Pharmacology note

1. AUTACOIDS ANDTHEIR
ANTAGONISTS
Prepared by: Mahreen Siddique
Lecturer (RLCP)

2. OBJECTIVES
To explain the autacoids and its classification.
To explain Mechanism of action, Pharmacological actions,
therapeutic uses and adverse effects of Histamine
To explain Mechanism of action, Pharmacological actions,
therapeutic uses and adverse effects of H1 antagonists
To explain Mechanism of action, Pharmacological actions,
therapeutic uses and adverse effects of H2 antagonist

3. AUTACOIDS
 Autacoids are naturally occurring
substances having widely different
structures and pharmacological activities.
 These are diverse substances produced by a
wide variety of cells in the body, having
intense biological activity, but generally act
locally (e.g. within inflammatory pockets)
at the site of synthesis and release.

4. They are released from non- neuronal tissues.
 The term autacoid is derived from Greek
“autos” = self and “akos” = remedy
They have also been called ‘local hormones’

5.  Many tissues contain substances that, when released by various stimuli,
cause physiologic effects such as reddening of the skin, pain or itching, and
bronchospasm.
 Later, it was discovered that many of these substances are also present in
nervous tissue and have multiple functions.
 Histamine and serotonin (5-hydroxytryptamine, 5-HT) are biologically
active amines that function as neurotransmitters and are found in non-
neural tissues, have complex physiologic and pathologic effects through
multiple receptor subtypes, and are often released locally.

6. CLASSIFICATION
AMINES
DERIVED
• Histamine
• Serotonin
PEPTIDE
DERIVED
• Angiotensin
• Kinins
• Substance P
• Vasoactive
intestinal
polypeptide (VIP)
LIPID DERIVED
• Prostaglandins
• Leukotrienes
• Interleukins
• Thromboxane
• Platelet
activating factors

7. FUNCTIONS
 Physiological (including modulating the activities of smooth muscles, glands,
nerves, platelets and other tissues)
 Pathophysiological (Reaction to injuries i.e; reddening of the skin, pain or
itching, and bronchospasm)
 Transmission and Modulation

8. HISTAMINE AND ANTI-
HISTAMINES

9. HISTAMINE
 Chemical messenger widely distributed in;
 Mast cells
 G.I. tract
 Lungs
 Skin
 CNS
 Chemically it is beta-imidazolethylamine.

10.  Mediates a wide range of cellular responses via multiple receptor systems
including;
Allergic and inflammatory reactions
Gastric acid secretion
Neurotransmission in parts of the brain
Role in immune function and chemotaxis of white blood cells
 Has no clinical applications, but agents that inhibit the action of
histamine (antihistamines) have important therapeutic applications.

11. LOCATION OF HISTAMINE
 Present in practically all tissues, with significant amounts in the
 Lungs
 Skin
 Blood vessels
 GI tract (parietal cells)
 At high concentration in;
 Mast cells
 Basophils
 As a neurotransmitter in the brain

12. SYNTHESIS OF HISTAMINE
Histidine Histamine
Imidazole acetic acid (IAA)
Decarboxylation
Histidine Decarboxylase
(neurons,
gastric
parietal
cells, mast
cells, and
basophils)
(Store in granules
bound with
heparin in Mast
cells)
Amine
oxidase
If not stored,
rapidly
inactivated

13. RELAEASE OF HISTAMINE
STIMULI RELEASE OF HISTAMINE
(Destruction of cells
as a result of cold,
toxins from
organisms, venoms
from insects and
spiders, and trauma,
Allergies and
anaphylaxis)
(Degranulation of
histamine from
mast cells and
basophils)

14. 1- Immunologic Release:
Histamine is released from mast cells by exocytosis during
inflammatory or allergic reactions (cell-fixed IgE antibodies interact
with an antigen).
Mast cells, if sensitized by surface IgE antibodies, degranulate and
rapidly release many active compounds including histamine when
exposed to specific antigen (the immediate (type I) allergic reaction).

15. 2- Non-immune mechanisms:
Mechanical/chemical release any physical or chemical agent that
injures tissue, skin or mucosa are particularly sensitive to injury and
will cause the immediate release of histamine from mast cells.
3- Drugs and other foreign compounds:
Morphine, dextran, quaternary ammonium compounds - d-
tubocurarine, penicillins, tetracyclines toxins, venoms.

17. MECHANISM OF ACTION
 Histamine exerts its biologic actions by combining with specific cellular
receptors located on the surface membrane.
 Four different histamine receptors have been characterized and are
designated H 1, H 2, H 3, H 4.
 These are G protein coupled receptors.

18. Receptor
Subtype
Distribution Post receptor
Mechanism
H1 Smooth muscle, endothelium, brain Gq, ↑ IP3, DAG
H2 Gastric mucosa, cardiac muscle,
mast cells, brain
Gs, ↑ cAMP
H3 Presynaptic autoreceptors and
heteroreceptors: brain, myenteric
plexus, other neurons
Gi, ↓ cAMP
H4 Eosinophils, neutrophils, CD4T cells Gi, ↓ cAMP

20. TISSUE AND ORGAN SYSTEM EFFECTS OF
HISTAMINE
 Histamine exerts powerful effects on;
Smooth and cardiac muscle,
 Certain endothelial and nerve cells,
 Secretory cells of the stomach,
 Inflammatory cells.

21. 1-Nervous system:
Powerful stimulant of sensory nerve endings, especially those
mediating pain and itching.
2-Cardiovascular system:
Causes a decrease in systolic and diastolic blood pressure and an
increase in heart rate.
Blood pressure changes are caused by the direct vasodilator action of
histamine on arterioles and precapillary sphincters mediated by nitric
oxide from endothelium.

22. Increase in heart rate involves both stimulatory actions of histamine
on the heart and a reflex tachycardia.
Flushing, a sense of warmth, and headache may also occur.
3-Bronchiolar smooth muscle:
Histamine causes bronchoconstriction mediated by H 1 receptors

23. 4-Gastrointestinal tract smooth muscle:
Histamine causes contraction of intestinal smooth muscle.
This action of histamine is mediated by H 1 receptors.
5- Secretory tissue:
Powerful stimulant of gastric acid secretion and, to a lesser extent,
of gastric pepsin and intrinsic factor production.
The effect is caused by activation of H 2 receptors on gastric
parietal cells.

24. 6-Metabolic effects:
Recent studies of H 3 -receptor knockout mice demonstrate that
absence of this receptor results in animals with increased food intake,
decreased energy expenditure, and obesity.
They also show insulin resistance and increased blood levels of leptin
and insulin.
It is not yet known whether the H 3 receptor has a similar role in
humans.

25. 7-The “triple response”:
 Intradermal injection of histamine causes a characteristic red spot,
edema, and flare response.
At the site of injection, a reddening appears owing to dilation of
small vessels, followed soon by an edematous wheal at the injection
site and a red irregular flare surrounding the wheal. A sensation of
itching may accompany these effects.

26. 8-Other effects possibly mediated by histamine receptors:
In addition to the local stimulation of peripheral pain nerve endings
via H 3 and H 1 receptors, histamine may play a role in nociception
in the central nervous system.

27. 9-Role in allergy and anaphylaxis:
The symptoms resulting from intravenous injection of histamine are
similar to those associated with anaphylactic shock and allergic
reactions.
These include;
Contraction of airway smooth muscle,
Stimulation of secretions,
Dilation and increased permeability of the capillaries,
Stimulation of sensory nerve endings.

29. CLINICAL USES OF HISTAMINE
In pulmonary function laboratories, histamine aerosol has been used as a
provocative test of bronchial hyperreactivity.
 Histamine has no other current clinical applications.

30. ADVERSE EFFECTS
 Adverse effects of histamine release, like those following administration of
histamine, are dose related.
Flushing
Hypotension
Tachycardia
Headache
Wheals
Bronchoconstriction
Gastrointestinal upset

31. CONTRAINDICATIONS
 Histamine should not be given to patients with asthma (except as part of a
carefully monitored test of pulmonary function) or to patients with active
ulcer disease or gastrointestinal bleeding.

32. HISTAMINE
RECEPTOR
ANTAGONISTS

33. H 1 -RECEPTOR
ANTAGONISTS
The H1-receptor blockers can be divided into
first- generation and second-generation.
The older first-generation drugs penetrate
the CNS and cause sedation
The second-generation agents are specific
for peripheral H1 receptors, do not
penetrate the blood–brain barrier, causing
less CNS depression than the first-
generation drugs

34. FIRST-GENERATION ANTIHISTAMINES
Ethanolamines
Carbinoxamine
Dimenhydrinate (salt of diphenhydramine)
Diphenhydramine
Piperazine derivatives
Hydroxyzine
Cyclizine
Meclizine
Alkylamines:
Brompheniramine
Chlorpheniramine
Phenothiazine derivative:
Promethazine
Miscellaneous:
Cyproheptadine

35. SECOND-GENERATION ANTIHISTAMINES
Piperidine:
Fexofenadine
Miscellaneous:
Loratadine
Desloratadine
Cetirizine

37. PHARMACOKINETICS
 Rapidly absorbed after oral administration, with peak blood
concentrations occurring in 1–2 hours.
 Widely distributed throughout the body, and the first-generation drugs
enter the central nervous system readily.
 Average plasma half-life is 4 to 6 hours.
 Some of them are extensively metabolized, primarily by microsomal
systems in the liver. Several of the second-generation agents are
metabolized by the CYP3A4 system
 The duration of action for many oral antihistamines is 24 hours, allowing
once-daily dosing.

38. Drugs Usual Adult dose
FIRST GENERATION
Carbinoxamine 4–8 mg
Dimenhydrinate 50 mg
Diphenhydramine 25–50 mg
Hydroxyzine 15–100 mg
Cyclizine 25–50 mg
Meclizine 25–50 mg
Brompheniramine 4–8 mg
Chlorpheniramine 4–8 mg
Promethazine 10–25 mg
Cyproheptadine 4 mg

39. SECOND GENERATION
Fexofenadine 60 mg
Loratadine 10 mg
Cetirizine 5–10 mg

40. MECHANISM OF ACTION
 Both neutral H 1 antagonists and inverse H 1 agonists reduce or block the
actions of histamine by reversible competitive binding to the H 1 receptor.
 They have negligible potency at the H 2 receptor and little at the H 3
receptor.

42. ACTIONS
 The first-generation H 1 -receptor antagonists have many actions in
addition to blockade of the actions of histamine.
 The large number of these actions probably results from the similarity of
the general structure to the structure of drugs that have effects at;
 Muscarinic cholinoceptor,
 α adrenoceptor,
 Serotonin,
 Local anesthetic receptor sites

43. 1. Sedation:
A common effect of first-generation H 1 antagonists is sedation, but
the intensity of this effect varies among chemical subgroups.
The effect is sufficiently prominent with some agents to make them
useful as “sleep aids” and unsuitable for daytime use.
Secondgeneration H 1 antagonists have little or no sedative.
2. Anti-nausea and antiemetic actions:
Several firstgeneration H 1 antagonists have significant activity in
preventing motion sickness.

44. 3. Anti-parkinsonism effects:
Some of the H 1 antagonists, especially diphenhydramine , have
significant acute suppressant effects on the extrapyramidal symptoms
associated with certain antipsychotic drugs.
4. Anti-cholinoceptor actions
Many first-generation agents, have significant atropine-like effects on
peripheral muscarinic receptors.This action may be responsible for
some of the (uncertain) benefits reported for nonallergic rhinorrhea but
may also cause urinary retention and blurred vision.

45. 5. Adrenoceptor-blocking actions:
Alpha-receptor blocking effects cause orthostatic hypotension in
susceptible individuals. Beta-receptor blockade is not observed.
6. Serotonin-blocking action:
Strong blocking effects at serotonin receptors have been
demonstrated for some first-generation H 1 antagonists, notably
cyproheptadine.
7. Local anesthesia:
Several first-generation H 1 antagonists are potent local anesthetics.
They block sodium channels in excitable membranes in the same
fashion as procaine and lidocaine.

47. THERAPEUTIC USES
1. Allergic and inflammatory conditions:
Oral antihistamines are the drugs of choice in controlling the
symptoms of allergic rhinitis and urticaria.
Useful for the treatment of allergic conjunctivitis.
2. Motion sickness and nausea:
Along with the antimuscarinic agent scopolamine, certain H1-receptor
blockers are the most effective agents for prevention of the symptoms
of motion sickness.

48. Usually not effective if symptoms are already present and, thus, should
be taken prior to expected travel.
Antiemetic action of these medications seems to be due to their
blockade of central H1 and M1 muscarinic receptors.
3. Somnifacients:
Although they are not the medications of choice, many first-generation
antihistamines, have strong sedative properties and are used in the
treatment of insomnia.
These agents are available over-the-counter (OTC), or without a
prescription.

49. ADVERSE EFFECTS
CNS:
Sedation is common with first-generation H1 antihistamines
Diphenhydramine may cause paradoxical hyperactivity in young children
Other central actions include fatigue, dizziness, lack of coordination, and
tremors
Sedation is less common with the second-generation drugs, since they do
not readily enter the CNS.

50. Other effects:
First-generation antihistamines exert anticholinergic effects, leading
not only to dryness in the nasal passage but also to a tendency to dry
out the oral cavity.They also may cause blurred vision and retention of
urine.
The most common adverse reaction associated with second-
generation antihistamines is headache.
Topical formulations of diphenhydramine can cause hypersensitivity
reactions such as contact dermatitis when applied to the skin.

51. DRUG INTERACTIONS
Patients taking monoamine oxidase inhibitors (MAOIs) should not take
antihistamines because the MAOIs can exacerbate the anticholinergic
effects of the antihistamines.
The first-generation antihistamines (diphenhydramine and others) with
anticholinergic (antimuscarinic) actions may decrease the effectiveness of
cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) in the
treatment of Alzheimer’s disease.

52. H 2 -RECEPTOR
ANTAGONISTS
Antagonists of the histamine H2 receptor
block the actions of histamine at all H2
receptors, their chief clinical use is as
inhibitors of gastric acid secretion in the
treatment of ulcers and heartburn.

53. H 2 -RECEPTOR ANTAGONISTS
 Four H 2 antagonists are in clinical use:
 Cimetidine,
 Ranitidine,
 Famotidine,
 Nizatidine.

54. PHARMACOKINETICS
 All four agents are rapidly absorbed from the intestine.
 Cimetidine, ranitidine, and famotidine undergo first-pass hepatic
metabolism resulting in a bioavailability of approximately 50%. Nizatidine
has little first-pass metabolism.
 The serum half-lives of the four agents range from 1.1 to 4 hours; however,
duration of action depends on the dose given.
 Cimetidine, ranitidine, and famotidine are also available in intravenous
formulations.
 The half-life of all of these agents may be increased in patients with renal
dysfunction, and dosage adjustments are needed.

55. MECHANISM OF ACTION
The H 2 antagonists exhibit competitive inhibition at the parietal cell H 2
receptor and suppress basal and meal-stimulated acid secretion.
 They are highly selective and do not affect H 1 or H 3 receptors .
 The volume of gastric secretion and the concentration of pepsin are also
reduced.

57. THERAPEUTIC USES
A. Gastroesophageal Reflux Disease (GERD):
 Patients with infrequent heartburn or dyspepsia (fewer than 3 times
per week)
 H 2 antagonists may be taken prophylactically before meals in an
effort to reduce the likelihood of heartburn
Frequent heartburn is better treated with twice-daily H 2 antagonists

58. B. Peptic Ulcer Disease:
Proton pump inhibitors have largely replaced H 2 antagonists in the
treatment of acute peptic ulcer disease. Nevertheless, H 2 antagonists
are still sometimes used.
Nocturnal acid suppression by H 2 antagonists affords effective ulcer
healing in most patients with uncomplicated gastric and duodenal
ulcers.

All the agents may be administered once daily at bedtime, resulting in
ulcer healing rates of more than 80–90% after 6–8 weeks of therapy.

59. C. Non-ulcer Dyspepsia:
 H 2 antagonists are commonly used as over-the-counter agents and
prescription agents for treatment of intermittent dyspepsia not caused
by peptic ulcer.
D. Prevention of Bleeding from Stress-Related Gastritis:
 used in Clinically important bleeding from upper gastrointestinal
erosions or ulcers result of impaired mucosal defense mechanisms
caused by poor perfusion.
Continuous infusions of H 2 antagonists are generally preferred to
bolus infusions because they achieve more consistent, sustained
elevation of intragastric pH.

60. ADVERSE EFFECTS
 H 2 -antagonists are extremely safe drugs.
Adverse effects occur in less than 3% of patients and include diarrhea,
headache, fatigue, myalgias, and constipation.
 Other central nervous system effects (such as confusion and altered
mentation) occur primarily in elderly patients and after intravenous
administration.
Cimetidine can have endocrine effects include gynecomastia and
galactorrhea (continuous release/discharge of milk).

61. DRUG INTERACTIONS
 Cimetidine interferes with several important hepatic cytochrome P450
drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9,
CYP2D6, and CYP3A4, interfere with the metabolism of many other drugs,
such as warfarin, phenytoin, and clopidogrel.
 Negligible interaction occurs with nizatidine and famotidine.

62. REFERENCE BOOKS
Katzung, B.G., 2011. Basic and
Clinical Pharmacology. 12th Ed.,
McGraw-Hill Medical Publishers,
NewYork, USA.
Richard, F., M. Clark and L.
Cubbedu, 2011. Lippincott’s
Illustrated Reviews, Pharmacology.
5th Ed., Lippincott William &
Wilkins, USA.