1.

12 Autacoids PHARMACOLOGY
Dr. Rivadillo| July 10, 2013 1st 2013-2014

OUTLINE
I. Autacoids b. Chemical
II. Histamine
A. Effects of Histamine
 Bound histamine in granules is displaced by other
B. Clinical Uses of Histamine substances like morphine, Tubocurarin or Vancomycin
C. How to Counteract the Effects of Histamine (resulting in Red Man syndrome)
D. Histamine receptor Antagonists  No degranulation is involved
E. Subgroups of 1st Generation Antihistamines  Not receptor mediated
F. Subgroups of 2nd Generation antihistamines
G. Uses of Antihistamines
III. Serotonin c. Mechanical/Physical
A. 5HT Receptor Agonists  Injuries result in mast cell damage (E.g. Vigorous
IV. Ergot Alkaloids scratching of skin produces wheals or red lines due to
A. Ergonovine Methylergonovine histamine release)
B. Ergotamine, Dihydroergotamine
C. Adverse Reactions of Ergot Alkaloids  Actions
D. Contraindications o Mediated by 4 types of GPCR
2+
V. Prostaglandins  H1 (Gq) – Increase in IP3 and intracellular Ca
A. Prostaglandin Analogs  H2 (Gs) – Increase in cAMP
VI. Nitric Oxides  H3 (Gi) – Decrease in cAMP
References: From Lecture  H4 (Gi) – Decrease in cAMP
Italicized: Basic Clinical Pharmacology-Katzung
Table 1. Histamine receptor Subtypes
Receptor Distribution Postreceptor
Subtype Mechanism
I. AUTACOIDS AND ANTI-AUTACOIDS H1 Smooth muscle, endothelium, Gq, Increased IP3,
Autacoids brain DAG
 Substances that act to remedy the body. From the Greek words H2 Gastric mucosa, cardiac Gs, Increased cAMP
autos (self) and akos (remedy). muscle, mast cells, brain
 Local hormones acting near their site of synthesis (paracrine). H3 Presynaptic autoreceptors and Gi, decreased cAMP
heteroceptors: brain,
 Biologically active diverse substances released in response to
myenteric plexus, other
various stimuli. neurons
 Main unifying feature: Act on smooth muscle H4 Eosinophils, neutrophils, CD4 Gi, decreased cAMP
 Autacoids to which drugs are available to mimic, enhance or T cells
antagonize their effects:
o Histamine
o Serotonin A. Effects of Histamine
o Ergot alkaloids 1. Cardiovascular System
o Prostaglandins, esp. prostanoids  Dilation of arterioles and pre-capillary sphincters
o Nitric oxide o Manifests as headache (dilation of cranial vessels) and
warmth, flushing and redness of the skin.
II. HISTAMINE o Receptors involved: H1 and H2
Histamine  H1: Immediate, short-lived response (mediated by
 Derived from amino acid histidine nitric oxide)
 Chief storage sites  H2: Slow, sustained response (mediated by cAMP
o Vesicles in mast cells and basophils and phosphokinase A pathway)
 The histamine content of many tissues is directly  Post-capillary vessels
related to their mast cell content o Increase in permeability
o In GIT: Enterochromaffin cells - H1-mediated
 Histamine functions as a gastric acid secretagogue  Edema- due to transudation of fluid and proteins
 Activates parietal cells of the mucosa  Urticaria (hives) – wheal formation signals
o In CNS: Histaminergic neurons presence of histamine
 Histamine functions as a neurotransmitter for  Direct cardiac effects
neuroendocrine control, cardiovascular regulation, o Increased force of atrial and ventricular contraction
thermal and body weight regulation and sleep and (H2)
wake cycles. o Increased depolarization of SA node resulting in
 Release of histamine tachycardia (H2)
a. Immunologic o Decreased AV node conduction (H1)
 Binding of antigen to IgE results in explosive  OVERALL EFFECT: Hypotension (due to arteriolar dilatation
degranulation of mast cells or basophils and increase in post-capillary vessel permeability) with
 Histamine is released along with other mediators reflex tachycardia (increased heart rate)
 Involved in Type I (Immediate) hypersensitivity

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Group Number 24: Hidalgo, Ibanez, Ibis, Icalabis, Imai, Jacoba, Jamito, Javier
 PHARMA 1.12

2. Gastrointestinal Tract  Distribution

st
 Increased gastric acid secretion (H2) – potent secretagogue 1 generation – can enter BBB (lipid-soluble)
nd
 Smooth muscle contraction (H1) – can promote diarrhea 2 generation – minimal or no entry to CNS (less
lipid-soluble and are substrates for P-glycoprotein
3. Respiratory System transporters, an efflux pump on the BBB)
 Asthmatic or highly sensitive airways – bronchoconstriction  Both are metabolized in the liver.
(H1)
 Normal airways – no effect Table 2. Pharmacokinetics of 1st and 2nd generation anti-histamines
1st 2nd
Absorption Good Good
4. Sensory Nerve Endings
Peak Levels 1-2 hrs. 1-2 hrs.
 Itch and pain in epidermis and dermis (H1)
Duration of 4-6 hrs. (most); 12-24 12-24 hrs.
effect hrs. (Meclizine/
5. Triple Response Bonamine)
 Intradermal (ID) injection of histamine causes red spot, Distribution Enter BBB (-)/ minimal
edema and flare response Metabolism Hepatic Hepatic
 3 cells involved: capillary or venular endothelium, sensory
nerve endings ad smooth muscle in the microcirculation o Pharmacodynamics
 3 responses:  MOA: Reduce or block histamine effects by reversible
o Reddening due to dilatation competitive binding to receptors
o Edematous wheal formation 1. Inhibit vasodilation (for head ache, flushing,
o Red irregular flare surrounding the wheal caused by warmth)
axon reflex 2. Block increase in capillary permeability (for edema
and urticaria)
B. Clinical Uses of Histamine 3. Suppress itching
 No therapeutic effect- noxious and life-threatening effects
o NO EFFECT on hypotension and bronchoconstriction
 Can be used for diagnostic tests
o Adverse Effects
o Bronchial hyperreactivity
1. Sedation
o Skin testing for allergies
- most prominent
st
 1 generation – common; intensity varies among
C. How to Counteract the Effects of Histamine subgroups
1. Use of physiologic antagonist, like Epinephrine or adrenaline, nd
2 generation – less or absent
esp. in cases of anaphylaxis  Manifestations: Sleepiness, decreased alertness,
2. Inhibiting release of Histamine slow reaction time
 Anti-asthma drugs, like mast cell stabilizers  Consequences: interfering with daytime activities,
 Reduce the degranulation of mast cells that results from performing tasks at work and impairing motor
immunologic triggering by antigen-IgE interaction skills
3. Antagonizing the effects of histamine at the receptors  Less common effect – Agitation or restlessness in
children
D. Histamine Receptor Antagonists
 MOA: block histamine effects by competitive antagonism 2. Cholinergic (Muscarinic) receptor blockade
st
o H2 receptor antagonist- used for treatment of peptic ulcer  Common in 1 generation
disease  Produces the following effects:
- Cough – dry mouth and respiratory passages
 H1-receptor antagonists - Constipation – decreased motility in GIT
st
o 1 Generation Anti-histamines - Urinary retention – decrease in bladder smooth
 Benadryl, Unisom (not available in the Phil.), Bonamine, muscle contraction
Bioflu Note:
nd
o 2 Generation anti-histamines Caution: In some elderly patients, obstruction
 Claritin, Allerta (both contain Loratidine) of urinary outlet (prostate enlargement) may
o Pharmacokinetics precipitate urinary retention

st nd
Both 1 and 2 generations are well-absorbed orally. - Blurring of vision – pupillary dilation (mydriasis)
 Both achieve peak levels after 1-2 hours. and paralysis of accommodation
 Duration of effect:
st
1 generation – most at 4-6 hours, except Meclizine 3. α-adrenergic receptor blockade
with lasts for 12-24 hours  Common in phenothiazine subgroup
nd
2 generation – 12-24 hours (can be taken less  Results in orthostatic hypotension- develops
frequently) when an individual assumes an upright position,
pooling of blood in the venous system is induced

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 PHARMA 1.12

by gravity, leading to decreased venous return  Less anticholinergic/ muscarinic effects

resulting to hypotension. a. Fexofenadine
 Normally, there should be a reflex activation of o Metabolite of terfenadine
the Sympathetic NS leading to vasoconstriction o Has no arrythmogenic potential
and increased HR but because of blockade of o Available as Allegra
adrenergic receptor, BP remains low.
 Manifestations: Dizziness and fainting or syncope *Terfenadine-­­prototype second generation H1 antagonist, but has
been pulled out because it causes cardiac arrhythmias, especially
4. GIT when combined with drugs that inhibit CYP3A4 (macrolides,
 Nausea, vomiting ketoconazole, itraconazole, and grapefruit juice). The mechanism for
 Loss of appetite cardiac arrhythmias is because of the blockade of the HERG potassium
 Epigastric distress channels in the heart that contribute to repolarization of the action
potential. The result is prolongation and a change in shape of the
E. Subgroups of 1st Generation Antihistamines action potential.
1. Ethanolamines
 Marked sedation b. Loratadine
 Strong muscarinic block o Claritin and Allerta
c. Desloratadine
 Low incidence of GIT adverse effects
o active metabolite of Loratadine
a. Diphenhydramine
o Oral solid & liquid
2. Piperazines
o Topical (lotion)
o Parenteral (IM or IV)- depends upon the severity  Minimal anticholinergic effects
o Brand name: Benadryl a. Cetirizine
nd
b. Dimenhydrinate o 2 Gen antihistamine
st
o Salt of diphenhydramine o Metabolite of hydroxyzine  1 Gen antihistamine
o Bound with chlorotheopyline to make it more stable o Contains active isomer Levocetirizine
o Anti-motion sickness effect o Verlix, Zyrtec
o Dramamine b. Levocetirizine (Xyzal)
c. Doxylamine o R-enantiomer of cetirizine
o Unisom
o Used as hypnotic agent 3. Phthalazinone
a. Azelastine
2. Piperazines o Oral (Tablet)
a. Hydroxyzine (ITERAX) o Topical – nasal spray and ophthalmic solution
o Atarax (brand name in other countries)
o Relieves pruritus and itch G. Uses of Antihistamines
b. Meclizine 1. Anti- allergy
o Aka Bonamine a. Urticaria (hives)- wheals with erythematous borders
accompanied by itching
3. Phenothiazine -H1 antagonists are the drugs of choice and effective if
 Represented by promethazine given prior to exposure
 Strong muscarinic block  Oral
 α–adrenergic block causes orthostatic hypotension o Diphenhydramine or Loratadine reduce the
 Marked sedation itchiness and erythema. Edema will not be
 Effective as anti-emetic (anti-vomitting) removed that fast
 Topical (Lotion)
4. Alkylamines o Calladril (Diphenhydramine) for mild and
1. Chlorpheniramine (Chlorphenamine) localized urticaria
o Less sedation/drowsiness  Parenteral
o Drug that can be used in daytime o Diphenhydramine Hydrochloride Injection for
o Also present in Bioflu. severe/serious ulticarial conditions
*Bioflu is a combination of anti-histamine (Chlorphenamine), b. Allergic Rhinitis- sneezing, watery eyes, runny and itchy nose,
analgesic antipyretic (Paracetamol), anti-­­congestant itchy throat
(Phenylephrine)  Oral
st nd
o 1 or 2 generation combined with +/-
F. Subgroups of 2nd Generation Antihistamines decongestant (Phenylephrine)
nd
o nasal spray (Azelastine- 2 Gen)
1. Piperidines
c. Allergic Conjunctivitis
 Highly selective for H1 receptors
 Edema and erythema of the conjunctiva and eyelids
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 PHARMA 1.12

 Watery and itchy eyes III. Serotonin

o Ophthalmic solution: Azelastine Serotonin
d. Other allergic conditions 1. synthesized from L-tryptophan by hyrdroxylation of the
 Asthma- does not respond to antihistamine. For acute indole ring followed by decarboxylation of the amino acid
attack, patient must be given bronchodilators 2. Storage
(Salbutamol); for prevention maintained on a. GIT: enterochromaffin cells (90%)
corticosteroids. b. Blood: platelets
 Anaphylaxis/ Laryngeal edema- systemic c. CNS- raphe nuclei of the brainstem
hypersensitivity wherein patient can develop - contains cell bodies of serotonergic neurons that
hypotension, bronchoconstriction and laryngeal edema synthesize, store and release serotonin
causing obstruction of breathing. Epinephrine 3. Actions of serotonin
IV/IM/auto-injector is used. Via serotonin receptors: 7 families (5-Ht)
Note: Patients with anaphylaxis should carry with them 6 is coupled in G protein
auto-injector of Epinephrine 1 is ligand gated ion channel- member of the nicotinic/
 Severe angioedema + +
GABAA family of NA , K channel proteins

2. Anti-motion sickness Serotonin involvement:

 Main transmitters: histamine and acetylcholine a) temperature control
 Arises when there is conflicting signals from vestibular b) sleep
apparatus, visual system and proprioceptors; vestibular c) appetite
nuclei which is close to the vomiting center d) mood
st
 Treated with 1 Generation antihistamines e) pain perception
 Given as PROPHYLAXIS 30 to 60 minutes before travel f) regulation of blood pressure
a. Diphenhydramine g) vomiting
b. Dimenhydrinate
c. Promethazine -serotonin appears to be involved in clinical conditions such
d. Meclizine as depression, anxiety and migraine.
 12- 24 hours efficacy
 Sedation is caused by this drugs 4. Clinical Use of serotonin: None
nd
 2 generation are not efficacious because it does not cross But there are drugs that can produce agonistic or
the blood brain barrier antagonistic effects on the receptors to manage effects of
 Scopolamine serotonin
o Not an antihistamine but an anti-muscarinic drug
o Antagonizes the muscarinic receptors A. 5- HT Receptor Agonist: Triptans (5-HT1d/1b)
 Very efficacious for motion sickness Migraine- severe throbbing headache.
 Oral, parenteral or transdermal - in its classical form, it is characterized by an aura of variable
 Recommended: Transdermal patch duration that may involve nausea, vomtting and even visual
 Effective for 72 hours and the patch should scotomas or even hemianopsia and speech abnormalities.
be applied 4 hours before the time of travel
1. used to abort acute migraine attacks (not for prophylaxis)
3. Anti‐emetic 2. MOA: activates 5-HT ID/IB Receptors present on cranial arteries
 Drug: Promethazine supplied by CN V
a. Vomiting due to chemotherapy or radiotherapy for - inhibit release if vasodilating peptides
malignancies - constrict the dilated cerebral blood vessels
b. Vomiting due to pregnancies are not recommended due to 3. Drug prototype: SUMATRIPTAN
ADRs - selective agonistsfor 5-HT1D/1B receptors
a. peak plasma levels
4. Anti Parkinsonism oral: .1.5-2 hr
 Drug: Diphenhydramine injection sc: 12 minutes
 2° to anti-psychotic (anti-schizophrenic) drugs single dose: 25-100mg(PO)
 Rigidity, tremors, abnormal movements due to imbalance in halflife: 2 hours
suppressing dopamine causing predomination of cholinergic b. Routes of administration
effects (extrapyramidal syndrome) Oral/SC/intranasal/rectal
 Centrally acting anticholinergics are used to control 4. ADR: chest discomfort or pain
extrapyramidal syndrome (EPS) - Muscle weakness: manifestation of severe vasospasm
- additional adverse effects are altered sensations (tingling,
5. Hypnotic (sleep aids) warmth), dizziness, neck pain, and for parenteral
a. Doxylamine sumatriptan injectionsite reaction.
b. Diphenhydramine
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 PHARMA 1.12

5. Contraindication : A. Ergonovine, Methylergonovine (US name)

a. coronary artery disease 1. Called Ergometrine and Methylergometrine in European
b. angina countries
c. peripheral vascular syndromes 2. MOA: stimulate uterine smooth muscle-> increased force,
d. uncontrolled hypertension frequency and duration of contraction
e. hepatic and renal impairment 3. causes marked smooth muscle contraction but blocks α-
5-HT receptor antagonist agonist vasoconstriction
4. -mixed partial agonist effects at 5-HT2 and α adrenoceptors
-Another disadvantage of the drugs is its shorter duration of effect 5. Uses:
than the duration of the headache. As a result, multiple doses may be 6. To control and prevent postpartum bleeding
required during prolonged duration of the headache. 7. To prevent or treat uterine atony/ relaxation
8. To treat migraine headache
ONDANSETRON and analogs acts as antagonist receptors 9. Given after delivery of placenta- may cause postpartum
a. 1. MOA: bind to 5-HT3 receptors in vomiting center (central) hemorrhage because uterus is extremely sensitive to ergots
and on intestinal vagal nerve terminal (peripheral) causing a prolonged and powerful spasm of uterine muscle;
b. use to prevent nausea and emesis associated with this may also cause reduced blood flow to the uterus
- cancer therapy causing fetal distress
- radiation therapy
- surgery
B. Ergotamine, Dihydroergotamine
Table. 3. Pharmacokinetics for triptan 1. MOA: partial agonists at 5-HT2 receptors on presynaptic
Drug Routes Time of Single Maximum Half- nerve endings->produce vasoconstriction
onset dose dose per life 2. Use: To abort acute migraine attacks as an alternative for
(hour) (mg) day (mg) (hour) triptans
Almotrip Oral 2.6 6.25- 25 3.3 3. Not used as prophylactic agents for migraine
tan 12.5 4. Combined with caffeine to facilitate absorption (100mg
Eletripta Oral 2 20-40 80 4 caffeine: 1 mg ergotamine)
n
Frovatrip Oral 3 2.5 7.5 27
tan C. Adverse Effects of Ergot Alkaloids
Naratript Oral 2 1-2.5 5 5.5 1. Nausea, vomiting, diarrhea- via activation of medullary
an vomiting center and serotonin receptors in the GIT; most
Rizatript Oral 1-2.5 5-10 30 2 common
an 2. Gangrene, bowel infarction- due to prolonged vasospasm;
Sumatrip Oral, nasal, 1.5 (0.2 for 25-100 200 2 most dangerous toxic effect
tan subcutaneous subcutaneo (PO)
3. Chest pain or discomfort- cardiac murmurs are caused by
us)
Zolmitrip Oral, nasal 1.5-3 1.25-2.5 10 2.8
connective tissue proliferation in the endocardial tissue of
tan the heart

D. Contraindications
IV. ERGOT ALKALOIDS 1. Peripheral and obstructive vascular disease
Ergot Alkaloids 2. Coronary artery disease
 chemical substances produced by the fungus Claviceps purpurea, 3. HPN
which infects grasses and grains under damp growing or storage 4. Pregnancy
conditions. 5. Collagen diseases
 ergotism was also called St. Anthony’s fire after the saint whose
help was sought in relieving of vasopastic ischemia
 the fungus was discovered, ingestion of infected grains produced
ergotism or ergot poisoning, wherein prolonged vasospasm may
cause gangrene, while some developed convulsions, its also
induces smooth muscle contraction, which in pregnancy may
result to abortion.
 the manifestations were caused by vasoconstriction
 acts on several receptors:
o Serotonin receptors
o Alpha-adrenergic
o Dopamine receptors
 effects are varied and therapeutic use is limited

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 PHARMA 1.12

Table 4. Agonist effects are indicated by +, antagonist by -, no effect by 0.  Progressive loss of ganglion cells
Relative affinity for the receptor is indicated by the number of + or – signs. PA  May lead to blindness
means partial agonist.
 Use: To treat open-angle glaucoma
Ergot alkaloid α Dopamine Serotonin Uterine
adrenoceptor receptor receptor smooth
(5-HT2) muscle 4. Alprostadil
contraction  vasodilator
 Maintain patency of ductusarteriosus (usually closes upon
Bromocriptine - +++ - 0 delivery of baby) after birth
 Uses:
Ergonovine ++ - (PA) +++ 1. In some infants with congenital heart conditions, the
Ergotamine -- (PA) 0 + (PA) +++ patency of the ductusarteriosus may be lifesaving. When
awaiting corrective surgery for congenital cardiac
Lysergic acid 0 +++ -- + anomalies, an infusion of alprostadil is used.
diethylamide ++ in CNS
2. Congenital Cardiac Anomalies where PDA is life saving:
(LSD)
a. Transposition of the great vessels (involves the
pulmonary artery and aorta)
MEthysergide +/0 +/0 --- (PA) +/0
b. Pulmonary artery stenosis
c. Pulmonary atresia (pulmonary valve is closed or
absent)
V. PROSTAGLANDINS NOTE: Doctor said to remember these conditions.
Prostaglandins 3. Treatment of erectile dysfunction
 from arachidonic acid passing to cyclooxygenase pathway - Relaxes the corpora cavernosal smooth muscles
 bind to GPCR Dosage Forms:
 Drug groups may be prostaglandin analogs or enzyme a. Urethral Suppository- ready to use prefilled
inhibitors plastic applicator
 Brand Name:Transurethral Medication
A. Prostaglandin Analogs (MUSE: Medicated Urethral Suppository for
1. Misoprostol (Cytotec) Erection)
 Inhibits secretion of gastric acid  Uses a plastic applicator prefilled with
pellets.
 prevent gastric ulcer induced by NSAIDs
 Onset: 5-10 minutes
 Stimulates uterine contractions, thus it is used illicitly to
terminate early pregnancy in combination with  Duration: 30-60 minutes
mifepristone; sometimes combined with anti- progesterone  Maximum dose: 2x in 24 hours (2 pellets)
receptor drug.
 PGE2 and PGF2α are used to induce labor in obstetrics b. Intracavernosal Injection
because of their potent oxytocic actions  Available as powder form reconstituted with
diluent then injected to intracavernosal
2. Dinoprostone and Carboprost tissues
 Prostaglandin analogs  Onset: 5-20 minutes
 Carboprost tromethamin (PGF2α analog)  Duration: 30-60 minutes
 Stimulate uterine contraction  Maximum dose: 3x/week at 24 hour intervals
 Uses:
o To terminate pregnancy (at any stage) *Alprostadil is delivered by invasive means
o To induce labor by softening/ ripening the cervix. (They There can be instances of Prolonged erection/ priapism (painful
increase the proteoglycan content of the cervical sustained erection)
connective tissue which makes it amenable to
dilatation.) VI. NITRIC OXIDE
o To treat postpartum bleeding like ergot alkaloids
 ADR: Emesis, diarrhea due to stimulation of intestinal Nitric Oxide
smooth muscle  Gaseous, highlyreactivecsignaling molecule->Activates guanylyl
 Success rate is approximately 80%, it is administered as a cyclase thus increasing cGMP. Cyclic GMP is an example of a
single 250 mcg intramuscular injection, repeated if second messenger,which produces vasodilatation.
necessary.  Conditions for which NO can be used: treatment of angina,
control of hypertension and erectile dysfunction
3. Latanoprost, Bimatoprost, Travoprost
 Increase outflow of aqueous humor from anteriorchamber *It is not NO that is given but drugs that produce the actions of NO
which lowers intra-ocular pressure (IOP) *Glaucoma-
increased IOP; most recognized factor for glaucoma

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 PHARMA 1.12

 Uses:
1. Drugs for angina and hypertension are called Nitric oxide
donors: ex. Nitroglycerin, isosorbidemononitrate and
dinitrate, sodium nitroprusside
 When metabolized, they generate NO
 Given to patients to increase perfusion to heart
 Na nitroprusside is used to treat severe hypertension

2. Treatment of Erectile Dysfunction

 Inhibit phosphodiesterase 5 (which is responsible for
the degradation of cyclic GMP)
 Major breakthrough in management of erectile
dysfunction
 Given orally, thus more convenient
 Not painful
 Less risk of priapism
 Lower cost

Phosphodiesterase 5 inhibitors
 Sildenafil (Viagra)
 Vardenafil (Levitra)

 Tadalafil (Cialis)
 Onset: 15-30 min
 Duration: 4 hours (Sildenafil &Vardenafil); 36 hours(Tadalafil)

 Adverse effects:
o Impaired color discrimination especially blue/green)
due toPDE 6 (found in retina) inhibition
o Flushing, headache, nasal congestion because of
vasodilatation
 Contraindications:
o patients using Nitroglycerin, Sodium nitropruside, and
any of NO donors because they may aggravate
vasodilatation leading to severe hypotension.
o α – adrenergic blockers bec they enhance
vasodilatation leading to significant hypotension.

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