165
Controls smooth muscles, exocrine and some endocrine secretions, rate and force of the heart, and certain metabolic processes.
Sympathetic 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.
• *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
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.
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)
NEUROTRANSMITTER
Definition:“substance that is released at a
synapse by one neuron and that affects a postsynaptic cell…in a specific manner”
Noradrenaline release causes
Heart beat
Blood Pressure
Pupil dilation
Dilation of trachea and
bronchi
Liver glycogenolysis
Peristalsis
Sphincters of rectal and bladder contraction
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.
Parasympathetic stimulation
Heart beat
Blood Pressure
Pupil constriction
Returns body function to
normal after sympathetic
stimulation
Increase blood flow to the skin and viscera
Peristalsis
Vagus keeps inflammation under controlLowers TNF-α production
#All motor nerve fibres (nicotinic R)
# All postganglionic parasympathetic (muscarinic R)
#The post-ganglionic sympathetic supplying sweat glands (muscarinic)
All post-ganglionic sympathetic (except sweat glands) nerve fibres, acting on α and β receptors.
# Autonomic ganglia (nicotinic)# Adrenal medulla (nicotinic}
Cell Membrane
Ca ++
Ca 2+
Ca ++ - d ependent protein kinase
SR
Phospholipase C
PI3
DAG
Phosphatidylino sitol diphosphat
e-Agonist
Protein kinase C
Gs
Cell MembraneAC Gi
Agonist
ATP
cAMPcAMP
No biological effect
-Enzyme PO4
AC= Adenylyl cyclase
Cell Membrane- receptor
-Agonist
ACGs
ATP
cAMPcAMP
Biological effect
-Enzyme PO4
AC= Adenylyl cyclase
Denervation supersensitivity:
If the nerve supplying the skeletal muscle is cut supersensitivity of the muscle to injected Ach occurs after denervation).
Mechanisms :
a) Receptor proliferation (up to 20 folds in sk. muscles).
b) Loss of transmitter removal mechanisms (e.g. reuptake and cholinesterase action on Ach).
* 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
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.
CATECHOLAMINE Synthesis & Storage
Characteristics of a norepinephrine (NE)-containing catecholamine neuron.
# Tyrosine (Tyr) accumulated by the neuron is metabolized to DOPA by tyrosine hydroxylaseDOPA 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.
CATECHOLAMINE Synthesis & Storage
Uptake of catecholamines: transporter
27
ACETYLCHOLINESynthesis and Storage
Inactivation of Norepinephrine
Heart (SAN)Heart (SAN)Increases rate Increases rate ((ββ1)1)
decreases rate decreases rate (M2)(M2)
Atrial musclesAtrial musclesIncreases force Increases force ((ββ1)1)
decreases force decreases force (M2)(M2)
3ِ3ِAV node AV node Increases Increases automaticity(automaticity(ββ1)1)
decreases cond. decreases cond. vel. (M2)vel. (M2)
Ventricular Ventricular musclesmuscles
Increases force Increases force ((ββ1)1)
No effectNo effect
Organ Sympathetic Parasymp.
M
ACGs Gi
-receptor
-Agonist
kinaseAT
P
Ca +
+
Ca++
Heart rate ConductionContraction
Vagu
s
HeartHeart
cAMPcAMP
Blood Vessels: Blood Vessels: arteriolesarterioles
Constriction (Constriction (αα1)1)No effectNo effect
CoronariesCoronariesDilation (Dilation (ββ2)2)No effectNo effect
musclesmusclesDilation (Dilation (ββ2)2)No effectNo effect
Viscera and skinViscera and skinConstriction (Constriction (αα1)1)No effectNo effect
BrainBrainConstriction (Constriction (αα1)1)No effectNo effect
Erectile tissueErectile tissueConstriction (Constriction (αα1)1)Dilation (M3)Dilation (M3)
Organ Sympathetic Parasymp.
BronchiBronchiDilation (Dilation (ββ2)2)Constriction Constriction (M3)(M3)
GlandsGlandsDecreses Decreses secretion (secretion (αα2)2)
Secretion (M3)Secretion (M3)
Intestinal Intestinal motilitymotility
Decreases Decreases ((αα1, 1, αα2, 2, ββ2)2)
Increases (M3)Increases (M3)
Pregnant uterusPregnant uterusConstriction (Constriction (αα1)1)VariableVariable
Non-pregnant Non-pregnant uterusuterus
relaxation (relaxation (ββ2)2)variablevariable
Male sex organsMale sex organsEjaculation (Ejaculation (αα1)1)Erection (M3)Erection (M3)
Organ Sympathetic Parasymp.
PupilPupilDilation Dilation ((αα1)1)
Constriction Constriction (M3)(M3)
Ciliary Ciliary musclesmuscles
Relaxation (Relaxation (ββ2)2)contraction (M3)contraction (M3)
Sweat glandsSweat glands))αα-cholinergic -cholinergic stimulationstimulation((
Increases (M3)Increases (M3)
Pilomotor Pilomotor musclesmuscles
Erection (Erection (αα1)1)No effectNo effect
Salivary Salivary secretions secretions
Thick viscid (Thick viscid (αα1)1)Increases (M3)Increases (M3)
LacrimationLacrimationNo effectNo effect Secretion (M3)Secretion (M3)
Organ Sympathetic Parasymp.
KidneyKidneyRenin secretion Renin secretion ( (β β 1)1)
No effectNo effect
LiverLiverGlycogenolysis Glycogenolysis ((ββ2)2)
No effectNo effect
Adipose Adipose tissuetissue
Lipolysis Lipolysis ββ33 No effectNo effect
Organ Sympathetic Parasymp.
Classification of adrenoceptors• α-receptors: NE > Epi > isoprenaline• β-receptors: Isoprenaline > Epi < NE• α- antagonists• Ergot alkaloids
• β1 : heart β2 : bronchi β3 : fat cells
• α 1 :NE (Prazosin)
• α 2 : methylnoradrenaline, clonidine (yohimbine)
• Partial agonist:
Adrenoceptor agonists
• Pharmcological actions:• Smooth muscle
• All contracted by α1 (except GIT) IP3 (Ca)i
ROCs
Splanchnic vascular beds , veins, arteries BP
Baroreceptors bradycardia
Vas deferens, spleenic capsule, eyelid retractor muscles (nictitating membrane),
Predicting Responses
Beta receptors
• β2- receptor stimulation
cAMPProtein kinase
Phosphorelates and inactivates myosin-light-chain kinase
Muscle relaxation Ca efflux* Nerve terminalsα2 inhibits the releaseHeart β1
Metabolism Glycogen Glucos
eFats Free fatty acidsGluconeogenesis (β1) (β3)
• Other effects:
• β2 in skeletal muscle tremors
β2 histamine
Alpha blockersNon-selective alpha blockersHaloalkylamines:
Phenoxybenzamine: (irreversible competitive)
It binds covalently with the receptors (> 24 h) BP HR
Phentolamne and tolazoline ( reversible comp. antag)
GIT (opposing para)
Labetalol (mixed α + β blocker)
Ganglionic blocking drugs Centrally acting
sympatholytics
NE depleting drugs
Drugs that inhibit NE synthesis
Adrenergicneuronal
blocking drugs
ᵅ-adrenergicantagonists
ᵦ-adrenergic antagonists
SYMPATHOLYTICS: Drugs that reduce or inhibit some or all of the actions of the sympathetic nervous
system.
Prazosin• α1 –selective antagonist
Decreases BP and HR
• Yohimbine, idazoxan (α2 –selective antagonist )
Sympathomimetic effect in some organs (α1 )
• α1+ α2 effects BP + VASODILATION
Aphrodisiac
Uses of alpha blockers
α1 –selective antagonist used in hypertension
Benign prostatic hypertrophy (BPH ), Pheochromocytoma
Prazosin, doxazosin, terazosin
Beta -adrenoceptor antagonists
☺ Dichloroisoprenaline (partial agonist)
☺ Propranolol (non selective blocker)
☺ Practolol (β1-blocker)
☺ Labetalol (α + β* -blocker)
► Pharmacological actions
◦ Increase H.R at rest e.g oxprenolol (partial agonist)
◦ Decrease H.R during exercise
◦ Antihypertensive via (takes several days)
β1
β2
C.O
Renin
CNS ACTIONBlock of presyna-
ptic β-receptors
◦ 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◙ OculomucocutaneousSyndrome (practolol)
Drugs that affect adrenergic neuronsI- On synthesis► alpha-methyltyrosine ► Carbidopa► Methyldopa (→α-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 antihypertensiveIII- on release► Prevention of exocytosis (neuron blocker)► Indirectly acting drugs (tyramine)► Alpha 2 – agonists (clonidine)► Decreasing the available stores (Reserpine,
MAOI)
Tyramine -- MAO inhibitors
tyramine not a drug, found in many foods (cheese)
tyramine is rapidly metabolized by MAO.
MAO inhibitors increase the stores o f catecholamines in vesicles.
Tyramine is a releaser of catecholamines
may occur hypertensive crisis due t o massive levels of NE
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-1Adverse effects:► Postural hypotension, diarrhea, nasal
congestion, sexual dysfunction
☺ 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
behaviourUses narcolepsy, hyperactive child, obesity
Amphetamine
►Inhibitors of NE-uptake• Uptake-I inhibitors: imipramine,
cocaine• Uptake-II inhibitors: • Phenoxybenzamne,• Corticosteroids• Uptake III inhibitors: Guanethidine
Uptake 3
Dopamine
• Presence: Sympathetic nerve terminal
BrainHypothalamuth →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
Wording• Sympathomimetic
drugs• Adrenomimetic dru
gs• Adrenergic agonist
s• Adrenoceptor agon
ists
Suggested Reading
Katzung BG. Basic & clinical pharma cology.
Katzung BG, Trevor AJ. Examination &board review pharmacology.
Goodman&Gilman. Basic pharmacol ogy.
Pharmacology, Lippincott’s Illustrat ed Reviews
Drugs Acting on Parasympathetic Nervous System
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 musclesCNS.
Cholinergic Neurotransmission
1. Synthesis:
• Choline Ach.
• Inhibited by hemicholinium.
2. Storage:
• Ach + ATP + proteoglycan.
etransferasacetylCholine
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.
4. Binding to receptors:
• Postsynaptic (organs) or presynaptic (nerve terminal).
• Initiate response mediated by 2ry messengers e.g. cAMP, IP3 & DAG.
5. Degradation of Ach:
• Ach choline & acetate.
• True cholinesterase (synaptic cleft) & pseudo cholinesterase (plasma & liver).
6. Recycling of choline:• Choline → neuron → Ach.
inesteraseacetylchol
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.
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.
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/textbook/Autonomic/Autonomic.html
DRUGS THAT DECREASE AQUEOUS PRODUCTION
I. 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 1-selective betaxolol), depression
II. 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]
III. 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
DRUGS THAT INCREASE AQUEOUS OUTFLOW
I. 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
II. 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 isn’t Ach used
III. Prostaglandins [latanoprost]
-Mechanism: May uveoscleral outflow by relaxing ciliary body muscle
-Administration: Topical drops -Side Effects: Iris color change
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.
Direct Acting P. SympathomimeticsAcetylcholine:A. 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.
B. Nicotinic effects:
• Relatively weak.
• Stimulate all autonomic ganglia (sympathetic & p. sympathetic).
• Ach (IV) + Atropine → ↑ BP (by ↑ symp ganglia → ↑ NE.
• Adrenal medulla Epi
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.
Carbachol:
• Resist cholinesterase → ↑ duration.
• Pharmacological actions: Both muscarinic & nicotinic effects. Adrenal medulla →↑ adrenaline
release.Eye (locally) → miosis & ↓ IOP.
• Uses: locally in glaucoma.
Pilocarpine:
• Pharmacological actions: Eye (locally): miosis & accommodation
for near vision.
• Uses: Glaucoma (emergency).Mitotic. Xerostomia. Alopecia.
• Adverse effects: sweating, salivation & CNS effects.
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.
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).
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.
Pyridostigmine:
• ↑ Duration (3-6 h) → used in chronic management of myasthenia gravis.
Edrophonium:• ↓ Duration (10-20 min) →
diagnosis of myasthenia gravis.
Irreversible anticholinesterase
Organic phosphates (insecticides, (local drugs
Isoflurophate, Echothiophate :• Pharmacological actions:
Bind covalently to cholinesterase. Aging (6-8 h). Generalized cholinergic stimulation.
• Uses: Glaucoma (locally once/week).
• Adverse effects: motor paralysis, convulsions.
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
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.
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.
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.
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.
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
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).
Other Atropine Substitutes:
• Pirenzepine: peptic ulcer.
• Ipratropium: bronchial asthma.
• Benztropine: Parkinson’s disease.
• Cyclopentolate: ophthalmology.
• Emepronium: urinary incontinence.
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.
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.
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.
Neuromuscular Blocking Drugs
These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of
skeletal muscle
A. Nondepolarizing (competitive) blockers Mechanism of action:They 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
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 blockers:They increase the neuromuscular block of tubocurarine and other competitive blockers as well as depolarizing blockers.
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
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
Autacoids(Local Hormones)
Response vs. distance traveledEndocrine 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 .
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.
Autacoids Include:
• Lipid derived eicosanoids: PGs, LTs & TXs.
• Naturally occurring amines: histamine & 5-HT.
• Endogenous polypeptides: angiotensin & bradykinin.
• Cytokines: interleukins & interferons.
• Nitric oxide (NO).
Why are Autacoids Important?
• Autacoids have complex physiologic & pathologic effects.
Thus:
• Drugs that mimics or antagonize effects of autacoids are therapeutically useful.
Eicosanoids
• Derived from arachidonic acid (derived from membrane phospholipids).
• Include:– Prostaglandins (PGs). – Prostacyclin (PGI2). – Thromboxanes (TXs).– Leukotrienes (LTs). – Lipoxins (LXs).
Cyclic Endoperoxides LTs & LXs
Phospholipase A2
Phospholipids
Arachidonic Acid
PGI2 PGE2 & PGF2αTXA2
TX SynthasePGI Synthase PG Synthase
COX Lipoxygenase
Pharmacological Effects of Eicosanoids:
I- Prostaglandins:• Pyretic effect & algesic effect.
• Inflammatory effect: vasodilation, ↑ vascular permeability & chemotaxis.
• GIT: ↓ HCl secretion & ↑ mucus formation.
• Bronchi: bronchoconstriction (PGF2α).
• Uterus: uterine contraction (PGE2 & PGF2α).
• Kidneys: vasodilation (PGE2 & PGI2).
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.
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.
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 (PGF2α): glaucoma.
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.
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.
HistamineSynthesis: 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.
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.
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.
Histamine Antagonists
• H1 receptor blockers.
• H2 receptor blockers.
• Mast cell stabilizers.
• Epinephrine.
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.
Uses:1. Allergic rhinitis.
– IgE-mediated. – Seasonal (hay fever) .– Symptoms: sneezing, rhinorrhea,
pruritus & nasal congestion.– Treated by: H1-blockers + nasal
decongestant.
2. Urticaria:– Vascular skin reaction.– Causes: food, drugs, insect bites, etc.– Treated by H1-blockers.
3. Motion sickness.
4. Vertigo or Meniere’s disease.
5. Pregnancy-induced nausea & vomiting.
6. Insomnia.
7. Not effective in asthma (LTs involved).
Adverse Effects:– Drowsiness, sedation & fatigue (1st
generation).– Dry mouth.
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 α1 & β2 receptors.
Serotonin
Synthesis: from L-tryptophan.Storage:
– GIT (90%).– Platelets– CNS.
Receptors: – 5-HT receptors (7/12 types).– G-protein coupled.
Pharmacological Actions:1. Regulates mood:
– SSRIs e.g. fluoxetine used as antidepressants.
– 5-HT1A agonist buspirone used as anxiolytic.
2. Regulates appetite:– Sibutramine (↓ 5-HT, NE & dopamine
reuptake) → anorexigenic.– Cyproheptadine (5-HT2 blocker)→ appetite
stimulant.
3. Vomiting: ondansetron (5-HT3 blocker)→ anti-emetic effect.
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%).
Treatment:– Sumatriptan & zolmitriptan (5-HT
agonists) → vasoconstriction & ↓ release of inflammatory neuropeptides → ↓ migraine pain.
– Ergotamine (5-HT agonist & α-blocker with agonist activity) → ↓ pulsation of cranial arteries.
• 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 (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 treats parkinsonism (e.g: Bromocriptine)
• CVS:– Vasoconstriction via -adrenoceptors and 5-HT2 receptors
(Ergotamine via 1 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.
Angiotensin
KidneyRenin
Angiotensinogen Angiotensin I
Angiotensin II
ACE
-
Factors affecting renin secretion:
• Renal vascular receptors (stretch receptors).
• Sympathetic NS activation → ↑ renin.
• Angiotensin II → ↓ renin.
• Drugs e.g. vasodilators, diuretics, β-agonists, α-blockers → ↑ renin.
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
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
Renin-Angiotensin-Aldosterone System
• Angiotensin II 1. Stimulates aldosterone production2. Stimulates ADH secretion from pituitary3. Highly potent vasoconstrictor4. Stimulates thirst5. Stimulates release of catecholamines by
adrenal medulla•
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.
Effects of Angiotensin II
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 (Stimulates nociceptive nerve fibers)
•
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 vasodilationBradykinin has a cardiac anti-ischemic effect, inhibited by
B2 antagonists (NO dependent)
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
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.
