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The autonomic nervous system

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Title: The autonomic nervous system


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The autonomic nervous system
Controls smooth muscles, exocrine and some
endocrine secretions, rate and force of the
heart, and certain metabolic processes. Sympatheti
c and parasympathetic systems have opposing
actions in some situations. The sympathetic
stimulation occurs in stress and the actions are
recovered at rest by the parasympathetic.
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  • It should be noted that the autonomic nervous
    system is always working. It is NOT only active
    during "fight or flight" or "rest and digest"
    situations. Rather, the autonomic nervous system
    acts to maintain normal internal functions and
    works with the somatic nervous system

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The Sympathetic Nervous System
  • The preganglionic motor neurons of the
    sympathetic system arise in the spinal cord and
    pass into sympathetic ganglia which are organized
    into two chains that run parallel to and on
    either side of the spinal cord.

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3) Leave the ganglia by way of a cord, leading
to special ganglion (e.g. the solar plexus) in
the viscera. It may here synapse with
post-ganglionic sympathetic neurons running to
the smooth muscular wall of the viscera. 4) Some
others pass to the adrenal medulla and may
synapse with the highly-modified post-ganglionic
cells, making the secretory portion of the
adrenal medulla. (epinephrine)
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NEUROTRANSMITTER
  • Definition
  • substance that is released at a synapse by one
    neuron and that affects a postsynaptic cellin a
    specific manner

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Noradrenaline release causes
Dilation of trachea and bronchi
Peristalsis
Heart beat
Pupil dilation
Liver glycogenolysis
Sphincters of rectal and bladder contraction
Blood Pressure
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Parasympathetic Nervous System
  • The main nerves are the tenth cranial and the
    vagus nerves that originate in the medulla
    oblongata.
  • Other preganglionic parasympathetic nerves also
    extend from the brain as well as the lower tip of
    the spinal cord.
  • Each preganglionic neurone passes into few
    post-ganglionic neurons located near or in the
    effector organ a muscle or gland.

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Parasympathetic stimulation
Returns body function to normal after sympathetic
stimulation
Peristalsis
Heart beat
Pupil constriction
Blood Pressure
Vagus keeps inflammation under control
Lowers TNF-a production
Increase blood flow to the skin and viscera
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Transmitters of the autonomic nervous system
Noradrenaline
Acetylcholine
All post-ganglionic sympathetic (except sweat
glands) nerve fibres, acting on a and ß
receptors.
All motor nerve fibres (nicotinic R)
All postganglionic parasympathetic (muscarinic
R)
Autonomic ganglia (nicotinic) Adrenal
medulla (nicotinic
The post-ganglionic sympathetic supplying sweat
glands (muscarinic)
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Phosphatidylinositol diphosphate
Ca
Cell Membrane
Gs
Phospholipase C
PI3
SR
DAG
Ca 2
Ca -dependent protein kinase
Protein kinase C
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a2
Cell Membrane
AC
Gi
ATP
cAMP
AC Adenylyl cyclase
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b -Agonist
Cell Membrane
b - receptor
AC
Gs
ATP
cAMP
Enzyme-PO4
AC Adenylyl cyclase
Biological effect
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The general Principles of chemical transmission
  • Denervation supersensitivity
  • If the nerve supplying the skeletal muscle is
    cut supersensitivity of the muscle to injected
    Ach occurs after denervation).
  • Mechanisms
  • Receptor proliferation (up to 20 folds in sk.
    muscles).
  • Loss of transmitter removal mechanisms (e.g.
    reuptake and cholinesterase action on Ach).

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Supersensitivity can take place due to
sustained pharmacological block of ganglionic
transmission, blockade of post-synaptic
receptors, resulting in rebound effects when the
blocker drug is stopped. This is due to receptor
upregulation e.g. rebound hypertension after
sudden withdrawal of beta-blockers
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Neuromodulation Many neuropeptides affect
membrane ion channels in such a way to increase
or decrease excitability and thus control the
firing pattern of the cell without participating
directly as transmitters.
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CATECHOLAMINE Synthesis Storage Characteristics
of a norepinephrine (NE)-containing
catecholamine neuron. Tyrosine (Tyr)
accumulated by the neuron is metabolized to
DOPA by tyrosine hydroxylase DOPA by DOPA
decarboxylase metabolized to dopamine (DA).
The DA is taken up through the vesicular
monoamine transporter into vesicles. DA is
metabolized to NE by dopamine-b-hydroxylase
(DBH), which is found in the vesicle. Once NE is
released, it can interact with postsynaptic
noradrenergic receptors or presynaptic
noradrenergic autoreceptors.
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CATECHOLAMINE Synthesis Storage

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Uptake of catecholamines transporter
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ACETYLCHOLINESynthesis and Storage
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Inactivation of Norepinephrine
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The main effects of the autonomic NS

decreases rate (M2) Increases rate (ß1) Heart (SAN)
decreases force (M2) Increases force (ß1) Atrial muscles
decreases cond. vel. (M2) Increases automaticity(ß1) ?AV node
No effect Increases force (ß1) Ventricular muscles
Organ
Sympathetic
Parasymp.
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Heart
b1-Agonist
Ca
Vagus
b1-receptor
M
AC
Gs
Gi
kinase
ATP
cAMP
Ca
Heart rate
Conduction
Contraction
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No effect Constriction (a1) Blood Vessels arterioles
No effect Dilation (ß2) Coronaries
No effect Dilation (ß2) muscles
No effect Constriction (a1) Viscera and skin
No effect Constriction (a1) Brain
Dilation (M3) Constriction (a1) Erectile tissue
Organ
Sympathetic
Parasymp.
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Constriction (M3) Dilation (ß2) Bronchi
Secretion (M3) Decreses secretion (a2) Glands
Increases (M3) Decreases (a1, a2, ß2) Intestinal motility
Variable Constriction (a1) Pregnant uterus
variable relaxation (ß2) Non-pregnant uterus
Erection (M3) Ejaculation (a1) Male sex organs
Organ
Sympathetic
Parasymp.
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Constriction (M3) Dilation (a1) Pupil
contraction (M3) Relaxation (ß2) Ciliary muscles
Increases (M3) (a-cholinergic stimulation) Sweat glands
No effect Erection (a1) Pilomotor muscles
Increases (M3) Thick viscid (a1) Salivary secretions
Secretion (M3) No effect Lacrimation
Organ
Sympathetic
Parasymp.
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No effect Renin secretion (ß 1) Kidney
No effect Glycogenolysis (ß2) Liver
No effect Lipolysis ß3 Adipose tissue
Organ
Sympathetic
Parasymp.
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Classification of adrenoceptors
  • a-receptors NE gt Epi gt isoprenaline
  • ß-receptors Isoprenaline gt Epi lt NE
  • a- antagonists
  • Ergot alkaloids
  • ß1 heart ß2 bronchi ß3 fat cells
  • a 1 NE (Prazosin)
  • a 2 methylnoradrenaline, clonidine (yohimbine)
  • Partial agonist

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Adrenoceptor agonists
  • Pharmcological actions
  • Smooth muscle
  • All contracted by a1 (except GIT) IP3

(Ca)i
ROCs
BP
Splanchnic vascular beds , veins, arteries
Baroreceptors
bradycardia
Vas deferens, spleenic capsule, eyelid retractor
muscles (nictitating membrane),
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Predicting Responses
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Beta receptors
  • ß2- receptor stimulation

Protein kinase
cAMP
Phosphorelates and inactivates myosin-light-chain
kinase
Ca efflux
Muscle relaxation
Nerve terminals a2 inhibits the
release Heart ß1 Metabolism Glycogen
Glucose
Gluconeogenesis (ß1) (ß3)
Fats
Free fatty acids
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  • Other effects
  • ß2 in skeletal muscle

tremors
ß2
histamine
Alpha blockers Non-selective alpha
blockers Haloalkylamines Phenoxybenzamine
(irreversible competitive) It binds covalently
with the receptors (gt 24 h)
GIT (opposing para)
BP
HR
Phentolamne and tolazoline ( reversible comp.
antag)
Labetalol (mixed a ß blocker)
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Drugs that inhibit NE synthesis
Ganglionic blocking drugs
Centrally acting sympatholytics
SYMPATHOLYTICS Drugs that reduce or inhibit
some or all of the actions of the sympathetic
nervous system.
NE depleting drugs
?-adrenergic antagonists
?-adrenergic antagonists
Adrenergic neuronal blocking drugs
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Prazosin
  • a1 selective antagonist
  • Decreases BP and HR
  • Yohimbine, idazoxan (a2 selective antagonist )
  • Sympathomimetic effect in some organs (a1 )
  • a1 a2 effects

BP VASODILATION
Aphrodisiac
Uses of alpha blockers a1 selective antagonist
used in hypertension Benign prostatic hypertrophy
(BPH ), Pheochromocytoma Prazosin, doxazosin,
terazosin
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Beta -adrenoceptor antagonists
? Dichloroisoprenaline (partial agonist) ?
Propranolol (non selective
blocker) ? Practolol (ß1-blocker) ? Labetalol (a
ß -blocker) ? Pharmacological actions ?
Increase H.R at rest e.g oxprenolol (partial
agonist) ? Decrease H.R during exercise ?
Antihypertensive via
(takes several days)
ß1
ß2
C.O
Renin
Block of presyna- ptic ß-receptors
CNS ACTION
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  • ? Bronchoconstriction (non-selective, C.I in
    asthma)
  • ? decrease in adrenaline-induced glucose release
    which occurs in response to hypoglycemia such as
    that caused by insulin in type-1 diabetes
  • ? Therapeutic uses
  • ? Hypertension
  • ? Pre-eclaptic toxaemia
  • ? In MI
  • ? antiarrhythmic
  • ? Glaucoma (Timolol)
  • ? Thyrotoxicosis
  • ? Anxiety states (adrenaline)
  • ? Migraine prophylaxis
  • ? Tremors

? Adverse effects ? Hypoglycemia ?
Bronchoconstriction ? Cardiac failure ? Physical
fatigue ? Cold extremities ? Bad dreams ?
Oculomucocutaneous Syndrome (practolol)
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Drugs that affect adrenergic neurons
  • I- On synthesis
  • ? alpha-methyltyrosine ? Carbidopa
  • ? Methyldopa (?a-methyl-noradrenaline)
  • ? 6- hydroxydopamine ( chem.l sympathectomy)
  • II- On storage
  • ? Reserpine (in low dose, it binds with
    transporter protein, preventing transport of NE
    into vesicles allowing its destruction by MAO),
    depletion of monoamines in brain ? depression
  • Used as antihypertensive
  • III- on release
  • ? Prevention of exocytosis (neuron blocker)
  • ? Indirectly acting drugs (tyramine)
  • ? Alpha 2 agonists (clonidine)
  • ? Decreasing the available stores (Reserpine,
    MAOI)

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  • Tyramine --MAO inhibitors
  • tyramine not a drug, found in many foods
    (cheese)
  • tyramine is rapidly metabolized by MAO.
  • MAO inhibitors increase the stores of
    catecholamines in vesicles.
  • Tyramine is a releaser of catecholamines
  • may occur hypertensive crisis due to massive
    levels of NE

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Noradrenergic neuron blocking drugs
  • ? Guanethidine, bretylium
  • ? It inhibits NE release
  • ? It causes release of NE
  • ? Depletion of NE
  • ? It abolish the response of tissues to
    sympathetic nerve stimulation
  • ? Local anaethetic like activity
  • ? Its action is opposed by amphetamine which
    inhibits uptake-1
  • Adverse effects
  • ? Postural hypotension, diarrhea, nasal
    congestion, sexual dysfunction

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? Amphetamine
  • ? It displaces NE in the cytosol (part of NE
    destructed with MAO, part diffuses outside the
    vesicles ? Inhibits uptake-1 ? MAO-inhibition
  • ? Reserpine abolishes its effect by depleting NE
  • ? MAO inhibitors potentiates its effect and that
    of tyramine (cheese reaction)
  • ? Uptake-1 inhibitors (imipramine) interfere with
    it
  • ? CNS effects (due to release of 5-HT and
    dopamine,
  • euphoria, wakefulness, tolerance and dependence
  • (depletion) ? Pressor effect ? Loss of appetite
  • ? Schizophrenia, hallucination and stereotyped
    behaviour
  • Uses
  • narcolepsy, hyperactive child, obesity

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Amphetamine
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  • ?Inhibitors of NE-uptake
  • Uptake-I inhibitors imipramine, cocaine
  • Uptake-II inhibitors
  • Phenoxybenzamne,
  • Corticosteroids
  • Uptake III inhibitors Guanethidine

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Uptake 3
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Dopamine
Sympathetic nerve terminal
  • Presence

Brain
Hypothalamuth ?decreases release of prolactin
from pituitary
Function of dopamine ? Role in movement (basal
ganglia) its decrease ? Parkinisonisn ?
Role in cognition (frontal lobes) , memory,
attention ? Role in pleasure and motivation
(striatum) Amphetamine, cocaine, inhibit dopamine
uptake (euphoria)
Dopamine ? Psychosis and Schizophrenia
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Wording
  • Sympathomimetic drugs
  • Adrenomimetic drugs
  • Adrenergic agonists
  • Adrenoceptor agonists

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Suggested Reading
  • Katzung BG. Basic clinical pharmacology.
  • Katzung BG, Trevor AJ. Examination board review
    pharmacology.
  • GoodmanGilman. Basic pharmacology.
  • Pharmacology, Lippincotts Illustrated Reviews

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Drugs Acting on Parasympathetic Nervous System
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Introduction
  • P. symp NS ? digestion elimination.
  • Main transmitter Acetylcholine (Ach).
  • Autonomic ganglia (symp p. symp).
  • Preganglionic symp fibers to adrenal medulla.
  • Postganglionic p. symp fibers.
  • Skeletal muscles
  • CNS.

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Cholinergic Neurotransmission
  • Synthesis
  • Choline
    Ach.
  • Inhibited by hemicholinium.
  • 2. Storage
  • Ach ATP proteoglycan.

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  • 3. Release of Ach
  • Action potential ? open Ca2 channels ? ?
    intracellular Ca2 ? exocytosis.
  • Botulinum toxin ? block Ach release.
  • Black widow spider venom ? release all stored
    Ach.

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  • 4. Binding to receptors
  • Postsynaptic (organs) or presynaptic (nerve
    terminal).
  • Initiate response mediated by 2ry messengers e.g.
    cAMP, IP3 DAG.

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  • 5. Degradation of Ach
  • Ach choline
    acetate.
  • True cholinesterase (synaptic cleft) pseudo
    cholinesterase (plasma liver).
  • 6. Recycling of choline
  • Choline ? neuron ? Ach.

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Cholinergic Receptors
  • 1. Nicotinic Receptors
  • Affinity ? nicotine ? muscarine.
  • Linked to ion channels.
  • Types
  • Neuronal nicotinic (NN) blocked by ganglionic
    blocker e.g. hexamethonium.
  • Muscular nicotinic (NM) blocked by NMBs e.g.
    curare.

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  • 2. Muscarinic Receptors
  • Affinity ? muscarine ? nicotine.
  • Linked to G-proteins (Gq Gi).
  • Types
  • M1 ganglia parietal cells.
  • M2 heart smooth muscles.
  • M3 smooth muscles secretory glands.
  • Atropine blocks all types pirenzepine blocks M1.

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Autonomic NS Effect on the Eye
RECEPTOR ACTIVATION WILL TO LOWER IOP, AIM FOR
IRIS, Circular Fibers mAchR Constrict Pupil ? Activity
IRIS, Radial Fibers ?1 R Dilate Pupil ? Activity
CILIARY MUSCLES mAchR Contract for Accomodation ?2 R Relax for Far Vision Activity ?Activity
Modified from http//pharma1.med.osaka-u.ac.jp/te
xtbook/Autonomic/Autonomic.html
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DRUGS THAT DECREASE AQUEOUS PRODUCTION
  • Beta-Blockers levobunolol, timolol, carteolol,
    betaxolol
  • -Mechanism Act on ciliary body to ? production
    of aqueous humor
  • -Administration Topical drops to avoid
    systemic effects
  • -Side Effects Cardiovascular (bradycardia,
    asystole, syncope), bronchoconstriction (avoid
    with b1-selective betaxolol), depression
  • Alpha-2 Adrenergic Agonists apraclonidine,
    brimonidine
  • -Mechanism ? production of aqueous humor
  • -Administration Topical drops
  • -Side Effects Lethargy, fatigue, dry mouth
    apraclonidine is a derivative of clonidine
    (antihypertensive) which cannot cross BBB to
    cause systemic hypotension
  • Carbonic Anhydrase Inhibitors acetazolamide,
    dorzolamide
  • -Mechanism Blocks CAII enzyme production of
    bicarbonate ions (transported to posterior
    chamber, carrying osmotic water flow),
    thus ? production of aqueous humor
  • -Administration Oral, topical
  • -Side Effects malaise, kidney stones,
    possible (rare) aplastic anemia

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DRUGS THAT INCREASE AQUEOUS OUTFLOW
  • Nonspecific Adrenergic Agonists epinephrine,
    dipivefrin
  • -Mechanism ? uveoscleral outflow of aqueous
    humor
  • -Administration Topical drops
  • -Side Effects Can precipitate acute attack in
    patients with narrow iris-corneal angle,
    headaches, cardiovascular arrhythmia, tachycardia
  • Parasympathomimetics pilocarpine, carbachol,
    echothiophate
  • -Mechanism ? contractile force of ciliary body
    muscle, ? outflow via TM
  • -Administration Topical drops or gel,
    (slow-release plastic insert)
  • -Side Effects Headache, induced miopia. Few
    systemic SE for direct-acting agonists vs. AchE
    inhibitors (diarrhea, cramps, prolonged paralysis
    in setting of succinylcholine). Why isnt Ach
    used
  • Prostaglandins latanoprost
  • -Mechanism May ? uveoscleral outflow by
    relaxing ciliary body muscle
  • -Administration Topical drops -Side
    Effects Iris color change

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Parasympathetic Acting Drugs
  • I- P. sympathomimetics stimulate p. sympathetic
    nervous system.
  • Direct act on muscarinic receptors.
  • Indirect inhibit cholinesterase ? ? Ach.
  • II- P. sympatholytics depress p. sympathetic
    nervous system.
  • Muscarinic blockers.
  • Ganglion blockers.

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Direct Acting P. Sympathomimetics
  • Acetylcholine
  • Muscarinic effects
  • Eye miosis, accommodation for near vision ?
    lacrimation.
  • GIT ? motility secretions.
  • RT bronchoconstriction ? bronchial secretions.
  • UT contraction of bladder.
  • CVS bradycardia, vasodilation (NO) hypotension.

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  • B. Nicotinic effects
  • Relatively weak.
  • Stimulate all autonomic ganglia (sympathetic p.
    sympathetic).
  • Ach (IV) Atropine ? ? BP (by ? symp ganglia ? ?
    NE.
  • Adrenal medulla Epi

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Bethanechol, Methacholine
  • Resist cholinesterase ? ? duration.
  • Pharmacological actions
  • GIT ? tone and motility.
  • UT stimulate detrusor muscle relax sphincter.
  • Uses atonic bladder intestinal atony. C.I in
    mechanical obstruction
  • Adverse effects sweating, salivation, nausea,
    abdominal pain, diarrhea, bronchospasm
    hypotension.

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Carbachol
  • Resist cholinesterase ? ? duration.
  • Pharmacological actions
  • Both muscarinic nicotinic effects.
  • Adrenal medulla ?? adrenaline release.
  • Eye (locally) ? miosis ? IOP.
  • Uses locally in glaucoma.

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Pilocarpine
  • Pharmacological actions
  • Eye (locally) miosis accommodation for near
    vision.
  • Uses
  • Glaucoma (emergency).
  • Mitotic.
  • Xerostomia.
  • Alopecia.
  • Adverse effects sweating, salivation CNS
    effects.

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Indirect Acting P. Sympathomimetics
  • Mechanism inhibit cholinesterase ? ? effects of
    endogenous Ach (muscarinic nicotinic).
  • Types
  • Reversible inhibitors e.g. physostigmine
    neostigmine.
  • Irreversible inhibitors e.g. isoflurophate.

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Physostigmine
  • Pharmacological actions
  • Stimulates M, NN NM receptors.
  • Passes BBB ? central effects.
  • Uses
  • Glaucoma (local).
  • Atonic bladder intestinal atony.
  • Treatment of atropine overdose.
  • Adverse effects bradycardia, convulsions (?
    dose).

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Neostigmine(quaternary ammonium compound)
  • Pharmacological actions
  • Profound effects on skeletal muscles.
  • No CNS effects.
  • Duration 2-4 h.
  • Uses
  • Myasthenia gravis (autoimmune disease for
    NM-receptors, circulating curare like
    substance-----muscle weakness
  • Antidote for NMBs (after surgery).
  • Stimulate GIT urinary bladder.

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  • Pyridostigmine
  • ? Duration (3-6 h) ? used in chronic management
    of myasthenia gravis.
  • Edrophonium
  • ? Duration (10-20 min) ? diagnosis of myasthenia
    gravis.

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Irreversible anticholinesteraseOrganic
phosphates (insecticides, (local
drugsIsoflurophate, Echothiophate
  • Pharmacological actions
  • Bind covalently to cholinesterase.
  • Aging (6-8 h).
  • Generalized cholinergic stimulation.
  • Uses
  • Glaucoma (locally once/week).
  • Adverse effects motor paralysis, convulsions.

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Pralidoxime (PAM)
  • Synthetic Oximes.
  • Reactivate inhibited cholinesterase.
  • Must be given before aging.
  • Not effective with newer nerve gases (aging
    within sec.).
  • Uses
  • Treats toxicity of insecticides together with
    atropine

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P. Sympatholytics
  • Muscarinic Blockers
  • Clinically beneficial compared to agonists.
  • Order of blockade sensitivity
  • Secretory glands ? ? secretions.
  • Eye ? dilation loss of accommodation.
  • Heart ? tachycardia.
  • GIT UT ? ? tone motility.
  • UT ? relaxation of detrusor muscle.

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Atropine
  • Pharmacokinetics
  • Duration orally (4h) topically in eye (days).
  • Pharmacological actions
  • Eye passive mydriasis, loss of light
    reflex/loss of accomodation cycloplegia.
  • GIT UT ? motility (urinary retention,
    constipation) no effect on acid secretion.

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  • Secretory glands
  • Xerostomia.
  • Xerophthalmia.
  • Hyperthermia.
  • CVS dose-dependent.
  • Low dose bradycardia (block presynaptic M1).
  • High dose (1 mg) tachycardia (block M2).
  • Toxic dose atropine flush.

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  • Uses
  • Ophthalmology, antispasmodic in heart block.
  • Pre-anesthetic medication.
  • Antidote for anticholinesterases.
  • Adverse effects
  • Dry mouth, blurred vision, tachycardia.
  • Urinary retention, constipation CNS effects.
  • Contraindications
  • Glaucoma.
  • Prostatic hypertrophy.

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How does it work? Atropine blocks
the receptors in the muscles of the eye
(muscarinic receptors). These receptors are
involved in controlling the pupil size and the
shape of the lens. By blocking these receptors,
atropine produces dilatation of the pupil
(mydriasis) It prevents the eye from
accommodating for near vision (cycloplegia).
Atropine is given as eye drops to dilate the
pupil and relax the lens so that eye examinations
can be carried out thoroughly. It is often used
to aid eye examinations in young children. It is
also used to relax the muscles that inflammed and
over-contract in the eye in conditions such as
uveitus
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Hyoscine (Scopolamine)
  • Pharmacological actions
  • Similar to atropine.
  • More CNS effects longer duration.
  • Uses
  • Motion sickness.
  • Block short-term memory(The amnesic action of
    scopolamine makes it an important adjunct drug in
    anesthetic).

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  • Other Atropine Substitutes
  • Pirenzepine peptic ulcer.
  • Ipratropium bronchial asthma.
  • Benztropine Parkinsons disease.
  • Cyclopentolate ophthalmology.
  • Emepronium urinary incontinence.

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Drugs Acting on Autonomic Ganglia
  • Ganglionic Stimulants
  • Stimulate NN in symp ganglia ? vasoconstriction,
    hypertension tachycardia.
  • Stimulate NN in p. symp ganglia ? ? GIT motility
    secretions.
  • Ganglionic Blockers
  • Block NN ? hypotension, mydriasis, dry mouth,
    constipation, urinary retention decreased
    secretions.

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Nicotine
  • Low dose
  • Stimulation of symp ganglia ? tachycardia ?
    BP.
  • Stimulation of p. symp ganglia ? ? GIT motility
    secretions.
  • High dose
  • Blockade of symp ganglia ? ? BP.
  • Blockade of p. symp ganglia ? ? GIT motility
    secretions.

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  • Trimetaphan
  • Short-acting competitive ganglionic blocker.
  • Used IV in emergency lowering of BP.
  • Mecamylamine
  • Long-acting competitive ganglionic blocker.
  • Used orally to lowering of BP.

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Neuromuscular Blocking Drugs These drugs block
cholinergic transmission between motor nerve
endings and the nicotinic receptors on the
neuromuscular end plate of skeletal muscle
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A. Nondepolarizing (competitive) blockers
Mechanism of actionThey interact with the
nicotinic receptors to prevent the binding of
acetylcholine and inhibit muscular
contractionActions Small, rapidly
contractingmuscles of the face and eye are most
susceptible and are paralyzed first, followed by
the fingers. Thereafter, the limbs, neck, and
trunk muscles are paralyzed. Then the intercostal
muscles are affected, and lastly, thediaphragm
muscles are paralyzed. They release histamine,
can produce a fall in blood pressure, flushing,
and bronchoconstrictionExamples tubocurarine,
mivacurium, and atracurium, gallamine
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All neuromuscular blocking agents are injected
intravenously, because their uptake via
oralabsorption is minimal. Drug interaction
Cholinesterase inhibitors can overcome the
action of nondepolarizing neuromuscular
blockers Aminoglycoside antibiotics
gentamicin inhibits acetylcholine release by
competing with calcium ions. They synergize with
tubocurarine enhancing the blockade.
Calcium-channel blockersThey increase the
neuromuscular block of tubocurarine and other
competitive blockers as well as depolarizing
blockers.
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B. Depolarizing agentsMechanism of action e.g.
succinylcholine attaches to the nicotinic
receptor and acts like acetylcholine to
depolarize the junction The depolarizing
agent first causes the opening of the sodium
channel associated with the nicotinic receptors,
which results in depolarization of the receptor
(Phase I). This leads to a transient twitching of
the muscle (fasciculations). Continued binding
of the depolarizing agent renders the receptor
incapable of transmitting further impulses.
With time, continuous depolarization gives way to
gradual repolarization as the sodium channel
closes or is blocked. This causes a resistance
to depolarization (Phase II) and a flaccid
paralysis
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Therapeutic uses To facilitate endotracheal
intubation during the induction of anaesthesia
It is also employed during electroconvulsive
shock therapy Adverse effects
Administration of succinylcholine with halothane
causes malignant hyperthermia in genetically
susceptible people.This is treated by rapidly
cooling the patient and by administration of
dantrolene, which blocks release of Ca2 from the
sarcoplasmic reticulum of muscle cells, thus
reducing heat production and relaxing muscle
tone.Apnea Administration of succinylcholine to
a patient who is genetically deficient in plasma
cholinesterase or has an atypical form of the
enzyme can lead to prolonged apnea.Hyperkalemia
Succinylcholine increases potassium release from
intracellular stores. This is dangerous in burn
patients
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Autacoids(Local Hormones)
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Response vs. distance traveled
Endocrine action the hormone is distributed in
blood and binds to distant target
cells.Paracrine action the hormone acts locally
by diffusing from its source to target cells in
the neighborhood.Autocrine action the hormone
acts on the same cell that produced it.
128
Autacoids
  • Biologically active substances synthesized in the
    body.
  • Possess both physiologic pathologic effects.
  • Act at or near their site of synthesis (local
    hormones).
  • Act quickly at different receptors.
  • Rapidly degraded.

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  • Autacoids Include
  • Lipid derived eicosanoids PGs, LTs TXs.
  • Naturally occurring amines histamine 5-HT.
  • Endogenous polypeptides angiotensin
    bradykinin.
  • Cytokines interleukins interferons.
  • Nitric oxide (NO).

130
Why are Autacoids Important?
  • Autacoids have complex physiologic pathologic
    effects.
  • Thus
  • Drugs that mimics or antagonize effects of
    autacoids are therapeutically useful.

131
Eicosanoids
  • Derived from arachidonic acid (derived from
    membrane phospholipids).
  • Include
  • Prostaglandins (PGs).
  • Prostacyclin (PGI2).
  • Thromboxanes (TXs).
  • Leukotrienes (LTs).
  • Lipoxins (LXs).

132
Phospholipids

Phospholipase A2
Arachidonic Acid
COX
Lipoxygenase
Cyclic Endoperoxides
LTs LXs
PGI Synthase
TX Synthase
PG Synthase
PGI2
PGE2 PGF2a
TXA2
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Pharmacological Effects of Eicosanoids
  • I- Prostaglandins
  • Pyretic effect algesic effect.
  • Inflammatory effect vasodilation, ? vascular
    permeability chemotaxis.
  • GIT ? HCl secretion ? mucus formation.
  • Bronchi bronchoconstriction (PGF2a).
  • Uterus uterine contraction (PGE2 PGF2a).
  • Kidneys vasodilation (PGE2 PGI2).

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  • II- Thromboxanes prostacyclins
  • Chief eicosanoids in platelets
  • PGI2 ? vasodilation ? platelet aggregation.
  • TXA2 ? vasoconstriction ? platelet aggregation.
  • PGI2 TXA2 balance ? regulation of BP
    thrombogenesis.
  • Imbalance ? hypertension, ischemia, thrombosis,
    coagulopathy, MI stroke.

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  • III- Leukotrienes lipoxins
  • LTs
  • Cause vasoconstriction bronchospasm.
  • Involved in pathology of asthma, arthritis,
    psoriasis, allergy hypersensitivity.
  • LXs
  • Negative regulators of LTs.
  • Important in resolution of inflammation.

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Therapeutic Uses of PG Analogues
  • Dinoprostone (PGE2) facilitation of labor.
  • Gemeprost (PGE1) medical abortion.
  • Misoprostol (PGE1) prevent NSAID-induced ulcer.
  • Epoprostenol (PGI2) pulmonary hypertension.
  • Alprostadil (PGE1) erectile dysfunction.
  • Latanoprost (PGF2a) glaucoma.

137
Types of COX
  • COX-1
  • Constitutive.
  • GIT kidney.
  • Inhibition ? gastric renal damage.
  • COX-2
  • Mostly inducible.
  • Induced in response to inflammation.
  • Inhibition ? ? inflammation no gastric or renal
    damage.

138
Drugs Inhibiting Eicosanoids Synthesis
  • Phospholipase-Inhibitors
  • e.g. Corticosteroids (? lipocortin).
  • COX-Inhibitors
  • e.g. NSAIDs (non-selective).
  • Celecoxib (selective COX-2).
  • LTs-Inhibitors
  • 5-Lipoxygenase inhibitors e.g. zileuton.
  • LTs receptor blockers e.g. montelukast.

139
Histamine
  • Synthesis decarboxylation of L-histidine.
  • Storage mast cells, basophils CNS.
  • Release
  • Immune reaction.
  • Drugs (morphine, tubocurarine succinylcholine).
  • Receptors G-protein coupled.
  • H1? VSM, endothelium brain.
  • H2 ? GIT, heart, VSM(vascular smooth muscles).
  • H3 ? brain, presynaptic.

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Pharmacological Actions
  • Effects mediated by H1 receptors
  • Contraction of bronchial intestinal smooth
    muscles.
  • ? Production of nasal bronchial secretions.
  • Itching pain.
  • Effects mediated by H2 receptors
  • ? HCl secretion.

141
  • Effects mediated by H1 H2 receptors
  • Vasodilation of blood vessels ? BP.
  • Vasodilation ? capillary permeability of skin
    blood vessels ? redness, wheal flare.
  • How?
  • H1 ? ? intracellular Ca2 ? activate NOS ? NO ?
    vasodilation.
  • H2 ? ? cAMP ? vasodilation.

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Histamine Antagonists
  • H1 receptor blockers.
  • H2 receptor blockers.
  • Mast cell stabilizers.
  • Epinephrine.

143
H1 receptor blockers
  • Types
  • 1st generation (sedating) e.g. promethazine,
    meclizine chlorpheniramine.
  • 2nd generation (non-sedating) e.g. loratidine
    terfenadine.
  • Pharmacological Actions
  • Antagonize all effects except ? HCl.
  • Some possess anti-cholinergic properties.

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  • Uses
  • Allergic rhinitis.
  • IgE-mediated.
  • Seasonal (hay fever) .
  • Symptoms sneezing, rhinorrhea, pruritus nasal
    congestion.
  • Treated by H1-blockers nasal decongestant.
  • Urticaria
  • Vascular skin reaction.
  • Causes food, drugs, insect bites, etc.
  • Treated by H1-blockers.

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  • 3. Motion sickness.
  • 4. Vertigo or Menieres disease.
  • 5. Pregnancy-induced nausea vomiting.
  • 6. Insomnia.
  • 7. Not effective in asthma (LTs involved).
  • Adverse Effects
  • Drowsiness, sedation fatigue (1st generation).
  • Dry mouth.

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  • H2 receptor blockers
  • ? HCl secretion e.g. ranitidine.
  • Used in peptic ulcer GERD (gastrointestinal
    esophageal reflux).
  • Mast cell stabilizers
  • Used for prophylaxis from asthma e.g. cromolyn
    nedocromil.
  • Ketotifen (mast cell stabilizer H1 blocker).
  • Epinephrine
  • Vasoconstriction bronchodilation.
  • Effects mediated by a1 ß2 receptors.

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Serotonin
  • Synthesis from L-tryptophan.
  • Storage
  • GIT (90).
  • Platelets
  • CNS.
  • Receptors
  • 5-HT receptors (7/12 types).
  • G-protein coupled.

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  • Pharmacological Actions
  • Regulates mood
  • SSRIs e.g. fluoxetine used as antidepressants.
  • 5-HT1A agonist buspirone used as anxiolytic.
  • Regulates appetite
  • Sibutramine (? 5-HT, NE dopamine reuptake) ?
    anorexigenic.
  • Cyproheptadine (5-HT2 blocker)? appetite
    stimulant.
  • 3. Vomiting ondansetron (5-HT3 blocker)?
    anti-emetic effect.

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  • 4. Migraine
  • Unilateral headache associated with nausea,
    vomiting sensitivity to light sound.
  • Common in females.
  • Starts in adolescence.
  • Causes
  • Vasodilation ? cranial arteries pulsations.
  • Perivascular inflammation edema.
  • Types
  • Classic with aura (15).
  • Common (85).

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  • Treatment
  • Sumatriptan zolmitriptan (5-HT agonists) ?
    vasoconstriction ? release of inflammatory
    neuropeptides ? ? migraine pain.
  • Ergotamine (5-HT agonist a-blocker with agonist
    activity) ? ? pulsation of cranial arteries.

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  • Ergot Alkaloids
  • Produced from fungus with a pharmacologically
    nonspecific actions at a-adrenoceptors, dopamine
    and 5-HT.
  • Basic Pharmacology
  • What is Ergot poisoning?
  • MOA
  • Act on several types of receptors either
    agonist, partial agonist, or antagonists (simply
    act on a-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
    treats parkinsonism (e.g Bromocriptine)

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  • CVS
  • Vasoconstriction via a-adrenoceptors and 5-HT2
    receptors (Ergotamine via a1 and increase NE)
  • 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
    (ergotamine and ergonovine) may progress to
    gangrene.

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Angiotensin
Renin
Kidney
Angiotensinogen
Angiotensin I
-
ACE
Angiotensin II
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  • Factors affecting renin secretion
  • Renal vascular receptors (stretch receptors).
  • Sympathetic NS activation ? ? renin.
  • Angiotensin II ? ? renin.
  • Drugs e.g. vasodilators, diuretics, ß-agonists,
    a-blockers ? ? renin.

155
Renin-Angiotensin-Aldosterone System
  • Increased Na reabsorption Increases blood volume
    and/or pressure.
  • Juxtaglomerular apparatus secretes renin.
  • Renin acts on angiotensinogen (gamma globulin
    from the liver) giving angiotensin I
  • Angiotensin converting enzyme (ACE) acts on
    angiotensin I giving angiotensin II

156
Renin-Angiotensin-Aldosterone System
  • Angiotensin converting enzyme (ACE) is also known
    as kinanase II
  • It converts angiotensin I to II (vasoconstrictor)
    and inactivates bradykinin (vasodilator)
  • The principal site of its action is vascular
    epithelium

157
Renin-Angiotensin-Aldosterone System
  • Angiotensin II
  • Stimulates aldosterone production
  • Stimulates ADH secretion from pituitary
  • Highly potent vasoconstrictor
  • Stimulates thirst
  • Stimulates release of catecholamines by adrenal
    medulla

158
Role of Angiotensin IIHypertensive
  • Angiotensin ll is a powerful vasoconstrictor. It
    constricts the blood vessels and raises the
    peripheral resistance, thereby acting to restore
    blood pressure.
  • Angiotensin ll also increases the secretion of
    aldosterone leading to Na reabsorption.

159
Effects of Angiotensin II
160
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

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  • 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 (Stimulates nociceptive nerve fibers)

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KininsReceptors, 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 dependent)

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KininsActions 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

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Nitric Oxide (NO)
  • Synthesis from L-arginine by NOS.
  • Types of NOS
  • Isoform I (nNOS) neurons.
  • Isoform II (iNOS or mNOS) macrophages.
  • Isoform III (eNOS) endothelial cells.
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