1.

histamine: Excess production of histamine in the body (eg, in systemic mastocytosis) can be
detected by measurement of its major metabolite, imidazole acetic acid, in the urine. Because it
is released from mast cells in response to IgE-mediated (immediate) allergic reactions, this
autacoid plays a pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and
angioneurotic edema. Histamine also plays a physiologic role in the control of acid secretion in
the stomach and as a neurotransmitter. Fish that has been stored improperly generates high
concentrations of histamine; consumption of such fish may produce severe histamine toxicity
(“scombroid poisoning”).

Serotonin: plays a physiologic role as a neurotransmitter in both the CNS and the enteric nervous
system and may have a role as a local hormone that modulates gastrointestinal activity. After
release from neurons, it is partially taken back up into the nerve ending by a serotonin reuptake
transporter (SERT). Serotonin is also stored (but synthesized to only a minimal extent) in
platelets.

2. The older members of the first-generation agents, diphenhydramine, are highly sedating
agents A newer subgroup of first-generation agents is less sedat- ing and has much less
autonomic effect. Chlorpheniramine and cyclizine, dimenhydrinate, cyclizine, meclizine, and
promethazine may be considered prototypes.

The second-generation H1 blockers, typified by cetirizine, fexofenadine, and loratadine, are far
less lipid soluble than the first-generation agents and have greatly reduced sedating and
autonomic effects.Most are metabolized extensively in the liver.

first-generation agents have anti-motion sickness effects.

H1 blockers have major applications in allergies of the immediate type (ie, those caused by
antigens acting on IgE antibody-sensitized mast cells). These conditions include hay fever
and urticaria. Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine
are used as anti-motion sickness drugs. Diphen- hydramine is also used for management
of chemotherapy-induced vomiting. Doxylamine, in combination with pyridoxine, is pro-
moted for the prevention of morning sickness in pregnancy.*

Adverse effects of the first-generation H1 blockers are some- times exploited

therapeutically (eg, in their use as hypnotics in over-the-counter sleep aids).

Some of the more common side effects of first-generation antihistamines can include:
drowsiness. dry mouth, nose, and throat. headache.

3. 5-HT1D/1B agonists—Sumatriptan they are the first-line treatment for acute migraine
and cluster headache attacks, an observation that strengthens the association of serotonin
abnormalities with these headache syndromes. These drugs are active orally; sumatriptan
is also available for nasal and parenteral administration. Sumatriptan selectively binds to
and activates serotonin 5-HT1D receptors in the central nervous system (CNS), thereby
constricting cerebral blood vessels. This may lead to a relief in pain from vascular
headaches.
4. 5-HT2C agonists—Lorcaserin has been approved for the treatment of obesity. It
activates receptors in the CNS and appears to moderately reduce appetite. Older agonist
drugs, fenfluramine and dexfenfluramine, appear to act directly and by releasing
neuronal 5-HT or inhibiting SERT, and thereby activat- ing central 5-HT2C receptors.

: Ketanserin, phenoxybenzamine, and cyproheptadine are effec- tive 5-HT2 blockers.

Ondansetron, granisetron, dolasetron, and alosetron are 5-HT3 blockers. The ergot
alkaloids are partial agonists (and therefore have some antagonist effects) at 5-HT and
other receptors (see later discussion).

8. Cyclooxygenase has at least 2 isoforms: COX-1 and COX-2. COX-1 is primarily

expressed in noninflammatory cells, whereas COX-2 is expressed in activated
lymphocytes, polymorphonuclear cells, and other inflammatory cells. Aspirin and
nonselective NSAIDs inhibit both cyclooxygenase isoforms and thereby decrease
prostaglandin and thromboxane synthesis throughout the body. Release of prostaglandins
necessary for homeostatic function is disrupted, as is release of prostaglandins involved in
inflammation. The COX-2-selective inhibitors have less effect on the prostaglandins
involved in homeostatic function, particularly those in the gastrointestinal tract.

The major difference between the mechanisms of action of aspirin and other NSAIDs is
that aspirin (but not its active metabolite, salicylate) acetylates and thereby irreversibly
inhibits cyclooxygenase, whereas the inhibition produced by other NSAIDs is reversible.
The irreversible action of aspirin results in a longer duration of its antiplatelet effect and
is the basis for its use as an antiplatelet drug

Aspirin—Aspirin has 3 therapeutic dose ranges: The low range (<300 mg/d) is effective in
reducing platelet aggrega- tion; intermediate doses (300–2400 mg/d) have antipyretic and
analgesic effects; and high doses (2400–4000 mg/d) are used for an anti-inflammatory
effect. Aspirin is readily absorbed and is hydrolyzed in blood and tissues to acetate and
salicylic acid. Salicylate is a reversible nonselective inhibitor of cyclooxygenase.
Elimination of salicylate is first order at low doses, with a half-life of 3–5 h. At high (anti-
inflammatory) doses, half-life increases to 15 h or more and elimination becomes zero
order. Excretion is via the kidney.

9.Acetaminophen is the only over-the-counter non-anti inflammatory analgesic.The

mechanism of analgesic action of acetaminophen is unclear. The drug is only a weak
COX-1 and COX-2 inhibitor in periph- eral tissues, which accounts for its lack of anti-
inflammatory effect. Evidence suggests that acetaminophen may inhibit a third enzyme,
COX-3, in the CNS.

Acetaminophen is an analgesic and antipyretic agent; it lacks anti- inflammatory or

antiplatelet effects.

Acetaminophen is effective for the same indications as intermediate- dose aspirin.

Acetaminophen is therefore useful as an aspirin substitute, especially in children with
viral infections and in those with any type of aspirin intolerance. Acetaminophen is well
absorbed orally and metabolized in the liver. Its half-life, which is 2–3 h in persons with
normal hepatic function, is unaffected by renal disease.

toxicity: However, when taken in overdose or by patients with severe liver impairment,
the drug is a dangerous hepatotoxin. The mechanism of toxicity involves oxidation to
cytotoxic inter- mediates by phase I cytochrome P450 enzymes.