Transcript AUTOCOIDS Students.ppt

AUTOCOIDS
BY
PROF. A. ALHAIDER
Department of Medical Pharmacology
College of Medicine
• Definition: Auto = self
Coids = Remedy
or some times called Local Hormones
Why are they very important?
• Classifications:
A. Amine Autociods:
1. Histamine
2. Serotonin
B. Eicosanoids (PGs; Thromboxane ;
Leukotriens)
C. Peptides Autociods:
1)Kinins
2) Renin; Angiotensins etc)
HISTAMINE
• Locations: mediators of allergic and
inflammatory reactions; also involved in
Gastric Acid Secretions ; and as
Neurotransmitter & Neuromodulator.
• Thus, it is located in:
a) Mast cells (lung,skin, GIT, BV…etc)
b) Basophiles, Platelets, Enterochromaffinlike (ECL) cells of the stomach
c) Brain
Storage and Release:
• Histamine is usually found in storage granules as complex
with sulfated polysacharides, heparin and released (locally)
by:
a) Immunologicl Mechanism (see Fig 56-5)
b) Tissue injury
Mast cell
degranulation
c) Chemical and physical Conditions ( see table 51-2)
Chemical and Physical Agents that
Release Histamine
Chemical Agents
Physical Agents
Antihistamine, H1–type, Chymotrypsin, Mechanical trauma,
Compound 48/80, Detergents, Dextran, Radiant energy,
DMSO (dimethyl- sulfoxide), Morphine Thermal energy
and other Opiods, Pentamidine ,
Polymyxin B, Polyvinyl pyrrolidine,
Propamidine, eserpine, Surface active
agents, Stilbamidine, Toxins,
Tubocurarine, venoms, X-ray contrast
media: Bradykinin, SP
• Mechanism of Action:
Histamine binds to three types of Receptors ,
namely H1 , H2 , H3 (see table 16-1)
Which one of them localized presynaptically?.
Histamine receptor sub type
Receptor sub
type
Distribution
Post receptor
Mechanism
Partially
Selecetive
Agonists
Partially
selective
Antagonists
H1
Smooth muscle ,
endothelium ,
brain
↑IP3 , DAG
2-( mfluorophenyl)histamine
Mepyramine ,
triprolidine
H2
Gastric mucosa ,
Cardiac muscle ,
mast cells , brain.
↑cAMP
Dimaprit,
impromidine ,
amthamine
Ranitidine ,
tiotidine
H3
Presynaptic:
brain, myentric
plexus, other
neurons
G protein –
coupled
(decrease Ca)
R- αMethylhistamine,
imetit , immepip
Thioperamide,
iodophenpropit ,.
clobenpropit
Effects on Organs
•
a) CVS:
systolic and diastolic blood pressure
Heart rate.
b) GIT:
Heart Contracility
Gastric acid secretion (H2) (very important)
Contractility (but less in human)
C) Bronchial smooth muscle contraction and
secretion.
What is the significant of such an effect?
d) Nerve ending (Pain & Itching)
Toxicity and contraindications:
• How does it occur?
• Manifestations
• Treatment
Histamine H1 – Receptor Antagonists
Histamine can be antagonized by the followings:
• a) Physiological Antagonism by epinephrine
• b) Mast cell release inhibitors (Sodium
Chromoglycate)
• C) Histamine Receptors Antagonists (The
Most Important Clin. Approach)
Pharmacokinetic of H1-antagonists)
( see Table 16-2)
• They are divided into first & Second
Generation based on t ½ and lipophilicity.
• Drugs that inhibit (Cyto.P450), will increase
the cardiac toxicity of the piperidines
derivatives.
Pharmacodynamics:
• Pham. Actions of H1 –antagonists could be attributed to their H1,
Muscarenic, alpha- adrenergic or serotonergic actions
•
a)
Antagonize Histamine Actions (e.g. Edema = capillary
permeability; vascular response; effects on smooth muscle)
These effects are utilized clinically for Allergy?
•
b)
Sedation (First Gen.) Is it useful?
•
c)
Antinausea & Antiemetic Actions I( First Gen.)
•
d)
Anticholinergic (first. Gen) Is it useful?.
•
e)
Strong serotonin blockade (Cyproheptadine)
•
f)
↓ Bronchial and nasal secretion
•
• G)
Local anesthetics
Clinical Uses:
•
•
a) Allergic Reactions (e.g.: Allergic
Rhinitis ; Urticarea , etc.
b) Motion Sickness & Vestibular
(Cyclizine; Meclizine)
• c) Nausea & Vomiting of Pregnancy
(Doxylamine (BendectinR)
d) Local anesthesia: first generation
(Diphenhyramine and promethazine)
Why Antihistamines are not used for
Asthma?.
• Side Effects: Should be predicted from the
pharmacological effects? Plus drug allergy after
local uses.
Receptors selectivity: 1st generation •
antihistamines are of poor H1 receptor
selectivity. They block other receptors leading to
adverse effects:
Cholinergic R blockade: dry mouth, urinary •
retention, & tachycardia
-adrenergic R blockade, by promethazine, •
leading to hypotension, tachycardia & dizziness
Serotonin R blockade leading to increased •
Some H1 antihistamine drugs in clinical use
FIRST – GENERATION ANTIHISTAMINES
DRUGS
ANTICHOL
ACTIVITY
COMMENTS
ETHANOLAMINES
Dimenhydrinate( salt of
dihphenhydramine (DramamineR)
+++
Marked sedation , antimotion sickness activity
Diphenhydramine (BenadrylR , ,etc
+++
Marked sedation ,antimotion sickness activity
Doxylamine (Decapyrin)
nd
Moderate sedation,
component of OTC “sleep aids”
PIPERAZINE derivatives
Hydroxyzine (AtaraxR etc
Cyclizine (Marzine)
nd
-
Used for itching
Marked sedation
Slight sedation , anti motion
sickness activity
FIRST – GENERATION ANTIHISTAMINES
Drugs
Ant-chol.
activity
Comments
Meclizine ( Bonine etc)
-
Slight sedation ,
(better than Dramamine
anti s motion sickness
ALKYLAMINE
Brompheniramine (Dimetane)
+
Slight sedation
PHENOTHIAZINE derivatives
Promethazine (PhenergaanR ,etc)
+++
Chlorpheniramine (Chlortrimeton etc)
+
Miscellaneous
Cyproheptadine (PeriactinR etc
+
Marked sedation ,
antiemetic
Slight sedation, common
component of OTC “cold
“medication
Moderate sedation, also has
SECOND GENERATION ANTI-HISTAMINES
Drugs
Anti-chol.
activity
comments
Piperidines
Astemizole (Hismanal)
_
Slow onset of action ( withdrawn)
(Arrhythmia)
Fexofenadine (Allegra)
_
Lower risk of arrhythmia
Terfenadine (Seldane)
_
Prompt onset of action (arrhythmia)
Miscellaneous
Loratidine(ClaritinR)
Cetrizine (ZyreticR)
_
Longer action (no arrhythmia)
Serotonin
• Definition and Location:
• it is a neurotransmitter found in
enterochromaffin cells in GIT (90%) , and in
plateletes and in raphe nuclei of brain stem.
• Is serotonin as important as N.E or
Histamine?
• Mechanism of action :
Interacts with 12 receptor subtypes (see
Figure 16-4)
• Why is 5-HT3 receptor differs from other 5HT receptors?
Pharmacological actions of Serotonin
• CVS:
1) Blood vessels:
Potent and direct contractions on smooth muscle (via 5HT2 ) EXCEPT : Skeletal Muscles and Heart blood
vessels.
•
Note : 5- HT can give rise to triple action:
Decrease BP due to chemoreceptor
response then increase BP due to
Vasoconstriction (5-HT2), then decrease B.P due to
skeletal muscle V.D
2) Platelet: Increase platelet aggregation via 5-HT2
• GIT:
• 1) increase contraction of smooth muscle (via
5- HT4 stimulated the release of ACH).
• What is the clinical significant?
2) Nausea and vomiting (via 5-HT3) therefore
5-HT3 antagonists are used for RX of ?
• Respiration : 5-HT may produce weak
bronchoconstriction.
• CNS: very important.(Appetite; depression
and mania; Pain; Anxiety; Schizophrenia).
• Clinical Uses of Serotonergic Drugs:
• Note1: Unlike NE or DA, serotonin its self
has no clinical uses, however, it agonists and
antagonists have very important therapeutic
applications.
• Note 2: Unlike histamine where only its
antagonists are used, serotonin agonists and
antagonists can be used.
Clin. Uses of Serotonergic Agonists:
1) Buspirone: 5-HT1A agonist used as anxiolytic agent.
2) Sumatriptan: 5-HT1D agonist for migraine (Treatment
and prophylactic).
3) Metoclopromide (Plasil): 5-HT4 agonist as prokinetic agent
(for Rx of gastroesophagial reflex). How does it work? And also
used for N/V via 5-HT3 antagonistic action.
4) Dexfenfuramine: Acts by stim. Release and inhib. Reuptake
of serotonin.
Used as anorexic agent.
What is the effect of serotonin antagonists on appetite?
Clinical Uses of Serotonergic
Antagonists:
1) Ondansetron & Granisetron: 5-HT3 antagonists Common
used for Rx of N/V induced by cytotoxic (chemotherapy) drugs.
2) Cyproheptadine: Both H1, 5-HT1,2 and cholinergic antagonist
used for Rx carcinoid tumor (significant increases in serotonin)
and to increase appetite..
3) Ketanserin: 5-HT2/1c antagonist and 1-adrenergic blocker.
(used as antihypertensive agent)
4) Methysergide: This is an ergot alkaloid acts as 5-HT1,2
antagonist used for Rx of migraine.
• Ergot Alkaloids
• Produced from fungus with a pharmacologically
nonspecific actions at -adrenoceptors,
dopamine and 5-HT.
• Basic Pharmacology
– What is Ergot poisoning?
• MOA: Act on several types of receptors either
agonist, partial agonist, or antagonists (see
Table 16-6) (simply act on -adrenoceptors);
Dopamine and 5-HT).
• CNS:
– Stimulation of 5-HT2 receptors leads to
hallucinogenic action (e.g.: by LSD)
– Stimulation of dopaminergic receptors especially in
the pituitary decrease prolactin release and
emoliorate the symptoms of parkinsonism (e.g:
Bromocriptine)
• CVS:
– Vasoconstriction via -adrenoceptors and 5-HT2
receptors (Ergotamine via 1 and increase NE)
Uterine Smooth Muscle:
Why they are more effective in pregnancy?
(e.g.: Ergonovine)
Clinical Uses of Ergot Alkaloids
– Migraine (Ergotamine (with caffeine) or
dihydroergotamine during the attack while
methysergide for prophylaxis)
– Hyperprolactenemia (Bromocriptine= Dopamine
Agonist))
– Parkinsonism (Bromocriptine = Dopamine
Agonist)
– Post partum hemorrhage (Ergonovine) To induce
vasoconstriction.
– Diagnosis of variant angina (Ergonovine)
Toxicity:
GIT as diarrhea; N/V; Prolongs vasospasm
Eicosanoids
• Definition:
• Classifications; (see figures 18-1; 18-2 ;18-3)
• a ) Cyclooxygenase derivatives
(prostaglandins and thromboxane)
• b) Lipoxygenase products ( leukotriens)
Synthesis of eicosanoids and sites of inhibitory effects of anti-inflammatory drugs
Membrane lipid
Corticosteroids
-
Phospholipase A2
Arachidonic acid
Cycloxygenase
Lipoxygenase
Hydroperoxides
(HPETES)
Leukotrienes
(LTB, LTC ,LTD, LTE)
NSAIDs
Endoperoxides
(PGG, PGH)
Prostacyclin
(PGI)
Thromoxane
(TXA)
Prostaglandins
(PGE, PGF)
Physiological and Pharmacological Actions of Eicosanoids
Mechanisms and Receptors:
Act on cell surface receptors
All coupled to G-protein.
PGI; PGE increases adenylate cyclase (decrease intracellular calcium)
while TXA2 increases IP3 (increases intracellular calcium)
Pharmacological & Physiological Effects: (Table 1 & 13-1)
A.
B.
C.
D.
E.
F.
G.
H.
J.
Uterine Tone
Blood pressure regulation (Dilatation and constriction)
Inflammation
Gastric Secretion and motility.
Platelet aggregation
Bronchial tone
Effect on kidney
CNS (Fever; Pain; Sleep)
Eye
Table 1: Effects of some eicosanoids
Effect
PGE2
PGF2α
PGI2
TXA2
LTB4
LTC4
LTD4
Vascular
tone
↓
↑
↓↓
↑↑↑
?
↑,↓
↑,↓
Bronchial
tone
↓↓
↑
↓
↑↑↑
?
↑↑↑↑
↑↑↑↑
Uterine
tone
↑↑
↑↑↑
↓
?
?
?
?
↑ or ↓
?
↓↓↓
↑↑↑
?
?
?
?
?
?
?
↑↑↑↑
?
?
Platelete
aggration
Leukocyte
chemotaxis
↑= slight increase, ↑↑= moderate, ↑↑↑=high, ↑↑↑↑=very high,
↓= slight decrease, ↓↓= moderate and, ↓↓↓= marked; ?= unknown effects
Clinical Uses of Eicosanoids and Inhibitors:
•
• A. Uses of Eicosanoids:
•
•
– Oxytocis agents: (e.g.: Dinoprostone PGE2) vaginally or
Misoprostol (p.o)
_ - Impotance: Alprostadil PGE2
_ -Glaucoma: Latanoprost PGF2
– Pulmonary Hypertension ( PGI2 or prostacyclin, Epoprostenol)
– Peptic Ulcer (PGE1 Misoprostol (Cytotec)
• B – uses of eicosanoids blockers:
– Asthma: Leukotrien antagonists (Zafirleukast; Montelukast);
or Lipoxegenase inhibitor e.g. Zileuton
•
– Anti-inflammatory and RA (NSAIDs)
– Antiplatelet action (Aspirin)
– Dysmenorrhea (NSAIDs)
Pulmonary Hypertension
C. Vasoactive Peptides
• A. Vasoconstrictors (angiotensin II;
vasopressin; endothelins and
neuropeptide Y.
• B. Vasodilators (Bradykinin and related
Kinins; Natriuretic Pepties; Vasoactive
Intestinal Peptide; substance P;
Neurotensin)
Kinins : (e.g. : Bradykinin & kallidin)
• Polypeptides present in plasma and several
tissues including the kidneys, pancreas,
intestine, sweat and salivary glands.
ACTIONS :
CVS : Very potent vasodilator (direct and via
increase EDRF). Also, increases the body
capillary permeability
• Bronchioles : Contraction of bronchial smooth
muscles (cough).
• Inflammation : Kinins can produce all the
symptoms of inflammation (pain and edema when
injected to tissue).
• Pain : Intradermal injection of kinins elicited potent
pain (Stimulate nociceptive nerve afferent fibers)
•
DOES BRADYKININ PLAY ANY ROLE IN
THE MECHANISM OF ACTION OF ACEIs?
Natriuretic peptides:
Locations: Atrial (ANB) and Brain (BNP) (Found in ventricle as well)
Clinical significant:
(increase in heart failure; renal failure; SISADH
Actions: decrease the secretion of renin, aldosterone and vasopressin;
decrease blood pressure and increase sodium excretion. Act via activation of
guanalyl cyclase.
Calcitonin: from thyroid and the most potent vasodilators in the body.
Vasoactive-intestinal peptides:
Vasopressin (Antidiuretic hormone ADH)
Uses:
Supstnace P: is an arteriolar vasodilator that is also pain-mediating
neurotransmitter but causes venoconstriction and
bronchoconstriction. Capsaisin releases substance P from nerve
ending (used for arthritic joints and for postherpetic neuralgia).
The Natriuretic Peptide Family
• Include atrial natriuretic peptide (ANP),
brain natriuretic peptide (BNP), C-type
natriuretic peptide (CNP)
• ANP derived from a 126 amino acids
prohormone, secreted primarily from
cardiac atria
• BNP, identified initially in brain, is
secreted from both atria & ventricles
• CNP identified in brain & in vascular
endothelial cells
• Stretch receptors in the atria and
ventricles detect changes in cardiac
chamber volume related to increased
cardiac filling pressures, resulting in
release of both ANP and BNP but not
CNP
The Natriuretic Peptide Family
• The actions of the natriuretic peptides are
•
•
•
•
mediated by natriuretic peptide receptors (NPRs),
NPR-A/B/C
NPR-A & NPR-B are coupled to membrane-bound
GC, increases levels of cGMP
NPRs are localized in vascular SM, endothelium,
platelets, the adrenal glomerulosa, & the kidney
ANP & BNP increase urine volume & sodium
excretion, decrease vascular resistance, and
inhibit release of renin and secretion of
aldosterone & vasopressin
Neutral endopeptidases (NEPs) inactivate NPs
2. Vasoconstrictor peptides:
Angiotensin II
You should remember its synthesis? (See Figure
Actions:
1. the most potent vasoactive agent in the body (direct and vai NE)
2. Stim release of aldosterone and renin as well.
3. Centrally, stim. Drinking and increase the secretion of vasopressin and
ACTH.
Endothelins:
•
•
Widely distributed in the body (in endothelial cells of blood vessels)
ACTIONS: Dose-depen. Vasoconstriction in most vascular beds, Thus:
– Decrease GFR
– Increase aldosterone, vasopressin and ANP
– Potent bronchoconstriction
Endothelin Antagonists: Endothelin-converting enzyme inhibitors:
(Bosentan) (4 pulmonary HTN)
Kinins
Receptors, Actions & Therapy
• The activate B1, B2, B3 receptors linked to PLC/A2
• Powerful Vasodilation→ decreased blood pressure
via B2 receptor stimulation (NO-dependent)
• Increase in capillary permeability inducing edema.
It produces inflammation & algesia (B2)
• Cardiac stimulation:
Compensatory indirect & direct tachycardia &
increase in cardiac output
• It produces coronary vasodilation
Bradykinin has a cardiac anti-ischemic effect,
inhibited by B2 antagonists (NO & PI2 dependent)
Kinins
Actions & Therapy
• Kinins produce broncho-constriction & itching in
respiratory system (antagonized by ASA)
• Therapeutic Use:
 No current use of kinin analogues
 Increased bradykinin is possibly involved in the
therapeutic efficiency & cough produced by ACEIs
 Aprotinin (Trasylolol), a kallekrein inhibitor, used
in treatment of acute pancreatitis, carcinoid
syndrome & hyperfibrinolysis
Cyproheptadine:
•
•
•
• H1 blocker
Weak anticholinergic and mild CNS
depressant
Used for skin allergies, cold urticaria
Counteract the sexual side effects of
SSRI’s