Autocoids

Lipid derived: Prostaglandins, Leukotrines, and Platelet activated factor

Amine derived: Histamine, Serotonin

Peptides : Bradykinin, Kallidin, Angiotensin

Prostaglandin

Preparation Name Use

Misoprostol PGE1 Peptic ulcer , Abortion used with
Mifepristone
Alprostadil PGE1 Erectile dysfunction , maintain
ductus arteriousus patent
Dinoprostone PGE 2 Induction of labour
Carboprost ,dinoprost PGF2alpha Induction of labour
Latanoprost PGF2alpha Glaucoma
Epoprostenol PGI2 Prostacyclin Pulmunory HT, maintain ductus
arteriousus patent

Histamine

Histamine is formed by decarboxylation of the amino acid L -histidine, a reaction catalyzed in

mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or
rapidly inactivated.

Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or basophils .

Non-mast cell histamine is found in several tissues, including the brain, where it functions as a
neurotransmitter. Important in brain functions such as neuroendocrine control, cardiovascular
regulation, thermal and body weight regulation, and sleep and arousal .

A second important nonneuronal site of histamine storage and release is the enterochromaffin-like (ECL)
cells of the fundus of the stomach.

Receptors

H1 receptor Smooth muscle, endothelium, brain

H2 receptor Gastric mucosa ,cardiac muscle , mast cells, brain
H3 receptor Brain, myentric plexus
H4 receptor Eosinophils, neutrophils,CD-4 Cells

*H3 receptors are expressed mainly in the CNS, especially in the basal ganglia, hippocampus, and cortex.
H3 receptors function as autoreceptors on histaminergic neurons, much like presynaptic a 2 receptors,
inhibiting histamine release and modulating the release of other neurotransmitters. H 3 antagonists
promote wakefulness; conversely, H3 agonists promote sleep.
H3-selective ligands may be of value in sleep disorders, obesity, and cognitive and psychiatric disorders.
Tiprolisant, an inverse H3-receptor agonist explored for use in humans with narcolepsy.

Histamine Receptor Blockers

H-1 receptor blockers

The H1 antagonists are conveniently divided into first-generation and second-generation agents. These
groups are distinguished by the relatively strong sedative effects of most of the first-generation drugs.
The first-generation agents are also more likely to block autonomic receptors. Second-generation H 1
blockers are less sedating, owing in part to their less complete distribution into the central nervous
system.

H-1 Blockers :

First generation

 Cyprohepatadine, cyclizine, meclizine, chlorpheniramine, promethazine,

diphenhydramine ,doxylamine
 Cyclizine,meclizine, diphenhydramine used for motion sickness
 Doxylamine, H1 antagonist used for the morning sickness in pregnancy

Second generation

The second generation histamine blockers have less sedative action are primarily used for allergic
reactions.

Red -FLAME

 Rupatidine
 FexoFenadine ( active metabolite of terfenadine )
 Loratidine / levocetrizine /Levocabastine
 Acrivastine / Azelastine /Astemizole
 Mizolastine
 Ebastine

Imp points

 Terfenadine Fastest acting

 Astemizole Slowest and longest acting
 Azelastine Maximal Topical activity
 Cetrizine and Mizolastine no active metabolites rest all second generation have active
metabolite

Serotonin :

 5–hydroxytryptamine or 5–HT
 Major role in multiple states
o aggression, pain, sleep, appetite, anxiety, depression, migraine, emesis
 Synthesis from Dietary tryptophan
 converted to 5–hydroxy– tryptophan by tryptophan hydroxylase and then to 5-HT by a non–specific
decarboxylase
 Specific transport system into cells
 Degradation mainly by monoamine oxidase (MAO–A > MAO–B)
 5–hydroxyindoleacetic acid (5-HIAA) is the metabolite in urine

 Enterochromaffin cells in the mucosa appear to be the location of the synthesis and most of the
storage of 5-HT in the body and are the source of circulating 5-HT.

 5-HT released from these cells enters the portal vein and is subsequently metabolized by MAO-A in
the liver.Serotonin receptor are at least 15 types and subtypes

5HT 1A Agonist Buspirone ( anti anxiety drug )

5 HT 1 B/D Agonist Sumatriptan ( anti migraine )
5 HT 2 Antagonist Atypical antipsycotics
Ketanserin ( also alpha blocker )
Cyproheptadine ( also h1 blocker)
Methysergide ( s.e retroperitoneal
fibrosis )
5 HT 3 Antagonist Ondansetron
5 HT 4 Agonist Cisapride , mosapride, tegaserod
 All serotonin receptors are GPCR except 5 HT 3 which is an ionotrophic

NSAID

Classification Drug name Remark

Non selective irreversible Aspirin Only irreversible inhibitor so used as ant platelet drug
inhibitor
Non selective reversible
inhibitors
Phenylbutazone Side effect of Agranulocytosis

Indomethacin Used for closure of PDA and also inhibits

phospholipase , causes headache and sedation as side
effect
Ketorolac NSAID available as IV
Diclofenac
Ibuprofen, ketoprofen, and Flurbiprofen used as eye drops
flurbiprofen
Piroxicam NSAID which undergoes enterohepatic circulation and
is the longest acting NSAID
Sulindac Prodrug
Naproxen, oxaprozin Inhibit leucocyte migration
Mephenamic acid
Preferential COX 2 Nimesulide Side effect of hepatoxicity
inhibitors
Nabumetone Pro drug , is the only NSAID which is not an acid
Miloxicam
Selective COX 2 inhibitors Celecoxib, rofecoxib, Less GIT toxicity, more chances of MI
etoricoxib, lumiracoxib
COX-3 inhibitor Paracetamol Phenacetin is pro drug of PCM withdrawn due to
analgesic nephropathy , PCM poor anti-inflammatory
NSAID do no work by Nefopam
inhibiting PG synthesis

ASPIRIN
Pharmacological actions

Analgesic
Anti-inflammatory
Anti-pyretic
Anti-platelet  Low dose 70-320 mg
 Irreversible inhibition is important for action
 Duration of action dependent on mechanism of action and not
pharmacokinetics
 Pre systemic inhibition is important for it anti platelet action
CVS Salt water retention, cardiac output and work is increased
Respiratory system Low dose stimulate and high doses inhibit
GIT Nausea , vomiting ,ulcer
Metabolic effects Hyperglycemia, uncoupling of oxidative phosphorylation
Pregnancy Reduced birth weight, premature closure of PDA
Uric acid Dose , less < 2g retention
2-5 g variable effect
More than 5 g excretion

Acid-base balance  Low dose stimulates respiration cause respiratory

alkalosis due to loss of CO 2
 High 2nd Metabolic Acidosis (High levels)
 Depletion of HCO3, accumulation of salicylic acids
derivatives, respiratory depression.
 3rd Mixed Acidosis (respiratory and metabolic).

Children  Can cause Reye syndrome, a type of hepatic

encephalopathy if aspirin given in viral infections
Hypersenstivity  Increase formation of leukotrine may lead to asthma
precipitation

Other uses

Aspirin : A – Alzheimer disease

S - Slowing of cataract progression

P- PIH

I - Infarction

R - Rectal polyp

I - Inflammation

N- Niacin induced flushing ( Prostaglandin mediated )

Bartter’s syndrome

• Mutations in a Na+:K+:2Cl- cotransporter

 • Biosynthesis of PGE2 is increased

• Indomethacin used in management reduces all symptoms except hypokalemia

Adverse effects

1. Central nervous system: Headaches, tinnitus, and dizziness.

2. Cardiovascular: Fluid retention hypertension, edema, and rarely, congestive heart failure.

3. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding.

4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia.

5. Hepatic: Abnormal liver function tests and rare liver failure.

6. Pulmonary: Asthma.

7. Rashes: All types, pruritus.

8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.

Paracetamol

 Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic
effect.
 It is metabolized by hepatic microsomal enzymes and converted to acetaminophen sulfate
and glucuronide, which are pharmacologically inactive
 A minor but highly active metabolite (N-acetyl-p-benzoquinone) is important in large doses
because it is toxic to both liver and kidney
 Toxicity
 Therpeutic dose upto 1 g per day
Hepatotoxicty above 10 g per day
Fatal dose above 20g per day

Symptoms

< 48 hours GIT distress ( Nausea, vomiting)

2-4 days Elevation of liver enzyme, hepatomegaly, jaundice, coauglopathy
>4 days Renal impairment,hepatic enchepalopathy
Management

 Activated charcoal within 4 hours of ingestion

 N- acetylcysteine only indicated in patients having high risk for hepatotoxicity
 MOA - Repletes GSH stores , may conjugate directly with NAPQI