Professor Dr Ahmed Abu Raghif PhD Pharmacology Complex Organ Control The Eye The pupil is under reciprocal control by the SANS via receptors on the pupillary dilator muscle and the PANS via ID: 931503
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Slide1
AUTONOMIC PHARMACOLOGY(CONTINUE)
Professor
Dr Ahmed Abu
Raghif
Ph.D
Pharmacology
Slide2Complex Organ Control: The EyeThe pupil is under reciprocal control by the SANS (via receptors on the
pupillary
dilator muscle) and the PANS (via
muscarinic
receptors on the
pupillary
constrictor).
The
ciliary
muscle, which controls accommodation, is under primary control of
muscarinic
receptors innervated by the PANS, with insignificant contributions from the SANS.
The
ciliary
epithelium,
on the other hand, has important
β
receptors that have a permissive effect on aqueous humor secretion.
Slide33/7/2017
Sympathetic: Contraction of radial muscle produces dilation (
mydriasis
)
Parasympathetic: Contraction of circular muscle produces constriction (
miosis
)
Slide4Cholinomimetic drugs
دكتور أحمد أبو رغيف
Ph.D
Pharmacology
Slide5Slide6Cholinomimetic drugs
are drugs that mimic acetylcholine by directly or indirectly activating the receptors with which acetylcholine interacts.
The direct-acting agents
combine with the
cholinoceptor
in the same way as acetylcholine.
a-
Choline
esters
(acetylcholine,
methacholine
,
carbachol
, and
bethanechol
)
b-Alkaloids
(
muscarine
,
pilocarpine
, nicotine,
lobeline
).
These agents differ in their spectrum of action (amount of muscarinic versus nicotinic stimulation) and in their pharmacokinetics. Both factors influence their clinical use.
Slide7The indirect-acting cholinesterase inhibitors have many effects like those of the direct-acting agonists, but they act by inhibiting the enzyme that terminates the action of endogenous acetylcholine.
Short-acting
anticholinesterases
edrophonium
Medium-duration
anticholinesterases
neostigmine
Physostigmine
Pyridostigmine
Irreversible
anticholinesterases
Organophosphate
:
parathion,
Echothiophate
Slide8Organ effects of cholinomimetic
drugs
Cardiovascular effects
.
These include cardiac slowing and a decrease in cardiac output.
The latter action is due mainly to a decreased force of contraction of the atria, because the ventricles have only a sparse parasympathetic
innervation
and a low sensitivity to
muscarinic
agonists.
Generalised
vasodilatation also occurs (a nitric oxide-mediated effect), and these two effects combine to produce a sharp fall in arterial pressure
Slide9Sinoatrial node Decrease in rate (negative chronotropy), but note important reflex response in intact subject
Atria Decrease in contractile force (negative
inotropy
); decrease in refractory period
Atrioventricular
node Decrease in conduction velocity (negative
dromotropy
), increase in refractory period
Ventricles Small decrease in contractile force
Slide10Effects on the eyeContraction of the ciliary muscle in response to activation of
muscarinic
r pulls the
ciliary
body forwards and inwards, thus relaxing the tension on the
suspensory
ligament of the lens, allowing the lens to bulge more and reducing its focal length. This parasympathetic reflex is thus necessary to accommodate the eye for near vision.
The constrictor
pupillae
is important also in regulating the intraocular pressure. In acute glaucoma, drainage of aqueous
humour
becomes impeded when the pupil is dilated, because folding of the iris tissue occludes the drainage angle, causing the intraocular pressure to rise.
Slide11Activation of the constrictor pupillae muscle by muscarinic agonists in these circumstances lowers the intraocular pressure, although in a normal individual it has little effect.
The increased tension in the
ciliary
muscle produced by these drugs may also play a part in improving drainage by realigning the connective tissue
trabeculae
through which the canal of
Schlemm
passes
Slide12Sympathetic: Contraction of radial muscle produces dilation (
mydriasis
)
Parasympathetic: Contraction of circular muscle produces constriction (
miosis
Slide13A-CHOLINE ESTERS
Acetylcholine
Activates
muscarinic
(M) and nicotinic (N) receptors
Rapidly hydrolyzed by cholinesterase (
ChE
); duration of action 5–30 s; poor lipid solubility
Bethanechol
:
Activates
muscarinic
(M) receptors; increases IP
3
and DAG
Indications:
Bladder and bowel
atony
, for example, after surgery or spinal cord injury , congenital
megacolon
post operative urine retention, post partum urinary retention
Slide14Pharmacokinetics: Oral, IM activity, poor lipid solubility: does not enter CNS; not active in eye after topical application Duration: 0.3–2 h
adverse effects:
All
parasympathomimetic
effects:
cyclospasm
, diarrhea, urinary urgency, plus
vasodilation
, reflex tachycardia, and sweating
Carbachol
Activates
muscarinic
(M) and nicotinic (N)
receptots
.Used locally in treatment of
glucoma
(
pilocarpine
is preferable)
Methacholine
Used to test bronchial hyper-reactivity
Slide15B-ALKALOIDS
Pilocarpine
:
It induce contraction of
ciliary
muscle and smooth muscle of the iris sphincter (
miosis
)
– facilitate
aqueous humor outflow, drainage of the anterior chamber(Activates muscarinic (M) receptors; increases IP
3
and DAG)
Indications:
-
Sjögren's
syndrome (increases salivation);
- Consider to be drug of choice in emergency treatment of glaucoma (causes
miosis
,
cyclospasm
)
Slide16Pharmacokinetics of
Pilocarpine
:
Oral, IM activity Good lipid solubility, duration of action 30 min to 2 h topical activity in eye Similar to
bethanechol
but may cause vasoconstriction via
ganglionic
effect
Nicotine
:
Activat
nicotinic(N)receptor Like
pilocarpine
;
duration of action 1–6 h; high lipid solubility
Slide17THE INDIRECT-ACTING CHOLINESTERASE INHIBITORS have many effects like those of the direct-acting agonists, but they act by inhibiting the enzyme that terminates the action of endogenous acetylcholine.
Reversible
anticholinesterases
Short-acting
anticholinesterases
edrophonium
The action of
edrophonium
is similar to
physeostigmine
, except that it is more rapidly absorbed and has short duration of action (10-20 min).
Used in diagnosis of myasthenia gravis(I.V injection lead to rapid increase in muscle strength)
Neostigmine
Action
: Inhibitor of cholinesterase; amplifier of endogenously released Ach plus small direct nicotinic agonist action
Reversal of N
M
block caused by
tubocurarine
, treatment of myasthenia(Myasthenia Gravis appears to be caused by the binding of anti-nicotinic receptor antibodies to the nicotinic cholinergic receptor)
It differ from
physeostigmine
in:
More polar(does not inter CNS) but orally active
Has greater effect on skeletal muscles
Duration: 2–4 h
Adverse effect: Generalized cholinergic stimulation
Slide19PhysostigmineAction: Inhibitor of cholinesterase; amplifier of endogenously released
ACh
Indications
:
Reversal of severe atropine poisoning (IV);
occasionally used in acute glaucoma (topical) (induce
miosis
and spasm of accommodation)
Used in intestinal
atony
(increases their motility)
Pharmacokinetics
: Lipid soluble; can be used topically in the eye. Duration of action: 2–4 h
Adverse effect
: Generalized cholinergic stimulation plus CNS effects: seizures
Slide20Irreversible anticholinesterasesOrganophosphates are long-acting drugs; they form an extremely stable phosphate complex with the enzyme. After initial hydrolysis, the phosphoric acid residue is released over periods of days to weeks. Recovery is due in part to synthesis of new enzyme
Effects
By inhibiting cholinesterase, these agents cause an increase in the concentration, half-life, and actions of acetylcholine in synapses where acetylcholine is released physiologically..
Slide21Therefore, the indirect agents have muscarinic or nicotinic effects depending on which organ system is under consideration Cholinesterase inhibitors do not have significant actions at
uninnervated
sites where acetylcholine is not normally released (
eg
, vascular endothelial cells).
Parathion
Insecticide only
Duration: days to weeks Highly lipid-soluble Highly
dangerous insecticide; causes all parasympathetic effects plus muscle paralysis and coma
Slide22Malathion
Insecticide and
scabicide
(topical)
Duration: days
Highly lipid-soluble but metabolized to inactive products in mammals and birds
Much safer insecticide than parathion
Ecothiophate
,
Therapeutic uses: An ophthalmic solution of the drug is used directly in the eye for the chronic treatment of open-angle glaucoma.
The effects may last for up to one week after a single
administration.
Echothiophate
is not a first-line agent in the treatment of glaucoma
.
Slide23Donepezil:
Cholinesterase inhibition plus variable other poorly understood effects USED in Alzheimer's disease Lipid soluble, enter CNS Half-lives: 1.5–70 h S.E Nausea, vomiting
Alzheimer’s Disease
pathology – loss of cholinergic neurons and reduced synthesis of
ACh
Anticholinesterases
may improve cognitive function and memory in up to 40% of patients
Slide24Toxicity by organophosphorus
is due to
A-
muscarinic
effects
(
bradycardia
,
bronchoconstriction
, excessive sweating, salivation,
lacrimation
,
miosis
, nausea, vomiting, abdominal cramps, urinary incontinence).
B- nicotinic effects
(muscle twitches, neuromuscular blockade of diaphragm and
intercostal
muscles).
C- CNS effects
(restlessness, insomnia, tremors, confusion, convulsions, coma, death from respiratory failure).
Slide25Management of organophosphorus Toxicity
After standard protection of vital signs
the antidote of first choice is the
antimuscarinic
agent
atropine
, but this drug has no effect on the nicotinic signs of toxicity.
Nicotinic toxicity is treated by regenerating active cholinesterase. Immediately after binding to cholinesterase, most organophosphate inhibitors can be removed from the enzyme by the use of regenerator compounds such as
pralidoxime
and this may reverse both nicotinic and
muscarinic
signs
If the enzyme-phosphate binding is allowed to persist, however, aging (a further chemical change) occurs and regenerator drugs can no longer remove the inhibitor.
Slide2626
Clinical uses of cholinergic drugs
1. Glaucoma
:
a. Short acting
(1-2hrs):
Pilocarpine
,
carbachol
b. Long acting
(100 hrs):
Ecothiophate
,
isofluorophate
2. Myasthenia gravis
:
a. Treatment
:
Neostigmine
(rapid & short acting, 2 hrs)
Pyridostigmine
(slow & long acting, 6 hrs
)
b. Diagnosis:
Edrophonium
(very short acting, 15 min)
3. Paralytic
ileus
& urine retention:
Post anesthesia & post operative
Neostigmine
,
bethanechol
27
4.
Reversal of muscle relaxation after anesthesia:
Neostigmine
,
edrophonium
5. Anti-cholinergic poisoning:
Physostigmine
(being tertiary amine, lipid soluble, crosses blood brain barrier), controls central & peripheral symptoms
6. Dry mouth in
Sjogren
syndrome:
Pilocarpine
7. Alzheimer’s disease:
Donepezil
,
torcine
8.
Helminthiasis
(
Scistosoma
haematobium
)
Metrifonate
Slide28Anticholinergic drugs
دكتور أحمد أبو رغيف
M B Ch B , M Sc,
Ph.D
Slide29Anticholinergic drugs:
These drugs prevent the action of acetylcholine at postganglionic parasympathetic endings.
Acetylcholine is released but its receptor site is completely blocked by
anticholinergic
drugs.
The
cholinoceptor
antagonists are grouped into subclasses on the basis of their spectrum of action (
ie
, whether they block
muscarinic
or nicotinic receptors).
Slide30Slide31Muscarinic AntagonistsMuscarinic
antagonists can be subdivided according to their selectivity for specific
M receptors
or their lack of such selectivity.
Atropine
is the prototypical nonselective
muscarinic
blocker
only 2 receptor-selective
M
1
antagonists
have reached clinical trials (
eg
,
pirenzepine
,
telenzepine
).
tolterodine
and
darifenacin
(
M
3
-selective
) are new drugs that act on the bladder to inhibit
micturition
, and are used for treating urinary incontinence
Slide32The muscarinic blockers can also be subdivided on the basis of their primary clinical target organs
(CNS, eye, bronchi, or gastrointestinal and genitourinary tracts).
Drugs used for their effects on the CNS or the eye must be sufficiently
lipid-soluble
Slide33Antimuscarinic, nonselectivetertiary amine
Atropine,Scopolamine
,
Benztropine
,
Homatropine
,
cyclopentolate
,
tropicamide
quaternary amine
Ipratropium
,
Oxybutynin
,
glycopyrrolate
Antimuscarinic
, selective
Darifenacin
,
tolterodine
(M3)
Pirenzepine
,
telenzepine
(M1)
Slide34Pharmacokinetics of AtropineAtropine is the prototypical nonselective muscarinic
blocker.
This alkaloid is found in
Atropa
belladonna
and many other plants. Because it is a tertiary amine, atropine is
relatively lipid-soluble
and readily crosses membrane barriers.
The drug is
well distributed into the CNS
and other organs and is eliminated partially by metabolism in the liver and partially unchanged in the urine.
The elimination half-life is approximately 2 h, and the duration of action of normal doses is 4–8 h
except in the eye,
where effects last for 72 h or longer.
Slide35Pharmacokinetics of Other Muscarinic Blockers
In ophthalmology
, topical activity (the ability to enter the eye after
conjunctival
administration) and duration of action are important in determining the usefulness of several
antimuscarinic
drugs .
Similar ability to cross lipid barriers is essential for the agents used in
parkinsonism
.
In contrast, the drugs used for their
antisecretory
or
antispastic
actions in the gut, bladder, and bronchi are often selected for minimum CNS activity; these drugs may incorporate
quaternary amine groups
to limit penetration through the blood-brain barrier.
Slide36Effects of Muscarinic Antagonists
The peripheral actions of
muscarinic
blockers are mostly predictable and include the ocular, gastrointestinal, genitourinary, and
secretory
effects.
The CNS effects are less predictable. CNS effects seen at therapeutic concentrations include sedation, reduction of motion sickness, and, as previously noted, reduction of some of the signs of parkinsonism