Drugs acting on the autonomic nervous system ph. rawan ghazwi Dept. of Pharmacology Second semester 2015

1-Review of the ANS. 2- Cholinergic drugs 3- Adrenergic drugs Agonists. Antagonists. 3- Adrenergic drugs

Divisions of the Nervous System

autonomic nervous system The autonomic nervous system is that part of the nervous system that controls the involuntary activities of the body (maintaining the internal environment of the body i.e homeostasis) Arterial pressure, gastrointestinal motility and secretion, urinary bladder emptying, sweating, body temperature, and many other activities.

There are two major subdivisions in the autonomic nervous system: a) Sympathetic nervous system. b) Parasympathetic nervous system. Drugs acting on the autonomic nervous system are those that produce their effect either by : Mimicking Altering The function of this system.

Neurotransmitters (NTs) Receptors Chemical signals to communicate between nerve cells & nerve cell & effector organs. Ex: Acetylcholine (Ach) . Norepinephrine (NE). Neurons naming by NTs : Neurons which secret Ach are cholinergic neurons. Neurons which secret NE are adrenergic neurons. Are structures which receive NTs from the axonal terminals of neurons. 1- Cholinergic receptors Muscarinic receptors Nicotinic receptors 2- Adrenergic receptors Alpha receptors Beta receptors

Within the ANS, two neurons are required to reach a target organ , a preganglionic neuron & a postganglionic neuron. All preganglionic neurons (end in the ganglia) release Ach as their transmitter. The Ach binds to nicotinic receptors on the postganglionic cell (the receptors are Nicotinic).

All of the parasympathetic postganglionic fibers release Ach. At the target organ Ach interacts with muscarinic receptors. MOST of the sympathetic postganglionic fibers release NE. At the target organ NE interacts with a variety of receptors (alpha & beta).

Postganglionic fibers Sympathetic Parasympathetic Arises from Thoracolumbar Craniosacral Function Adjusting response to stressful situations. ‘’Fight or Flight’’ Activation of these nerves is sometimes called (‘’ Rest and Digest response’’) Maintain essential body functions. Preganglionic fibers Short Long Ganglia Close to midline Close to or within effector organ Postganglionic fibers Neurotransmitter Norepinephrine (mainly) Acetylcholine Receptors (effector organs) α receptors β receptors (Adrenergic receptor ) Muscarinic and nicotinic receptors (cholinergic)

Fibers and Neurotransmitters of ANS the somatic system; there is NO ganglia here but the fibers that come from the CNS to the skeletal muscles forming neuromuscular junctions that release acetylcholine as neurotransmitter & stimulate receptors which are referred to as Nicotinic receptors.

Fibers and Neurotransmitters of ANS The adrenal medulla is also regarded as a Ganglia so it has a sympathetic supply, epinephrine (80%) is the neurotransmitter.

Where we can find nicotinic receptors. So, 1. Adrenal medulla. 2 Where we can find nicotinic receptors??? So, 1. Adrenal medulla. 2. sympathetic ganglia. 3. Parasympathetic ganglia. 4. NMJ. all have NICOTINIC receptors and the neurotransmitter is ACETYLCOHLOINE

Remember that the nicotinic receptors at the neuromuscular junctions are NOT exactly the same as the nicotinic receptors in the ganglia, because drugs that block these receptors at the neuromuscular junctions are NOT the same as those which block the nicotinic receptors at the ganglia.

The neurotransmitter of the sympathetic system is MAINLY norepinephrine in the effector cells, EXCEPT sweat glands, its ACETYLCHOLINE . The neurotransmitter of the parasympathetic system is ALWAYS acetylcholine.

Hypertension & Tachycardia : The effects of sympathetic & parasympathetic systems are -in most cases- opposing each other,ex : - Hypertension & Tachycardia : Due to sympathetic stimulation. While in: Hypotension & Bradycardia. Due to parasympathetic stimulation.

Q) What is the effect of ANS on saliva? The one exception to the opposite- effect rule is the salivary gland. Both sympathetic and parasympathetic systems increase secretion in salivary gland , but the secretions are of different types. sympathetic its very thick leads to having dry mouth. parasympathetic its very thin & plenty leads to running nose ,lacrimation & salivation (Exocrine gland)

Effects of the ANS on the effector organ

Parasympathetic Response Body Tissue/Organ Sympathetic Response Parasympathetic Response Eye (mydriasis) (miosis) Lungs Dilates bronchioles and reduce secretion Constricts bronchioles and increase secretions Heart Increases heart rate and contractility. Decreases heart rate and contractility. Blood vessels Constricts (skin,mucous memb) Dilates GI -Relaxes smooth muscles. -decrease peristalsis (constipation) and tone -Contraction of smooth muscle -Increases peristalsis (diarrhea) and increase tone. Bladder Relaxes bladder muscle /contraction of sphincter. Constricts bladder/relax of sphincter (urination) Uterus Relaxes uterine muscles ___________ Salivary gland Increases salivation (thick and viscous) Increases salivation (thin and watery secretion)

Genitalia Stimulates ejaculation Stimulates erection. Kidney Secretion of renin ----------- Adrenal medulla Secreted NE & epinephrine (EP) ---------

There are two type of muscle in the iris: 1- The radial muscle: which supplied by the sympathetic system. Mydriasis (dilate of pupil) contraction of the radial muscle 2- The iris sphincter (circular ) muscle : which supplied by the parasympathetic system. Miosis (constrict of pupil) contraction of the iris sphincter (circular) muscle.

Ciliary muscle is responsible for accommodation Supply by parasympathetic fibers -Ciliary muscles -Suspensory ligaments Suspended the lens of the eyes

Anti- Cholinergic drugs: Ciliary muscle (relax ) Suspensory muscle (contract) mydriasis Ciliary muscle (contract ) Suspensory muscle (relax) miosis Lens become more flattened Lens become more convex and spherical Cycloplagia Pts unable to (loss of) Accommodate (far vision) Blurred vision Ex. u can’t read at normal distance need for further distance to read well. Fixed accommodate Near vision Ex. Bring the book closer to ur eyes.

Q) Which one of the following is characteristic of parasympathetic stimulation? A. Decrease in intestinal motility. B. Inhibition of bronchial secretion. C. Contraction of sphincter muscle in the iris of the eye (miosis). D. Contraction of sphincter of urinary bladder. E. Increase in heart rate.

Drugs affecting the autonomic nervous system are divided into : The cholinergic drugs: act on receptors that are activated by acetylcholine. The adrenergic drugs :act on receptors that are stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the ANS.

Parasympathetic division

Cholinergic Agonists

or parasympathomimetics agents. Cholinergic agonists cholinomimetics or parasympathomimetics agents. Cholinergic drugs are drugs that produce effects that mimic the effects of the endogenous Acetylcholine (ACh).

Synthesis, Storage and Release of ACh

Synthesis, Storage and Release of ACh

Cholinergic receptors (cholinoceptor) Muscarinic receptors Stimulate smooth muscle Nicotinic receptors Stimulate skeletal muscle M1. Neurons and Parietal cells Nm or N1. Neuromuscular Junction M2. Heart. Presynaptic neurons Nn or N2. CNS Autonomic Ganglia Adrenal Medulla M3. Bladder,. Exocrine glands (salivary,bronchial,sweat). Smooth muscles (vascular) M4 M5

General Effects of Cholinergic Drugs

* Very short duration of action. *Non-selective (affected all organs) Ach : is the substance that transmits nerve impulses a cross the parasympathetic branch of the ANS . Acetylcholine (Ach) is rapidly broken down by cholinesterase so not used therapeutically??? Ach choline + acetate. * Very short duration of action. *Non-selective (affected all organs)

Classification of Cholinergic Drugs Direct-Acting Cholinergic Agonists Have a direct action on the receptor for ACH .some drugs are specific & selective for the muscarinic receptor; others are specific for the nicotinic receptor; other on both. Ex, Bethanechol Pilocarpine

(cholinesterase inhibitors) II) Indirect-Acting Cholinergic Agonists (cholinesterase inhibitors) Act by blocking the metabolism of ACH by *acetylcholinesterase (AchE) , they compete with ACH for the active site on the cholinesterase enzyme. These drugs effectively increase the concentration of ACH at all cholinergic synapses. Reversible Anticholinesterases Irreversible Anticholinesterases *enzyme destroys Ach

Mushrooms of Amanita species contain muscarine, which if ingested can cause intoxication

I- Direct-Acting Cholinergic Agonists

1- Bethanechol : 1-Treatment of urinary retention ??? 2- paralysis of intestine. 3- Stimulate GI motility should not be given if there is mechanical obstruction of intestine or urine flow.

2- Pilocarpine: Uses: as eye drop: The drug of choice in the emergency lowering of intraocular pressure of Glaucoma causes miosis.

S/Es: Salivation ↓ BP Bronchospasm Colic, Diarrhea. Bradycardia

(II) Indirect-Acting Cholinergic Agonists These drugs produce their effect by inactivating the enzyme Acetylcholinesterase, thus increasing ACh level at the receptors (non-selective) Also called Anticholinesterases They affect muscarinic and nicotinic receptors of the ANS nicotinic receptors of the neuromuscular junction and they also affect the brain

II) Indirect-Acting Cholinergic Agonists Cholinesterase inhibitors 1. Reversible Anticholinesterases

treatment of Myasthenia Gravis(ORALLY) Paralytic ileus Bladder a tony Neostigmine Its effect on NMJ of voluntary muscles. Can be given orally, I.M., S.C. treatment of Myasthenia Gravis(ORALLY) Paralytic ileus Bladder a tony it is used as an antidote for competitive neuromuscular blocking agents(IV). (At end of operation). Edrophonium Is very short duration (10-20 mins) . Used in the diagnosis of Myasthenia Gravis (MG) given as (IV)….. why?? If they have MG  dramatically improve muscle strength. Pyridostigmine Their durations of action are 3 – 6 hours. It is used in the chronic management of myasthenia gravis.

Myasthenia Gravis Is an autoimmune disease that involves rapid fatigue of skeletal muscle and weakness . caused by circulating antibodies against the nicotinic receptors at the postsynaptic neuromuscular junction( lack of ACh released at the nerve endings of parasympathetic) Using indirect cholinergic drugs will inhibit the activity of AchE &promote muscle contraction.

2. Irreversible Anticholinesterases Organophosphate compounds Lipid soluble(cross BBB) will abs from skin,lung,gut & conjunctiva. They form a covalent bond with acetylcholinesterase thus irreversibly inactivating it. - They are used as nerve agents in the military Some of them are used in insecticides Ex, Echothiophate is used in the management of glaucoma

Organophosphates: – Insecticides – Nerve gases • Malathion • Parathion • Sarin • Tabun • Soman

Organophosphates poisoning Toxicity will produce (All cholinergic effects) DUMBLESS -- Runny nose, chest tightness, constricted pupil -- Excessive salivation, urination ,diarrhea and defecation -- Muscle weakness and paralysis -cough, wheezing, bronchoconstriction. -- Coma, convulsions -- Death D:diarrhea U:urination M:miosis B:bronchial constriction ,bradycardia L:lacrimation E:excitation (convulsions) S:salivation S: sweating

Antidote: Decontamination of clothing Atropine (2mg every 15-60 mins) Mechanical ventilation. Diazepam. Pralidoxime (PAM) enzyme reactivation  Active AchE.

Cholinergic Crisis A condition in which there’s severe cholinergic effects Caused by excessive intake of irreversible Anticholinesterases inhibitors Features: - All the usual cholinergic effects - Muscle paralysis Treatment : withdrawal drug and we can used atropine.

Major uses of the cholinergic drugs in the treatment of : 1- Urinary retention. 2- Myasthenia gravis. 3- Glaucoma. 4- Paralytic ileus. 5- Bladder a tony