MODULE VI: AUTACOIDS

HISTAMINE AND ANTIHISTAMINE AGENTS

HISTAMINE:
L-Histidine (basic a.a.) L-histidine decarboxylase Histamine
SITE: mast cells and basophils

RECEPTOR LOCATION RESPONSE

H1 ❖ Vascular smooth muscle Vasodilation
❖ Non-vascular smooth muscle Bronchoconstriction
(bronchi)
❖ Endothelial cells of capillaries Capillary contraction
❖ Sensory endings Itching and pain
❖ Brain CNS stimulation
H2 ❖ Parietal cells of the stomach Gastric acid secretion

Histamine and Antihistamine Agents:

1. Histamine Agonists
2. Histamine 1 receptor Antagonists (1st Gen and 2ndGen Antihistamines)
3. Mast Cell Stabilizers
4. Dual-Acting Antihistamines
5. Histamine 2 Receptor Antagonists

1. Histamine Agonists
Histamine PO4 To Dx impairment of the acid-producing cells of the stomach and vascular d/ses---also induce
pdn of HCl
Betazole HCl Same with Histamine PO4

2. Histamine 1 Receptor Antagonists

FIRST GENERATION H1 RECEPTOR ANTAGONISTS
a. Aminoalkyl ethers/ Ethanolamines
1. Diphenhydramine HCl (BENADRYL) Antihistaminic, antiemetic, antidyskinetic (adjunct in
the mgt of PD) antitussive, sedative
2.Dimenhydrinate (DRAMAMINE) Recommended for the nausea of motion sickness and
for hyperemesis gravidarum
3. Doxylamine succinate (DECAPRYN, UNISOM soft Comparable with diphenhydramine
gel cap)
4. Clemastine fumarate (TAVIST) Has significant antimuscarinic/antichollnergic effects

FIRST GENERATION H1 RECEPTOR ANTAGONISTS

b. Ethyldiamines – high frequency of CNS depression and GI S/Es
1. Tripenelamine - citrate – more palatable
- HCl – lesser S/Es
2. Pyrilamine maleate (ANTERGAN) Local anesthetic effect on buccal mucosa
3. Methapyrilene HCI (HISTADLY) Withdrawn from the market
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4. Thonzylamine HCI Similar to tripenelamine but less toxic

PhChem201 LEC 2nd sem Prep by: GMBayeng, RPh.

 FIRST GENERATION H1 RECEPTOR ANTAGONISTS
c. Propylamine derivatives or Pheniramines/Alkylamine/Monoaminopropyl derivatives
1. Pheniramine maleate Causes sedation and less potent
2. Pyrrobutamine Has feeble antihistaminic properties
3. Triprolidine (ACTIDIL) comparable effect with dexchlorpheniramine

FIRST GENERATION H1 RECEPTOR ANTAGONISTS

d. Phenothiazine derivatives
1.Promethazine HCI (PHENERGAN) moderately potent, has a prolonged action (12-24 hrs.) and pronounced
sedating SEs
2. Trimeprazine (TEMARIL) pronounced antipruritic axn
3. Methdilazine (TACARYL) taken orally with food for antipruritic effect

e. Cyproheptadine – used in the mgt of serotonin syndrome

FIRST GENERATION H1 RECEPTOR ANTAGONISTS
f. Piperazine derivatives/Cyclizines
1. Cyclizine HCI (MAREZINE) Tx for motion sickness
2. Mecilizine HCI (BONAMINE, ANTIVERT, DIZITAB) moderately potent
3. Bucilizine HCI (BUCLADIN) CNS depressant, anti-emetic, antihistaminic
4. Hydroxyzine (ITERAX) slow onset, long duration

SECOND GENERATION H1 RECEPTOR ANTAGONISTS

A. True Non-sedating: No dosing effect
1. Fexofenadine HCI (ALLEGRA, FEXET, TELFAST, Oxidative metabolite of terfenadine
FENAFEX) Do not cause Torsades de Pointes
2. Loratadine (CLARITIN, ALERTA, ZYLOHIST, OMENIN, Related to azatadine and cyproheptadine no
LORID) substantial CNS or autonomic S/E or cardiotoxicity
3. Desloratadine (AERIUS) Active metabolite of loratadine

SECOND GENERATION H1 RECEPTOR ANTAGONISTS

B. Less-sedating
1.Ceterizine (ZYRTEC, CETRIZ, AFORVIR, VIRTEX, Only 2nd gen antihistamine that causes sedation
CETIMIN) polar, long-acting, rapid onset of action
2. Activastine ([+] PSEUDOEPHEDRINE) Analogue of triprolidine but does not display
SEMPREX) significant anticholinergic activity

3. Mass Cell Stabilizers/ Inhibitor of Histamine Release

- prevent degranulation – X histamine release – used in the tx of allergy
- release of histamine is due to the degranulation of mast cells and basophils
Mast Cell Stabilizers (Prototype: Khellin from Ammi visnaga)
1. Cromolyn Na (INTAL) Local activity, for bronchial asthma tx, prevention of exercise-induced
bronchospasm
2.Nedocromil Na (TILADE) Broader pcologic action than cromolyn
3. Lodoxamide (ANALIDE) tx vernal keratoconjunctivitis and vernal keratitis
4. Pemirolast (ALAMAST) Prevention of allergic conjunctivitis (eye itching)
5. Azelastine (HISMANAL) When admin ophthalmically - transient blurring and stinging sensation on
2

instillation
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PhChem201 LEC 2nd sem Prep by: GMBayeng, RPh.

 4. Dual acting Antihistamines – inhibit the release of histamine and other inflammatory mediators & stabilize
the mast cells. Also, they are selective histamine inhibitors → blocks histamine receptors
Products:
1. Ketotifen (ZADITOR)- ADR: conjunctival infection, HA, rhinitis

5. Histamine 2 Receptor Antagonists – “tidine” used in tx of acid-peptic d/o like gerd & peptic ulcer
1. Cimetidine Has antiandrogenic activity – gynecomastia and galactorrhea
(TAGAMET) Decrease libido, and short acting requiring & poorly selective
Inhibit CYP450 enzyme system in the liver
2. Famotidine - does not cause gynecomastia & also not an inhibitor of CYP enzyme
(PEPCID, H2-BLOC) - 40-55% bioavailable – taken OD
- absorption is not affected by food
3. Ranitidine -50-60% bioavailable ----- - week inhibitor of the CYP enzyme
(ZANTAC) - antacids lowers absorption
4. Nizatidine (AXID) - 90% (excellent) bioavailability----- -doe not inhibit the CYP enzyme
- not anti-androgenic effect

Serotonin

aka: 5-hydroxytryptamine OR5 HT

Tryptophan hydroxylation 5-hydroxytryptophan decarboxylation 5-hydroxytryptamine

SITE: enterochromaffin cells (small intestine), brain, platelets

RECEPTORS LOCATION REPONSE

5-HT1A Presynaptic in the raphe nuclei of the CNS Inhibition of further release of
central serotonin
5-HT1D/1B Peripheral blood vessels Vasoconstriction
5-HT2A Peripheral smooth muscles including vascular Contraction
smooth muscles
5-HT3 Area postrema of the CNS Chemoreceptor Trigger Vomiting – emesis, abdominal rain
Zone
5-HT4 GIT peristalsis

SUMMARY OF EFFECTS

Central Peripheral

Mood regualation, temperature and BP regulation, Vasoconstriction of all blood vessel

appetite, paln perception, vomiting platelet aggregation
peristalsis

Drugs:
1. 5-HT1A – Buspirone (BUSPAR) – anxiolytic relieves anxiety
→ Partial agonist
2. 5-HT18/1D – Triptans – full agonist for mngt of migraines but may worsen HTN, & precipitate angina
-- Contraindicated to CAD
3

- Sumariptan (IMIGRAN, SUMIGRAN)

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- Zolmeriptan (RELPAX, ZOMIG)

PhChem201 LEC 2nd sem Prep by: GMBayeng, RPh.
 - Naratripan (AMERGE)
→ Agonists
3. 5-HT2A – agonists: Vasoconstrictors
→ Ergotamine (CAFERGOT, MIGRIL, AVAMIGRAN)
- tx of migraine
→ Ergonovine (ERGOTRATE)
- oxytocic; for mgt of post-partum hemorrhage
- antagonists:
→ Methysergide (DESERIL,SANSERT)
- prophylaxis of migraine HA
4. 5-HT3 – antagonists: Setrons (antiemetics – mgt of chemotherapy-induced emesis)
→ Ondansetron (CIPLA, ZOFRAN)
→ Granisetron (KYTRIL)
5. 5-HT4 – agonist:
→ Tegaserod (ZELNORM)
- used in IBS and constipation

SEROTONIN RECEPTORS
Receptors Location Effect
5-HT1A Peripheral CNS Inhibition of release of serotonin
5-HT1B/1D Blood vessel Vasoconstriction
5-HT2A Smooth muscles Contraction
5-HT3 CNS-Chemoreceptor Triger Zone Emesis, abdominal pain
5-HT4 GIT Peristalsis

Eicosanoids
• Eicosatetraenoic acid – derived from membrane phospholipids – requires Phospholipase A2
• Arachidonic acid – 20C polyunsaturated FA with 4 double bonds at C5,8,11,14
- enters Cox and LOX pathways
**LOX Pathway – Leukotrienes
- LTB4 – chemotactic factor
- LTC4 slow reacting substances for anaphylaxis
- LTD4 - bronchoconstriction

Effects of Eicosanoids
Location Effect Eicosanoids
Blood vessels Vasoconstriction TXA2, PGF2alpha
Vasodilation PG12, PGE series
GIT Cytoprotection PGE series esp. PGE1
Platelet Aggregation (clumping of platelets) TXA2
Inhibit aggregation PG12, PGE1
Bronchi Bronchoconstriction – Asthma LTC4, LTD4, TXA2
Bronchodilation PG12, PGE series
Uterus Uterine Contraction PGE series
Dysmenorrhea PGF2alpha
Eyes Decrease intraocular pressure PGE series, PGF2alpha
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PhChem201 LEC 2nd sem Prep by: GMBayeng, RPh.

 Antineoplastic Agents

CANCER- group of diseases characterized by uncontrolled growth & the spread of abnormal cells which when
left untreated may lead to death

CANCER CELLS- infinite dividing, lack of growth controls, ability to invade local tissue, ability to spread

Cell Life Cycle/ Phases of the Cell Cycle

1. M Phase/ Mitosis- cell divides into two daughter cells
2. G1 Phase/ Post- mitotic gap phase- where RNA & CHONs for special fxns are synthesized
3. S Phase- DNA synthesis
4. G2 Phase/ Pre-mitotic/ Post synthetic gap- RNA & topoisomerase enzymes I & II are produced
5. G0 Phase/ Resting Phase- cell is not dividing, not sensitive to chemotherapy

CHEMOTHERAPY – refers to drugs that are used to kill cells & includes both antibiotics & agents used in the
treatment of cancer.
Chemotherapeutic Agents: Usually in combination to affect different phases of the cell cycle & produce a great
cell kill.
GENERAL TYPES OF CHEMOTHERAPEUTIC AGENTS
1. Phase- specific Agents a. M Phase- vinca alkaloids, taxanes
b. G1 Phase- asparaginase, prednisone
c. S Phase- antimetabolites
d. G2 Phase- bleomycin, etoposide
2. Phase Non- specific Agents Effective in cells on the active cycle not necessarily in a particular phase
(Eg. Alkylating agents, Antitumor antibiotics, Cisplatin)
3. Cell-cycle non- specific Effective in all phase including G0 (Eg. Nitrosureas, Radiation)

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

1. Alkylating Agents Prototype is meclorethamine/ nitrogen mustard
Causes cross- linking & base pairing of DNA strands to inhibit DNA
replication
2. Antitumor Antibiotics Cause alkylation or intercalation (sliding between DNA pairs to inhibit
DNA synthesis)
3. Antimetabolites Inhibit DNA synthesis by acting as false substitutes in nucleic acid
production
4. Plant Alkaloids Vinca alkaloids- prevent formation of mitotic spindle
Camptothecins- inhibit topoisomerase I
Podophyllotoxins- inhibit topoisomerase II (responsible for DNA
replication & RNA transcription)
Taxanes- promote microtubule assembly prohibiting cell division
5. Hormones Varying effects
6. Asparaginase Enzyme that degrades essential amino acid aspartic acid & ammonia
Not synthesized by cancer cells
7. Biologic Response Modifiers Alter or enhance immune system to fight cancer or lessen side effects

“it’s the possibility of having a dream come true that makes life interesting so never give up.”
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PhChem201 LEC 2nd sem Prep by: GMBayeng, RPh.