PARASYMPATHOMIMETICS

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PARASYMPATHOMIMETICS : 

PARASYMPATHOMIMETICS Drugs that produce pharmacological effects similar to that produced by parasympathetic stimulation.

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DRUGS ACTING ON CHOLINERGIC SYSTEM

Cholinergic Receptors: Where are they? : 

Postganglionic parasympathetic neuroeffector junctions All autonomic ganglia At the neuromuscular endplate Cholinergic Receptors: Where are they?

Cholinergic Receptors: Types : 

Muscarinic receptors Nicotinic receptors Based on selective activation and antagonism. Cholinergic Receptors: Types

Receptors and signal transduction in the ANS : 

Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic Ganglionic Skeletal Muscle Neuronal CNS

Receptors and signal transduction in the ANS: Nicotinic Receptors : 

Receptors and signal transduction in the ANS: Nicotinic Receptors

Receptors and signal transduction in the ANS: Nicotinic Receptors : 

Receptors and signal transduction in the ANS: Nicotinic Receptors

Receptors and signal transduction in the ANS : 

Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic M1 M5 M3 M4 M2

Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors : 

Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors

Receptors and signal transduction in the ANS: Muscarinic receptors(M1, M3, M5) : 

Receptors and signal transduction in the ANS: Muscarinic receptors(M1, M3, M5) NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP 3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response

Receptors and signal transduction in the ANS: Muscarinic Receptors : 

Receptors and signal transduction in the ANS: Muscarinic Receptors (M2 and M4)

Parasympathetic N. S. : 

Parasympathetic N. S.

Slide 16: 

Parasympathetic N. S.

Slide 17: 

Parasympathetic N. S.

Parasympathomimetics : 

The main effect produced by these drugs resemble the effect of parasympathetic stimulation. On the basis of their mode of action they can be divided into two groups. Direct acting Parasympathomimetics (muscarinic receptor agonists) Indirectly acting Parasympathomimetics (anticholinesterases) Parasympathomimetics

Mechanism of action of parasympathomimetic : 

1-directly acting parasympathomimetic: Directly stimulate the cholinergic receptors(M,Nm,Nn) in the effectors organs 2-Indirectly acting parasympathomimetic: inactivate the choline esterase enzyme leading to accumulation of acetylcholine at the cholinergic receptors. Mechanism of action of parasympathomimetic

Parasympathetic Agonists(Parasympathomimetics) : 

Direct-Acting Cholinoceptor Stimulants (Choline Esters): Esters of Choline: 1. Acetylcholine 3. Carbachol 2. Metacholine 4. Betanechol B. Alkaloids: 1. Muscarinic Muscarine, Pilocarpine, Oxotremorine 2. Nicotinic Nicotine, Lobeline, Dimethylphenylpiperazinium (DMPP) Parasympathetic Agonists(Parasympathomimetics)

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Parasympathetic Agonists(Parasympathomimetics)

Parasympathetic Agonists(Parasympathomimetics) : 

Naturally-occuring: Pilocarpine Arecholine Muscarine Parasympathetic Agonists(Parasympathomimetics) Direct-Acting (Choline Esters):

Pharmacological actions : 

Cardiovascular effects These include cardiac slowing and a decrease in cardiac output. The latter action results mainly from a decreased force of contraction of the atria, since 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. Negative ionotropy Negative chronotropy Negative dromotropy Blood pressure.: Small dose produces transient drop in BP due to generalized vasodilatation. Large dose induces lesser vasodilatation due to sympathetic stimulation , so BP is not markedly lowered. Pharmacological actions

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Smooth muscle Smooth muscle other than vascular smooth muscle contracts in response to muscarinic agonists. Peristaltic activity of the gastrointestinal tract is increased, which can cause colicky pain, and the bladder and bronchial smooth muscle also contract. Peristalsis

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peristaltic waves of the ureters Skeletal muscles : Contractions due to stimulation of Nm in the motor-end plate. Improved cognition: M1-selective agonists are being developed for possible use in treating dementia but are not yet in general use.

Effects on the eye : MIOSIS (constriction of pupil) : 

The parasympathetic nerves to the eye supply the constrictor pupillae muscle, which runs circumferentially in the iris, and the ciliary muscle, which adjusts the curvature of the lens. Contraction of the ciliary muscle in response to activation of muscarinic receptors 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, therefore, necessary to accommodate the eye for near vision. The constrictor pupillae is important not only for adjusting the pupil in response to changes in light intensity but also in regulating the intraocular pressure. Aqueous humour is secreted slowly and continuously by the cells of the epithelium covering the ciliary body, and it drains into the canal of Schlemm, which runs around the eye close to the outer margin of the iris. The intraocular pressure is normally 10-15 mmHg above atmospheric, which keeps the eye slightly distended. Abnormally raised intraocular pressure (associated with glaucoma) damages the eye and is one of the commonest preventable causes of blindness. Effects on the eye : MIOSIS (constriction of pupil)

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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. Activation of the constrictor pupillae muscle by muscarinic agonists in these circumstances lowers the int raocular pressure, though 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.

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Ach: Radiply hydrolysed DOA by i.v. : 5-20 sec Methacholine: 3 times resistant than Ach DOA: longer Bethanechol: longest DOA

Indirectly acting parasympathomimetics ( Anticholinestrases) : 

They competitively inhibit the enzyme cholinesterase and thus increase the concentration and duration of effect of acetylcholine at its receptors. According to the stability of the complexes formed with cholinesterase, these drugs are divided into two groups: Reversible Irreversible In general, reversible anticholinestrases are of more clinical value, whereas the irreversible ones are used as insecticides and war gasses. Indirectly acting parasympathomimetics ( Anticholinestrases)

Slide 37: 

Parasympathetic Agonists(Parasympathomimetics) REVERSIBLE (Anticholinesterases): Physostigmine Neostigmine Pyridostigmine Amebonium Edrophonium Tacrine, Donezepil, Rivastigmine, Galantamine Indirect-Acting :

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Parasympathetic Agonists(Parasympathomimetics) IRREVERSIBLE Organophosphates Isoflurophate Echothiophate Malathion, Parathion Chemical Warfares Sarin, Soman Indirect-Acting :

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M/A of anticholinesterase

Comparsion between indirectly acting reversible parasympathomimetics : 

Comparsion between indirectly acting reversible parasympathomimetics

Neostigmine substitutes : 

Advantages in comparison to Neostigmine More selective action ( lesser adverse effects). Longer duration of action ( improve patient compliance ). Pyridostigmine & ambenonium: More selective action on NMJ than Neostigmine. Longer duration of action than Neostigmine. Mainly used for ttt. Of myasthenia gravis. Neostigmine substitutes

Edrophonium : 

More selective action on NMJ than Neostigmine. Very short duration. Uses : 1-diagnosis of myasthenia gravis. & myasthenic crisis. 2-diff. between myasthenic crisis & cholinergic crisis. 3-antidote of curare. Edrophonium

Contraindication of parasympathomimetic : 

1-CVS: -bradycardia,heart block -heart failure -hypotension 2-respiratory: bronchial asthma 3-GIT: peptic ulcer,organic obstruction 4-Endocrinal: hyperthyroidism as it increase the atrial conduction in already sensitized heart→Atrial Fibrillation Contraindication of parasympathomimetic

Glaucoma and its treatment : 

It is an eye disease in which the optic nerve is damaged. This can permanently damage vision in the affected eye(s) and lead to blindness if left untreated. It is normally associated with increased fluid pressure in the eye (AQUEOUS HUMOUR) = raised INTRAOCCULAR PRESSURE (IOP). Glaucoma can be roughly divided into two main categories, "open angle" and "closed angle“ glaucoma. The angle refers to the area between the iris and cornea, through which fluid must flow to escape via the trabecular meshwork. Glaucoma and its treatment

Signs and symptoms : 

Open-angle glaucoma accounts for 90% of glaucoma: It is painless and does not have acute attacks. gradually progressive visual field loss, and optic nerve changes chronic glaucoma progress at a slower rate and patients may not notice they have lost vision until the disease has progressed significantly. Closed-angle glaucoma accounts for less than 10% of glaucoma sudden ocular pain, seeing halos around lights, red eye, very high intraocular pressure (>30 mmHg), nausea and vomiting, sudden decreased vision, and a fixed, mid-dilated pupil. Acute angle closure is an emergency. Signs and symptoms

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The major risk factor for most glaucomas, and focus of treatment, is increased intraocular pressure, i.e. ocular hypertension. Intraocular pressure is a function of production of liquid aqueous humor by the ciliary processes of the eye, and its drainage through the trabecular meshwork. FLOW OF AQUEOUS HUMOR ciliary processes posterior chamber, bounded posteriorly by the lens anteriorly by the iris through the pupil of the iris into the anterior chamber From here the trabecular meshwork drains aqueous humor via Schlemm's canal into scleral plexuses general blood circulation.

Treatment : 

Miotic agents (parasympathomimetics), such as PILOCARPINE, work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humour. ECHOTHIOPHATE, an acetylcholinesterase inhibitor, is used in chronic glaucoma. Prostaglandin analogs, such as LATANOPROST , bimatoprost and travoprost , increase outflow of aqueous humor. Topical beta-adrenergic receptor antagonists, such as timolol, levobunolol and betaxolol, decrease aqueous humor production by the ciliary body. Alpha2-adrenergic agonists, such as brimonidine and apraclonidine, work by a dual mechanism, decreasing aqueous humor production and increasing uveoscleral outflow. Carbonic anhydrase inhibitors, such as dorzolamide , brinzolamide, and ACETAZOLAMIDE , lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body. PHYSOSTIGMINE is also used to treat glaucoma. Treatment

Organophosphate poisoning : 

Results from exposure to organophosphates (OPs), which cause the inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine (ACh) in the body. Organophosphate poisoning most commonly results from exposure to insecticides or nerve agents. Organophosphates inhibit AChE, causing OP poisoning by phosphorylating the serine hydroxyl residue on AChE, which inactivates AChE. AChE is critical for nerve function, so the irreversible blockage of this enzyme, which causes acetylcholine accumulation, results in muscle overstimulation. This causes disturbances across the cholinergic synapses and can only be reactivated very slowly, if at all. Organophosphate poisoning

Symptoms : 

Symptoms 1. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. 2. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are tachycardia, hypertension, and hypoglycemia. 3. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. 4.When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur.

Irreversible Anticholinestrases : 

Organophosphorus compounds: All are highly lipid soluble, except echothiophate which is water soluble. They are rapidly absorbed from intact skin, mucosal surfaces and GIT, and cross BBB. They inhibit AChE.(irreversibly) Irreversible Anticholinestrases

Treatment : 

Current antidotes for OP poisoning consist of a pretreatment with carbamates to protect AChE from inhibition by OP compounds and post-exposure treatments with anti-cholinergic drugs. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (obidoxime), Diacetyl monoxime (DAM) CHOLINESTERASE REACTIVATORS: Oximes (acetylcholinesterase reactivators) Relieve the nicotinic symptoms Pralidoxime chloride and others Poor CNS penetration Pretreatment (prophylaxis) Pyridostigmine, reversible anticholinesterase agent, at 30 mg, 3 times daily ATROPINE: 2 mg i.v. repeated for 10 min Maintainenece dose 1-2 weeks One other agent that is being researched is the Class III anti-arrhythmic agents. Hyperkalemia of the tissue is one of the symptoms associated with OP poisoning. Treatment

Mechanism of action : 

Pralidoxime has quarternary nitrogen binds to anionic site ----oxime end + phosphourous atom of esteric site = OXIME-PHOSPHONATE--- diffuse away--- reactivated enzyme. This is known as "regenerating" or "reactivating" acetylcholinesterase allowing the breakdown of Ach at the synapse. After some time though, some inhibitors can develop a permanent bond with cholinesterase, known as aging, where oximes such as pralidoxime can not reverse the bond. Pralidoxime is often used with atropine (a muscarinic antagonist) to help reduce the parasympathetic effects of organophosphate poisoning. Pralidoxime can also be used to treat neostigmine or pyridostigmine (both ACHase inhibitors) overdoses due to its ACHase regenerating capacities. Pralidoxime has an important role in reversing paralysis of the respiratory muscles but due to its poor blood-brain barrier penetration, it has little effect on centrally-mediated respiratory depression. This is why atropine which has excellent blood-brain barrier penetration, is concomitantly administered with pralidoxime during the treatment of organophosphate poisoning. Mechanism of action

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Therapy: maintenance of VS  respiration Decontamination Drugs: Atropine + Pralidoxime ATROPINE sulfate  1 to 2 mg IV every 5- 15 min until signs of effect appears (maximum of 1 gm per day) PRALIDOXIME  A cholinesterase enzyme regenerator compound - 1 to 2 gm given over 30 min by IV infusion

Myasthenia gravis : 

is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter acetylcholine on nicotinic receptors throughout neuromuscular junctions. The hallmark of myasthenia gravis is FATIGABILITY. Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expressions, chewing, talking, and swallowing are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Myasthenia gravis

Slide 61: 

In MG, the autoantibodies most commonly act against the nicotinic acetylcholine receptor (nAChR),the receptor in the motor end plate for the neurotransmitter acetylcholine that stimulates muscular contractions. Some forms of the antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors, either by complement fixation or by inducing the muscle cell to eliminate the receptors through endocytosis. The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into plasma cells by T-helper cell stimulation. To carry out this activation, T-helpers must first be activated themselves, which is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment.

Signs and Symptoms : 

In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in MG varies greatly among patients, ranging from a localized form that is limited to eye muscles (ocular myasthenia), to a severe and generalized form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in type and severity, may include asymmetrical ptosis (a drooping of one or both eyelids), diplopia (double vision) due to weakness of the muscles that control eye movements, an unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, dysphagia (difficulty in swallowing), shortness of breath and dysarthria (impaired speech, often nasal due to weakness of the velar muscles). Signs and Symptoms

Treatment : 

Acetylcholinesterase inhibitors: neostigmine and pyridostigmine can improve muscle function by slowing the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor. Usually, doctors will start with a low dose, e.g. 3x20mg pyridostigmine, and increase until the desired result is achieved. If taken 30 minutes before a meal, symptoms will be mild during eating. Side effects, such as perspiration and diarrhea, can be countered by adding atropine. Pyridostigmine is a short-lived drug, with a half-life of about four hours. Immunosuppressive drugs: prednisone, cyclosporine, mycophenolate mofetil and azathioprine may be used. Patients are commonly treated with a combination of these drugs with an acetylcholinesterase inhibitor. Treatments with some immunosuppressives take weeks to months before effects are noticed. Other immunomodulating substances, such as drugs that prevent acetylcholine receptor modulation by the immune system, are currently being researched Plasmapheresis and IVIG If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the putative antibodies from the circulation. Also, intravenous immunoglobulins (IVIGs) can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits, typically measured in weeks Thymectomy, the surgical removal of the thymus, is essential in cases of thymoma in view of the potential neoplastic effects of the tumor. Treatment

Diagnosis: Differentiating between Myasthenia gravis and cholinergic crisis : 

Cholinergic Crisis: It is a condition of muscle weakness resulting from overdose of anticholinesterase which causes persistent depolarization of motor end-plate resulting in muscular weakness. Myasthenia Crisis: It is a condition of muscle weakness which is due to insufficient dose of anticholinesterase drug. These two conditions may be differentiated by administration of EDROPHONIUM i/v with facilities of respiratory resuscitation. An improvement in strength signifies Myasthenia crisis, whereas a further decrease in strength indicates cholinergic crisis. Diagnosis: Differentiating between Myasthenia gravis and cholinergic crisis

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