOR
ANTAGONISTS
Pharmacokinetics:
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


Well absorbed from GIT (oral)
Onset – 30 minutes, duration – 3 to 6 hours
Widely distributed
Biotransformed in the liver; microsomal
enzyme inducer
 Excretion – kidneys
Adverse Effects:
1.
2.
3.
4.
5.
6.
CNS : sedation, agitation, nervousness, delirium,
tremors, incoordination, hallucinations, &
convulsions - common in first generation
antihistamines
GIT : vomiting, diarrhea, anorexia, nausea, epigastric
distress, constipation
- dryness of mouth, throat & airway, urinary retention
- first generation
Headache, faintness
Chest tightness, palpitations, hypotension
Visual disturbances
Hematological - leukopenia, agranulocytosis, HA
Therapeutic Uses:
1.
2.
3.
4.
5.
6.
7.
dermatosis
allergic rhinitis
motion sickness & emesis
Parkinson’s disease
EPS
Insomnia
Adverse reactions
Histamine Antagonists
I.
A.
1.
2.
3.
4.
B.
1.
2.
3.
C.
1.
2.
First Generation Agents
Ethanolamines
Carbinoxamine maleate
Clemastine fumarate
Diphenhydramine HCl
Dimenhydrinate
Ethylenediamines
Pyrilamine maleate
Tripelennemine HCL/citrate
PPA
Alkylamines
Chlorpheniramine maleate
Brompheniramine maleate
II. Second Generation Agents
A. Alkylamines

Acrivastine
B. Piperazines

Cetirizines HCl
C. Piperidines

Astemizole

Levocabastine

Loratadine

Terfenadine

Fexofenadine
FIRST GENERATION AGENTS
D. Piperazines
1. Hydroxyzine HCl/pamoate
(long acting)
2. Cyclizine HCl/lactate
3. Meclizine HCl
4. Chlorcyclizine
E. Phenothiazines
1. Promethazine HCl
Structural Class
Prototype
First Gen. Agents:
1. Ethanolamine
Diphenhydramine
Characteristics
Significant antimuscarinic
activity
Sedation, somnolence
 Incidence of GI symptoms
Effective in emesis & motion
sickness
2.Ethylenediamine/
Ethylamine
3. Alkylamine
Pyrilamine
Mepyramine
Pyranesamine
Most specific H1 antagonist
 Anticholinergic activity
Feeble CNS effects
Chlorpheniramine
Pheniramine
Most potent
Not so prone to develop
drowsiness
More suitable for older patients
Chlorphenamine
4. Piperazine
Chlorcyclizine
Somnolence GI s/s common
Sedation/CNS stimulation
Oldest member
More prolonged action
 Incidence of drowsiness
Structural Class
Prototype
Hydroxyzine
Characteristics
Long acting
Widely used for skin allergies
CNS depressant
More prominent antipruritic
action
Cyclizine
Counters motion
sickness (primarily)
Meclizine/Meclozine
Counters motion
sickness & emesis
Structural Class
Prototype
5. Phenothiazine Promethazine
Second Gen.Agents Terfenadine
1. Piperidine
2. Alkylamine
Acrivastine
Characteristics
Anticholinergic
Prominent sedation
Counters motion sickness
primarily antiemetic
Highly selective for H1
receptor
Non-sedating
(-) anticholonergic action
(-) pass BBB
 incidence of S/E
Rapid onset of action (30 mins)
(-) anticholinergic effects
Reduce both wheal & flare response
 Potential to penetrate BBB
Skin allergy
Allergic rhinitis
3. Piperazine
Cetirizine
Rhinitis, urticaria
(-) pass BBB
H2 RECEPTOR ANTAGONISTS
Pharmacodynamics:
•Inhibit gastric acid secretion
•(-) effect of gastric motility, emptying time,
LES sphincter, pancreatic & mucous
secretion
Adverse Effects
Cimetidine:  headache, dizziness
• constipation, diarrhea
•skin rashes
•alterations of hepatic function
•CNS disturbances (elderly & impaired
RF)
•BM depression – rare
•Serum prolactin elevation
•Sexual dysfunction & gynecomastia
Ranitidine:  Serum prolactin elevation
Drug Interactions:
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Cimetidine inhibits cyto p-450 – accumulation
of warfarin, phenytoin, theophylline,
propanolol, diazepam & phenobarbital
Ranitidine – weak inhibitor
Nizatidine & famotidine – do not inhibit
cyto P – 450
Therapeutic Uses: Peptic acid disorders
Vasoactive Peptides
 Vasoconstrictors—angiotensin
II,vasopressin, endothelins,
neuropeptide Y
 Vasodilators—bradykinin, natri-uretic
peptides, vasoactive intestinal peptides,
substance P, neurotensin and calcitonin
gene-related peptide (CGRP)
BRADYKININ & KALLIDIN
 Peptides that act locally to produce
pain, vasodilatation,  vascular
permeability & PG synthesis
Synthesis:
 Liver
 Percursors: kininogens—SERINE
PROTEASES (HMW & LMW)
Pharmacologic Properties

CVS :
(+) inotropic & chronotropic effects
vasoconstriction
 Smooth Muscle:
Bronchoconstriction
 GIT:
Enhanced motility
Functions
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pain – excites primary sensory neurons &
provokes release of substance P,
neurokinin A & CGRP
inflammation -  permeability in
microcirculation
production of IL-1 & TNF - 
respiratory disease
Pharmacological Properties
1. CVS – potent vasodilator (10x more than
histamine)
 Stimulate histamine release
2. Kidney -  RBF
3. Others:
 spermatogenesis & promotes
sperm motility
• dilatation of fetal pulmonary artery
closure of ductus arteriosus
constriction of umbilical vessels
5 HYDROXYTRYPTAMINE
(5HT)


Found in enterochromaffin cells (90%),
platelets and CNS
Sources : tunicates, mollusks, anthropods,
colenterates, fruits, nuts, wasps &
scorpions
Synthesis:
Tryptophan
Hydroxytryptophan
5 hydroxytryptamine
(Serotonin)
5-hydroxyindole acetaldehyde
5-hydroxyindole acetic acid
(principal metabolite)
acid 5-hydroxytrytophol
N-acetyl5-HT
Melatonin
Antagonists:
1. Clozapine:
Reduce incidence of EPS
High affinity for dopamine receptors
Reduced negative symptoms of schizophrenia
2. Risperidone:
D2 receptor blocker
Reduced negative symptoms of schizophrenia
Low incidence of EPS
1. Clozapine:
•
Reduce incidence of EPS
• High affinity for dopamine receptors
•
Reduced negative symptoms of schizophrenia
2. Risperidone:
•
D2 receptor blocker
•
Reduced negative symptoms of schizophrenia
•
Low incidence of EPS
3. Methysergide:
used for diarrhea & malabsorption in patients
with carcinoid tumors
Cyproheptadine:
•
•
•
• H1 blocker
Weak anticholinergic and mild CNS
depressant
Used for skin allergies, cold urticaria
Counteract the sexual side effects of
SSRI’s
LIPID-DERIVED
AUTOCOIDS
Eicosanoids
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formed from PUFA (AA)
release from cellular stores by PLA2
human platelets – DAG lipase
coupled to G proteins
EFA (diet)
Lipoxygenase
12-HPETE
12-HETE
Esterified acid
in cell lipid
Arachidonic acid
PLA2
Cyclooxygenase
X ASA, indomethacin
5-HPETE
5-HETE
84
LTA4 LTC4
LTB4
LTD4
LTE4
LTF4
Cycloxygenase
PGG2
PGH2
PGG2
PGF1
PGE2 PGF2 PGD2
TXA2
TXB2
Inhibitors of Biosynthesis
1.
2.
3.
drugs that reduce the availability of Ca
glucocorticoids – induce lipocortin
synthesis which inhibits PLA2
ASA & related NSAID
Pharmacological
Properties
Therapeutic Uses
1.
2.
3.
PGE1 (Misoprostol) – suppress gastric
ulceration
PGE1 & PGI2 – improve harvest and storage of
platelets for therapeutic transfusion
- improve blood flow & tissue oxygenation in
neonates (ductus arteriosus – vasodilatation)
PGE1 – treatment of impotence
PLATELET ACTIVATING
FACTOR (PAF)
Synthesized by platelets,
neutophils,monocytes, mast cells,
eosinophils, renal mesangial cells,
renal medullary cells & vascular
endothelial cells
Pharmacological
Properties
A. CVS: Potent vasodilator
vascular permeability 1000x more than
histamine/bradykinin
B. Leukocyte: Chemotaxis
C. Smooth Muscle:

Contraction

Airway resistance & responsiveness to other
bronchoconstrictors
D. Stomach

Potent ulcerogen