AUTONOMIC PHARMACOLOGY (CONTINUE) - PowerPoint Presentation

Slide1

AUTONOMIC PHARMACOLOGY(CONTINUE)

Professor

Dr Ahmed Abu

Raghif

Ph.D

Pharmacology

Slide2

Complex 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.

Slide3

3/7/2017

Sympathetic: Contraction of radial muscle produces dilation (

mydriasis

)

Parasympathetic: Contraction of circular muscle produces constriction (

miosis

)

Slide4

Cholinomimetic drugs

دكتور أحمد أبو رغيف

Ph.D

Pharmacology

Slide5

Slide6

Cholinomimetic 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.

Slide7

The 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

Slide8

Organ 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

Slide9

Sinoatrial 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

Slide10

Effects 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.

Slide11

Activation 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

Slide12

Sympathetic: Contraction of radial muscle produces dilation (

mydriasis

)

Parasympathetic: Contraction of circular muscle produces constriction (

miosis

Slide13

A-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

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Pharmacokinetics: 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

Slide15

B-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

)

Slide16

 Pharmacokinetics 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

Slide17

THE 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)

Slide18

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

Slide19

PhysostigmineAction: 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

Slide20

Irreversible 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..

Slide21

Therefore, 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

Slide22

  Malathion

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

.

Slide23

Donepezil:

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

Slide24

Toxicity 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).

Slide25

Management 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.

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26

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

Slide27

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

Slide28

Anticholinergic drugs

دكتور أحمد أبو رغيف

M B Ch B , M Sc,

Ph.D

Slide29

Anticholinergic 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).

Slide30

Slide31

Muscarinic 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

Slide32

The 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

Slide33

Antimuscarinic, nonselectivetertiary amine

Atropine,Scopolamine

, 

Benztropine

,

Homatropine

,

cyclopentolate

,

tropicamide

quaternary amine

Ipratropium

,

Oxybutynin

,

glycopyrrolate

Antimuscarinic

, selective

Darifenacin

,

tolterodine

(M3)

Pirenzepine

,

telenzepine

(M1)

Slide34

Pharmacokinetics 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.

Slide35

Pharmacokinetics 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.

Slide36

Effects 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