DRUGS WITH

IMPORTANT ACTIONS ON
SMOOTH MUSCLE

AUTACOIDS
DON D. CUA, M.D.,FPSECP
OLFU College of Medicine
Department of Pharmacology
 Objectives:
• List the major organ system effects of
autacoids
• Describe the major clinical applications of:
a. anti-histamines
b. ergot drugs
c. angiotensin antagonists
d. leukotriene antagonists
e. prostaglandins
• Describe targets of leukotriene
antagonists and prostaglandins
• Describe converting enzymes
• Describe enzymes/drugs that cause the
release of endogenous nitric oxide
 AUTACOIDS
1. Histamine
2. Vasoactive peptides
Bradykinin & Kallidin
3. 5 Hydroxytryptamine (5HT)
-serotonin
4. Autacoids derived from
membrane phospholipid
a. Eicosanoids– arachidonic acid
(PG, PGI, TXA2, Leukotrienes)
b. Modified phospholipids – PAF
OTHER AUTACOIDS:
1. Ergot Alkaloids
2. Nitric Oxide
 HISTAMINES
plants, animal tissues;
component of venoms and stings

Chemistry:
imidazole ring + amino group
connected by 2 methylene groups
 Synthesis
• Decarboxylation of amino acid L-histidine catalyzed by
pyridoxal PO4-dependent L-histidine decarboxylase.
• Ingested from food or formed by bacteria in the GIT
• Storage sites:
1. perivascular tissue – mast cell
2. circulation – basophil (bound to chondroitin SO4)
3. others – GIT, lungs, skin, heart, liver, neural
tissue, reproductive mucosa, rapidly growing
tissues and body fluids
NOTE: brain (non-mast cell) – neurotransmitter
(neuroendocrine control, CVS regulation,
thermal and body weight regulation)
 Histamine Metabolism :
• Major pathways
deamination – small intestine, liver, kidney
and monocytes (imidazole acetic acid)

methylation – small intestine, liver, skin,

kidney, thymus & leukocytes
(N-methyl imidazoleacetic acid)
principal urinary metabolite
(N- methylhistamine)
 Functions:
1. role in allergic responses = Ag + IgE (bound to
mast cells & basophils)--preformed mediators
2. Mediator of inflammatory reactions
(modest role – anaphylaxis)
3. release of other autacoids
4. release by drugs (morphine, urase, amines),
peptides, venoms & other agents
5. release by urticarias( cold, solar and chemical)
6. gastric acid secretion
7. neurotransmitter and neuromodulator 
(increased wakefulness, and arousal
thermoregulation, body weight regulation)
 Selected Actions of Histamine
Organ Tissue Action Receptor

CARDIOVASCULAR
Vascular
Facial cutaneous  TPR H1, H2
Forearm Vasodilatation H2
Gastric mucosa  Blood flow H1, H2
Carotid artery
Pulmonary artery  Blood flow, relaxation H2 (?)
Basilar artery constriction H1
Coronary artery relaxation H2
Other pre & post cap Arterioles constriction H2
Post-capillary vessels vasodilatation - edema H1
Heart vasodilatation H1

 SA rate H2
 Force of contraction H2

Atrial & ventricular automaticity

 Organ Tissue Action Receptor
RESPIRATORY

Bronchiolar smooth muscle Constriction (more prominent) H1

Relaxation (rabbits) H2

GASTROINTESTINAL
Gastric parietal cells Acid and pepsin secretion, If H2
GI smooth muscle Relaxation &
Contraction (more prominent) H1
Gallbladder smooth muscle Relaxation (?) H2 (?)

SENSORY NERVE ENDINGS Pain & itching (FLARE) H1, H2 (?)

(esp to insect bites & needle stings)

CNS Nociception H2 (?)

ADRENAL MEDULLA Epinephrine release (high conc.) H1

BASOPHILS Inhibition of IgE – dependent H2

degranulation
• H1, H2 - located in post synaptic
membrane
• H3 – pre-synaptic
• H1 – predominant in endo-tracheal &
smooth muscle
• H2 – facial veins, carotid a, pulmonary a,
heart, gastric mucosa, heart, smooth
muscle & some immune cells
• H3 – several areas in CNS
• H4 –eosinophils, neutrophils, CD4 T cells
• Triple response – redness, flare, & wheal
 Triple response
• Red spot - smooth muscle; dilation of small
vessels
• Flare response – axon reflex (sensory
nerve endings
• Edema – post-capillary vessels → separation
of endothelial cells → transudation of fluid and
molecules into the perivascular tissues
• Accompanied by itching
 Clinical use of Histamine
• Provocative test for bronchial
hyperreactivity (e.g. asthma,cystic fibrosis)

Adverse effects: flushing, hypotension,

tachycardia, headache, wheals,
bronchoconstriction and GI upset
 Histamine Antagonists
• Physiologic antagonist – epinephrine
• Release inhibitors – reduce mast cell
degranulation (Cromolyn Na, Nedocromil)
• Histamine receptor antagonist
H1 receptor antagonists
H2 receptor antagonist for Peptic Ulcer
Burimamide - H2 blocking action with no effect on H1,
H2, H3 receptors (analgesia)
H3-receptor antagonist (thioperamide and clobenpropit)
experimental
 Histamine Antagonists
First Generation Agents
A. Ethanolamines D. Piperazines
1. Carbinoxamine maleate 1. Hydroxyzine HCl/pamoate
2. Clemastine fumarate (long-acting)
3. Diphenhydramine HCl 2. Cyclizine HCl/lactate
4. Dimenhydrinate 3. Meclizine HCl
B. Ethylenediamines
1. Pyrilamine maleate 4. Chlorcyclizine
2. Tripelennemine HCL/citrate E. Phenothiazines
3. Phenylpropanolamine(PPA) 1. Promethazine HCl
C. Alkylamines F. Misc.
1. Chlorpheniramine maleate 1. Cyproheptadine
2. Brompheniramine maleate
Histamine Antagonists
Second Generation Agents
A. Alkylamines
Acrivastine

B. Piperazines
Cetirizines HCl
Levocetirizine

C. Piperidines
Astemizole*
Levocabastine
Loratadine
Terfenadine*
Histamine Antagonists
Third Generation Agents
A. Piperazines
Levocetirizine Hcl

B. Piperidines
Fexofenadine
Desloratadine
 H1 RECEPTOR ANTAGONISTS:
FIRST Generation
Pharmacokinetics:
• Well absorbed from GIT (oral)
• Onset :30 minutes ; duration: 4-6 hrs
• Widely distributed
• Biotransformed in the liver; metabolism can
be affected by ketoconazole (inhibitor)
• Excretion – kidneys
 H1 RECEPTOR ANTAGONISTS:
SECOND Generation
Pharmacokinetics:
• Well absorbed from GIT (oral)
• Onset :30 minutes ; duration: 12-24 hrs
• Less lipid soluble
• Substrates of P-glycoprotein transporter
• Bio-transformed in the liver; metabolism
can be affected by ketoconazole (inhibitor)
• Excretion – kidneys
 PHARMACODYNAMICS:
• SEDATION – block autonomic receptors
• ANTI-NAUSEA AND ANTI-EMETIC
• ANTI-PARKINSONISM EFFECT (diphenhydramine)
• ANTI-CHOLINOCEPTOR ACTION (ethanolamine,
ethylene diamine)
• ADRENOCEPTOR-BLOCKING ACTION (promethazine)
• SEROTONIN-BLOCKING ACTION (cyproheptadine)
• LOCAL ANESTHESIA (diphenhydramine and
promethazine)
• OTHERS: inhibit mast cell release of histamine
(cetirizine – unknown mechanism)
Clinical uses of H1 receptor Antagonists

• Allergic reaction:
(allergic rhinitis or hay fever, urticaria)
• Motion sickness and vestibular
disturbances (diphenhydramine,
promethazine, dimenhydrinate)
• Nausea and vomiting of pregnancy
(teratogenic effect: doxylamin/bendectin)
 Adverse Effects:
1. CNS - agitation, excitation, convulsions, coma
– common in first generation anti-histamines
2. dryness of mouth, throat & airway
3. urinary retention – first generation
4. headache, faintness
5. chest tightness, palpitations, hypotension

Drug Interactions:
2nd generation anti-histamines (terfenadine)
+
ketoconazole, itraconazole, macrolides
(erythromycin), cimetidine, grapefruit juice
 Therapeutic Uses:
Uses
1. Dermatosis
2. Allergic rhinitis
3. Motion sickness & emesis
4. Parkinson’s disease
5. Extrapyramidal (EPS)
6. Insomnia
7. Adverse reactions
Structural Class Prototype Characteristics
Significant anti-muscarinic
First Gen. Agents: activity
1. Ethanolamine Diphenhydramine Sedation, somnolence
 Incidence of GI symptoms
Effective in emesis & motion
sickness
Most specific H1 antagonist
2.Ethylenediamine/ Pyrilamine
 anti-cholinergic activity
Ethylamine Mepyramine Feeble CNS effects
Pyranesamine Somnolence GI s/s common
Most potent
3. Alkylamine Chlorpheniramine Not so prone to develop
Pheniramine drowsiness
More suitable for older patients
Chlorphenamine Sedation/CNS stimulation

Oldest member
4. Piperazine Chlorcyclizine
More prolonged action

 Incidence of drowsiness
Structural Class Prototype Characteristics
Anticholinergic
5. Phenothiazine Promethazine Prominent sedation
Counters motion sickness
primarily antiemetic

Highly selective for H1

Second Gen.Agents Terfenadine receptor
1. Piperidine Non-sedating
(-) anti-cholinergic action
(-) pass BBB
 incidence of S/E
Rapid onset of action (30 mins)
2. Alkylamine Acrivastine (-) anticholinergic effects
Reduce both wheal & flare
response
 Potential to penetrate BBB
Skin allergy

Allergic rhinitis

3. Piperazine Cetirizine Rhinitis, urticaria

(-) pass BBB
Structural Class Prototype Characteristics
Long acting
Widely used for skin allergies
Hydroxyzine CNS depressant
More prominent anti-pruritic
action

Cyclizine Counters motion

sickness (primarily)

Meclizine/Meclozine Counters motion

sickness & emesis
H2 RECEPTOR ANTAGONISTS

Pharmacodynamics:
•Inhibit gastric acid secretion
•(-) effect of gastric motility, emptying
time, pancreatic & mucous secretion
 Adverse Effects
Cimetidine:  headache, dizziness
• constipation, diarrhea
• skin rashes
• alterations of hepatic function
• CNS disturbances
(elderly & impaired renal filtration)
• BM depression – rare
• Serum prolactin elevation
• Sexual dysfunction & gynecomastia
Ranitidine:  Serum prolactin elevation
 Drug Interactions:
• Cimetidine inhibits CYP450 – accumulation of
warfarin, phenytoin, theophylline, propanolol,
diazepam & phenobarbital
• Ranitidine – weak inhibitor
• Nizatidine & famotidine – do not inhibit CYP450

Therapeutic Uses: Peptic Acid Disorders

 SEROTONIN
(5-HYDROXYTRYPTAMINE)
• Metabolite: 5-hydroxytryptophan
• Serotonin and Enteramine
• Sources : tunicates, mollusks, arthropods,
fruits, nuts, wasps & scorpions
 SYNTHESIS:
Tryptophan

Hydroxytryptophan

5 hydroxytryptamine
(Serotonin)

5-hydroxyindole acetaldehyde

(aldehyde dehydrogenase)
5-hydroxyindole acetic acid 5HIAA acid 5-hydroxytrytophol
(principal metabolite)
N-acetyl- 5-HT
Melatonin
 Pharmacologic Properties
• CVS :
(+) inotropic & chronotropic
effects, vasoconstriction
• Smooth Muscle:
Bronchoconstriction
• GIT: Enhanced motility
SEROTONIN: chemistry and kinetics
• Pineal gland: precursor to melatonin
• Enterochromaffin cells cells (90%): unknown but seen in
carcinoid tumors
• Blood (platelets) and CNS (10%)
• Brainstem: mood, sleep, appetite and temperature
regulation
- involved in depression, anxiety and migraine
• Metabolized by MAO
• 5HIAA – measure of serotonin synthesis
- diagnostic test (carcinoid tumors – serotonin level)
• Reserpine - depletes stored serotonin
 Serotonin: Dynamics
Receptors: 5-HT1A, 1B, 1D, 1E, 1F, 1P, 5-HT2A, 2B, 2C,
5-HT3, 5-HT4, 5-HT5AB, 5-HT6,7
• Receptor signaling mechanisms (13 receptor subtypes)
• Nervous system 5HT1p/5HT4: neurotransmitter, precursor of
melatonin,
5HT3 vomiting center; pain stimulant; vagal nerve: Bezold-Jarisch
reflex or chemoreceptor reflex-bradycardia and hypotension
• Respiratory system 5HT2a: small, direct stimulant
• Cardiovascular system 5HT2: vascular smooth muscle –
contraction; heart – vasodilation; veins – constriction with ↑
capillary filling (flush); platelet aggregation
• GIT 5HT2: ↑ tone and peristalsis; 5HT4: enteric NS – prokinetic
(Acetylcholine release)
• Skeletal muscle 5HT2: contractions
 Serotonin Agonists
• No clinical applications as a drug
• Receptor subtype-selective agonists:
Buspirone – effective nonbenzodiazepine anxiolytic (5HT1A)
Dexfenfluramine – appetite suppression but withdrawn
(5HT2C)
Sumatriptan – migraine (5HT1D/1B)
Cisapride – (compassionate use) motility disorders
and GERD
Tegaserod – Irritable Bowel Syndrome with constipation
(5HT4 patial agonist)
Fluoxetine and SSRIs
 Migraine
• Involves trigeminal nerve and intracranial arteries;
these nerves release peptide neurotransmitter
(CGRP) – most potent vasodilator
• Extravasation of plasma and plasma proteins in
perivascular space
• Mechanical stretching
• Activation of nerve endings
 Migraine HEADACHE
• Tryptans (sumatriptan)
• NSAIDs (aspirin, ibuprofen)
• Β-adrenoceptor blockers (propanolol)*
• Ca channel blockers (Flunarizine, Verapamil)*
• TCAs (amitriptyline)*
• Anticonvulsants ( topiramate, clonazepam)*
valproic acid*
another drug:ergotamine
 5HT Antagonists
1. Clozapine: 5HT7
Reduce incidence of EPS
High affinity for dopamine receptors
Reduced negative symptoms of schizophrenia

2. Risperidone:
D2 receptor blocker
Reduced negative symptoms of schizophrenia
Low incidence of EPS
 3. Methysergide:
Used for diarrhea & mal-absorption in patients with carcinoids
4. Cyproheptadine: 5HT2
Treatment of smooth muscle manifestations of carcinoid tumor and
cold induced urticaria (12-16mg/d in 3-4 divided doses)-- H1 blocker,
weak anticholinergic and mild CNS depressant, used for skin
allergies,counteract the sexual side effects of SSRI’s
5. Ondansetron: 5HT3
nausea and vomiting 2° to chemotherapy and radiotherapy
6. Ketanserin-partial 5HT2A
blocks platelet aggregation by serotonin
( Europe – hypertension and vasospastic condition)
7. Ritanserin: 5HT2
alters bleeding time, reduce thromboxane formation
8. Phenoxybenzamine
 ERGOT ALKALOIDS
• Produced by Claviceps purpura (fungus in grass and drain
– rye)
• Ergotism (ergot poisoning) - dementia with florid
hallucinations, prolonged vasospasm resulting to gangrene
and uterine smooth muscle stimulation (St. Anthony’s fire)
• oral dose is 10x larger than IM
• Amine and peptide alkaloids
• Affects different receptors:
- alpha-adrenoceptor (Ergonavine)
- dopamine receptor (LSD, Bromocriptine)
- serotonin receptor (5-HT2) (Ergonavine, Ergotamine, LSD)
 Ergot alkaloids: organ system effects

• CNS - hallucinogens LSD

(postjunctional 5HT2 receptors);
-suppress prolactin release (dopamine
receptors) bromocriptine, cabergoline, pergolide
• Vascular smooth muscle – constrict vessels;
“epinephrine reversal” and blockade on other
α agonists
• Uterine smooth muscle - contraction
• Others: nausea, vomiting and diarrhea
 Ergot Alkaloids: Clinical uses
• Migraine - Ergotamine (caffeine - absorption) 6mg / attack
or IV /IM at 0.25mg-0.5mg
Dihydro-ergotamine 0.5 mg – 1 mg IM (intractable)
Methysergide - withdrawn due to toxicity
• Hyperprolactinemia - Bromocriptine 2.5mg 2-3x daily
Cabergoline
Pergolide - suppress lactation but has CV toxicity
• Postpartum hemorrhage - ergonavine maleate 0.2mg IM
• Diagnosis of variant angina - Ergonavine IM
• Senile cerebral insufficiency – Dihydro-ergotaxine –
no useful evidence
 Ergot alkaloids: Toxicity and CI

• GIT disturbances
• Prolonged vasospasm (overdosage)
• Connective tissue proliferation in
retroperitoneal space , valve damage
(methysergide)
• CI: obstructive vascular diseases and
collagen diseases
• Caution: migraine in pregnancy
 Vasoactive Peptides
• Vasoconstrictors - Angiotensin II,
Vasopressin, Endothelins, Neuropeptide Y,
Urotensin

• Vasodilators – Bradykinin and related

kinins, Natriuretic peptides, Vasoactive
Intestinal Peptides (VIPs), Substance P,
neurotensin and Calcitonin gene-related
peptide (CGRP) and Adrenomedullin
 Vasoactive peptides (VASODILATORS):
BRADYKININ & KALLIDIN
• Peptides that act locally to produce pain,
vasodilatation,  vascular permeability
& prostaglandins synthesis
Synthesis:
• Liver
• Percursors: kininogens
SERINE PROTEASES (HMW & LMW)
LMW
 Vasoactive Peptides (VASODILATORS):
KININS
Synthesis:
kininogens (LMW/HMW) → kallikrein/kininogenase
→ kinins
• Kinins: bradykinin, lysylbradykinin (kallidin),
methionyllysylbradykinin
• B1 and B2 receptors
• Kininase I (liver) and kininase II (plasma, vascular
endothelium)
• Completely hydrolyzed in pulmonary vascular bed
• Action is enhanced by ACE inhibitors
 Functions
• Pain – excites primary sensory
neurons & provokes release of
substance P, neurokinin A &
CGRP…Sensory nerves- pain producing (skin, viscera)
• Inflammation -  permeability in
microcirculation– redness, local heat, swelling
• production of IL-1 & TNF - 
• respiratory disease
 KININS (physiologic and pathologic effects)
• Cardiovascular: vasodilation in heart, kidney, intestine,
skeletal muscle and liver
increased capillary permeability
• Endocrine and exocrine glands – modulators of blood
flow; regulate GI motility; may activate pro-insulin,
pro-renin
• Others: may play a beneficial role in CV disease,
ischemic stroke
 Pharmacological Properties
1. CVS – potent vasodilator
(10x more than histamine)
• Stimulate histamine release
2. Kidney -  RBF
3. Others:
• Spermatogenesis
• Promotes sperm motility
Fetal to Neonatal circulation
-dilatation of fetal pulmonary artery
-closure of ductus arteriosus---PATENCY
-constriction of umbilical vessels
 Drugs affecting the Kallikrein-Kinin system

• Icatibant - 2nd generation B2 receptor

antagonist; promise for use in the
treatment of hereditary angioedema
and pain
• SSR240612
• Aprotinin
 Vasoactive Peptides
• Vasoconstrictors - Angiotensin II,
Vasopressin, Endothelins, Neuropeptide Y,
Urotensin

• Vasodilators – Bradykinin and related

kinins, Natriuretic peptides, Vasoactive
Intestinal Peptides (VIPs), Substance P,
neurotensin and Calcitonin gene-related
peptide (CGRP) and Adrenomedullin
Vasoactive Peptides (VASOCONSTRICTORS):
ANGIOTENSIN
• BIOSYNTHESIS:
- enzymatic cleavage of Ang 1 from
angiotensinogen by renin
- conversion of Ang 1 to Ang II by ACE
- degradation of Ang II by several
peptidases
• receptor signaling mechanism: G proteins
and 2nd messengers
 Actions of Angiotensin II

• BP - potent pressor agent

• Adrenal cortex – aldosterone synthesis
• Kidney – renal vasoconstriction, ↑Na
reabsorption, inhibit secretion of renin
• CNS – dipsogenic effect, ↑ vasopressin
and ACTH secretion
• Cell growth – mitogenic (CV hypertrophy)
AT1 (predominant) and AT2 receptors
Inhibition of the renin-angiotensin system

• Drugs that block renin secretion: Clonidine

Propanolol and other βadrenoceptor blocking
agents
• ACE-inhibitors: Captopril, Enalapril
• ARBs:peptide: Saralasin (investigative)
nonpeptide: Losartan, Valsartan,
eprosartan, Irbesartan, Candesartan,
Olmesartan, Telmisartan
• Renin inhibitors: Aliskiren
• Pro-renin receptors
Vasoactive peptides (VASOCONSTRICTORS):

VASOPRESSIN (ADH)
• Regulates arterial pressure by its
vasoconstrictor action and increases
water reabsorption in the kidneys
• 3 G-coupled receptors:
V1a - vasoconstriction
V1b – potentiates the release of ACTH
V2 – antidiuretic action
 Vasopressin-like Peptides:
vasodilatory shock states
• V1 vasoconstrictor:
(Phe2,Ile3,Orn8) vasotocin
• V2 anti-diuretic analogs:
1-deamino (D-Arg8)arginine vasopressin
1-deamino (Val4,D-Arg8)arginine vasopressin
• Terlipressin
 Vasopressin antagonists:

• Potential for the treatment of HPN and HF

• Relcovaptan - nonpeptide V1a receptor
antagonist
• (1-(β-mercapto-ββ-
cyclopentamethylenepropionic acid) arginine
vasopressin – antioxytocic activity
• Conivaptan - hyponatremia
Vasoactive Peptides (VASOCONSTRICTORS):

ENDOTHELINS
• (+) inotropic and chronotropic actions on the heart
• Kidneys – vasoconstriction, ↓ glomerular filtration rate
and Na and water excretion
• Resp. system – contraction of tracheal and bronchial
smooth muscle
• ↑ secretion of renin, aldosterone, vasopressin, ANP
• IV administration cause rapid decrease in arterial blood
pressure (release of prostacyclin and nitric oxide from
the vascular epithelium) followed by a prolonged
increase (contraction of smooth muscle)
 Endothelin Synthesis and Action Inhibitors

• Selectively and nonselectively (ETa-ETb receptors)

• Pulmonary hypertension, cardiac hypertrophy, MI
• AE: nausea, vomiting, constipation; hepatotoxicity
• Bosentan – nonselective blocker
• Sitaxsentan and Ambrisentan - research
• Phosphoramidon – research; enzyme inhibitor
Vasoactive Peptides (VASOCONSTRICTORS):
NEUROPEPTIDE Y (NPY)
• Gut endocrine peptides (peptide YY and pancreatic
polypeptide)
• Not important in the regulation of hemodynamics but
maybe increased in hypertension and heart failure
• Vasoconstrictors and co-transmitter of NE; suppress
renin secretion (cerebral blood vessels, heart
(+) inotropic and chronotropic effects
• Y1-Y6 receptors; G-coupled receptors
• Antagonists: BIBP3226, BIB03304, H409/22,
SR120107A, SR120819A
Vasoactive Peptides (VASOCONSTRICTORS):

UROTENSIN (U-II)
• Kidneys – source
• Brain, spinal cord, kidneys – organs
of expression
• Minor role in health but ↑ levels in
hypertension, HF, DM and renal
failure
• Antagonist: Palosuran - research
 Vasoactive Peptides
• Vasoconstrictors - Angiotensin II,
Vasopressin, Endothelins, Neuropeptide Y,
Urotensin

• Vasodilators – Bradykinin and related

kinins, Natriuretic peptides, Vasoactive
Intestinal Peptides (VIPs), Substance P,
neurotensin and Calcitonin gene-related
peptide (CGRP) and Adrenomedullin
Vasoactive Peptides (VASODILATORS):
NATRI-URETIC PEPTIDES
1. ANP (atrial natriuretic peptide) heart
- marked Na excretion and urine flow
- inhibits release of renin, aldosterone, vasopressin
- vasodilation and ↓ arterial BP
2. BNP (brain natriuretic peptide) heart
- natriuretic, diuretic, hypotensive activities
3. CNP (C-type natriuretic peptide) CNS, other tissues
- vasodilator
3 receptor subtypes: ANP A, ANP B, ANP C
Metabolized by neutral endopeptidases
Vasoactive Peptides (VASODILATORS):
NATRIURETIC PEPTIDES
• Nesiritide (BNP) – severe heart failure; IV –
cause fatal renal damage
• Ularitide (urodilatin) – decompensated HF or
cirrhosis; IV
• Vasopeptidase inhibitors:
- inhibits 2 metalloprotease enzymes:
NEP24.11 and ACE
Omapatrilat (HF; AE: angioedema, cough,
dizziness), Sampatrilat, Fasidotrilat
 Vasoactive Peptides (VASODILATORS):
VASOACTIVE INTESTINAL PEPTIDES (VIPs)

• Glucagon-secretin family
• Central and peripheral vessels
• Functions: metabolic processes, secretion of
endocrine and exocrine glands, cell differentiation,
smooth muscle relaxation and immune response;
CV-vasodilation, (+) inotropic and chronotropic
effects
• G-coupled protein: VPAC1, VPAC2
• Research on DM type 2, COPD; VIP receptor
antagonists
 Vasoactive Peptides (VASODILATORS):
Substance P
tachykinin family - undecapeptide
neurokinin A, neurokinin B – decapeptides
Substance P
implicated in behavior, anxiety, depression, nausea and emesis;
potent arteriolar vasodilator (mediated by release of NO)
- vasoconstriction on venous, intestinal, bronchial smooth muscle
• - stimulates secretion of salivary glands, causes diuresis and natri-
natri
uresis by kidneys.
G-protein coupled receptors: NK1, NK2, NK3
•NK1 receptor antagonist:
Aprepitant – prevention of chemotherapy-induced nausea and
vomiting
Vasoactive Peptides (VASODILATORS):
NEUROTENSIN
• Present in GIT; contains Neuromedin N
• Neurotransmitter and neuromodulator in CNS (produces
hypothermia, anti-nociception and modulation of dopamine
neurotransmission); peripherally, vasodilation, hypotension,
↑vascular permeability, ↑adenohypophysis,
hyperglycemia, inhibition of gastric acid and pepsin
secretion and inhibition of gastric motility
• Receptor subtypes: NT1, NT2, NT3
• NT agonists: PDI49163, NT661, NT671, NT771 –
schizophrenia and Parkinson’s disease
• NT receptor blocker: SR142948A, SR48692
Vasoactive Peptides (VASODILATORS):
CALCITONIN GENE- RELATED PEPTIDE (CGRP)
most potent among the vasodilators

• C cells of thyroid gland; CNS and PNS; GIT

• CNS effects: hypertension and suppression
of feeding
• Systemic effects: hypotension and
tachycardia (vasodilation)
• Pathophysiology of migraine (trigeminal
nerve) ; B1BN4096BS
Vasoactive Peptides (VASODILATORS):
ADRENOMEDULLIN
• Adrenal glands, hypothalamus, anterior
pituitary; kidneys, lungs, CVS, GIT
• Effects: dilates resistance vessels –
hypotension and reflex tachycardia;
↑ Na excretion, inhibition of aldosterone and
insulin secretion
• Receptor: CPLR
• Functions as a physiologic antagonists to ET-
1 and ANG II
 LIPID-DERIVED AUTACOIDS

Eicosanoids
• Products of PUFA
• AA – eicosanoid precursor
• Release from cellular stores by PLA2
9(cPLA2, sPLA2 and iPLA2)
• Human platelets – DAG lipase
• Coupled to G proteins
 AA is oxygenated
by the following routes:
• Cyclo-oxygenase
• Lipo-oxygenase
• P450 epo-oxygenase
• Iso-eicosanoid
EFA (diet) Esterified acid Arachidonic acid
in cell lipid PLA2

Lipo-oxygenase Cyclo-oxygenase (ASA, indomethacin)

12sHETE 5-HETE

12rHETE 5-HETE LTA4 LTC4

LTB4 LTD4

LTE4

LTF4
 Cyclo-oxygenase

PGG2

PGH2

PGG2 PGE2 PGF2 PGD2 PGI TXA2

PGF1 TXB2
 Cyclo-oxygenase

• PGH synthase-1 (COX-1) – “housekeeping”,

gastric epithelial cyto-protection
• PGH synthase-2 (COX-2) – inflammation
endothelial COX 2 – source of vascular PGI2
(prostacyclin) while renal COX2 is for normal
renal development and maintenance of renal
function
 Lipo-oxygenase
• Metabolism of AA by (5-, 12-, 15-) LIPO-OXYGENASE
→ hydroperoxyeicosatetranoic acids (HPETE)→ HETEs and
leukotrienes
• Associated with asthma, anaphylactic shock and CV disease
• Present in leukocytes and mast cells
• LTA4, LTB4, LTC4 + LTD4 and LTE4 – cysteinyl leukotrienes
LTC4 and LTD4 - potent bronchoconstrictors and primary
components of SRS-A ( approaches: 5-LOX enzyme inhibitors,
inhibitors of FLAP, leukotriene-receptor antagonists,
phospholipase A2 inhibitors)
epidermal LOX – feature in psoriasis and ichthyosis
 Epo-oxygenase

• Hydroxy or Epoxyeicosatrienoic acid

(EETs) and DHETs
• Cause vasodilation
• Function as endothelium derived
hyperpolarizing factors
 Iso-eicosanoids

• Peroxidation of arachidonate by free radicals

• Potent vasoconstrictor effects
• Modulate leukocyte and platelet adhesive
interactions and angiogenesis
• May contribute to the pathophysiology of
inflammation
 Pharmacological Properties
A. CVS
12(S)HETE-potent chemoattractant for
smooth muscle---role of myocardial proliferation
12(R)HETE—potent inhibitor of Na+/K+ATPase
in cornea
vasodilators-PGE,PGI (5X)
vasoconstrictors-PGF2α and TXA2
B. BLOOD
PGI-inhibits platelet aggregation
TXA2-platelet aggregator

LTB4-potent chemotactic agent

PG-inhibit lymphocyte function and proliferation
C. Smooth Muscle
Broncho/Trachea
constrictors—PGF,PGD2,TXA2,LTC,D
dilators---PGE2and PGI2
Uterus
contraction—Non-pregnant-PGF,TXA2
Pregnant-PGF and PGE2
(both at low concentration)
relaxation—Non-pregnant-PGE
Pregnant—PGI2 and PGE2
(at high concentration)
Gastro-intestinal
Contraction—PGE2 (longitudinal) and
PGF2α (circular)
Relaxation – PGE2 (via EP4)
PGE and PGI2—inhibit GIT secretions

D. KIDNEYS
Increased RBF—PGE and PGI
Decreased RBF—TXA2
Increase renin---PGI2, PGE2 and PGD2
 Therapeutic Uses
1. PGE1 (Misoprostol) – suppress gastric ulceration
2. PGE1 & PGI2 – improve harvest and storage of platelets
for therapeutic transfusion
- improve blood flow & tissue oxygenation in neonates
(ductus arteriosus – vasodilatation)
3. PGE1 – treatment of impotence ---Alprostadil
(+) guanyl cyclase, increases cGMP-direct
Non-PGE-1---Sildenafil, Vardenafil, Taldalafil
(-) phosphodiesterase Type 5-indirect
4. Leukotriene inhibitors
Zileuton- 5-LOX inhibitor
Montelukast, Pranleukast and Zafirlukast - selective
leukotriene receptor antagonist
5. NSAIDs - aspirin - irreversible COX inhibitor
6. Latanoprost---PGF2α derived(glaucoma)
7. COX 1 inhibitors and COX 2 inhibitors
Indomethacin and Sulindac- slightly selective for COX 1
Meclofenamate and Ibuprofen
– non-selective COX 1 and COX 2
Celecoxib = Sulindac < Rofecoxib = Lumiracoxib <
Etoricoxib – COX 2
8. Prostacyclin (PGI2, epoprostenol)
---vasodilator and inhibitor of platelet aggregation
(pulmonary HPN and porto-pulmonary HPN)
PLATELET ACTIVATING FACTORS
(PAF)
Synthesized by platelets, neutrophils,
monocytes, mast cells, eosinophils,
renal mesangial cells, renal medullary
cells & vascular endothelial cells
 Pharmacological Properties
A. CVS: Potent vasodilator
vascular permeability 1000x more than
histamine/bradykinin
B. Leukocyte: Chemotaxis
C. Smooth Muscle:
Contraction
Airway resistance & responsiveness to other
bronchoconstrictors
D. Stomach
Potent ulcerogen
 NITRIC OXIDE
• Inhibition of platelet aggregation and vaso-relaxation
(EDRF)
• Classes of Nitric oxide donors:
1. Organic nitrates - nitroglycerine
2. Organic nitrites – amyl nitrites
3. Sodium nitroprusside
4. NO gas inhalation – pulmonary HPN, acute hypoxemia,
cardiopulmonary resuscitation
5. Alternate strategies – sildenafil (prolongs duration of NO
induced cGMP elevations) by inhibiting
phosphodiesterase Type 5
 Role of Nitric Oxide in Disease
• Vascular effects: vasodilator: inhibits proliferation and migration of
vascular smooth muscle; antithrombotic effect; reduces endothelial
adhesion of monocytes and leukocytes (atheromatous plaques);
antioxidant (blocks LDL oxidation)
• Septic shock: inflammatory mediators induce NO: hypotension,
shock and death in sepsis (role of NOS inhibitor in gm(-) sepsis)
• Inflammation: stimulates synthesis of inflammatory PGs by COX2
activation leading to vasodilatation, vascular permeability and
edema; cytoprotection with TH1 cells
• CNS: neurotransmitter
• PNS: relaxation of smooth muscle in the corpora cavernosa (penile
erection); PDE inhibitor to indirectly inhibit the breakdown of cGMP
• Respiratory Disorders: dilates pulmonary vessels, resulting to
decreased PVR and reduced pulmonary arterial pressure
( treatment of pulmonary HPN)
In summary…..
• List the major organ system effects of
autacoids
• Describe the major clinical applications of:
a. anti-histamines
b. ergot drugs
c. angiotensin antagonists
d. leukotriene antagonists
e. prostaglandins
• Describe targets of leukotriene antagonists
and PGs
• Describe converting enzymes
• Describe drugs that cause the release of
endogenous nitric oxide