Pharmacology How Drugs affect the Autonomic Nervous system & Sympathetic Nervous system Lecture 6 Done By:

Maher.Khatib

The Doctor talked for 10 minutes about the last lecture, I heard it and found nothing is not mentioned in the previous lectures, so I will begin my lecture with Anti-cholinesterase Irreversible Inhibitors Anti-cholinesterase irreversible inhibitors last for weeks and days such as Organophosphate anticholinesterase. Some of these irreversible inhibitor drugs are used for treatment purposes or good purposes like the Insecticides, Parathion, Isoflurophate, or used as War gas. (Q) What would be the effect when a person is exposed to irreversible organophosphate? Irreversible organophosphate poisoning is commonly seen in farmers and unintended children. *Clinical features of Organophosphate poisoning: Generalized cholinergic stimulation in the CNS and peripheral tissues because Acetylcholine level is high due to Acetyocholinesterase is blocked. Low heart rate (Bradycardia)- 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. - Muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors, there will be symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, and a Generalized increase in body secretions such as increased bronchial secretions, increased salivation, lacrimation, diaphoresis, sweating, peristalsis, and uncontrolled urination can occur. - Uncontrolled deification means Gastrointestinal motility and causing diarrhea, vomiting, nausea, intestinal colic. - High Acetylcholine levels in the CNS will cause excitation followed by Respiratory and Cardiovascular central depression. - Muscle weakness, fatigue, Muscle cramps, fasciculation, and paralysis of the Muscle, especially Respiratory Muscles which will lead to breathing difficulties and death. So as a conclusion, We can put Organophosphate poisoning Clinical Manifestation into one Word: DUMBBLESS D: diarehea U: urinaton M: miosis B: brady cardia associated with hypotension B: bronchoconstriction L: lacrimation

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How to Treat Organophosphate Poisoning ?! How to Overcome this poisoning ? We want to reverse these symptoms. We will use a drug act on the level of Muscarinic Receptor. 1) Muscarinic Blocker, A drug that overcome high or excess Ach action by blocking the receptor ex. Atropine which can reverse many actions of Ach by blocking the Muscarinic Receptor of O.P.P. 2) PAM: which won't act at the Receptor, It's Working Mechanism is re-generate or re-activate the inhibited Enzyme,"cholinesterase" The figure below, shows How PAM works on the deactivated Enzyme and reactivate it, Dyflos is a kind of Organophosphate which bind to the active enzyme, and phosphorolate the enzyme and the enzyme becomes Inactive, If we add (PAM), (PAM) will re-generate the enzyme by removing the phosphate group, the enzyme is reactivated again, and it begins metabolizing the excess Ach.

Cholinergic Antagonists Cholinergic antagonists are Drugs that block Ach effect either on the level of * Muscarinic receptor or Nicotinic receptor. A- Muscarinic antagonist If we block a Muscarinic receptor at the effector Organ of parasympathetic nerve system which secretes Ach Effects of Ach On the heart > "Tachycardia", this will cause an increase in the Heart rate. On the bronchial tree > Bronchial Dilatation, Relaxation of the bronchial muscles which > will decrease the bronchial secretion. On the eye > Mydriasis in the eyes accompanied with Cycloplegia. On the urinary bladder > urinary retention. On the GIT > constipation. GIT Motility and Secretion

Cycloplegia is paralysis of the ciliary muscles of the eye, and these Muscles control the lens of the eye, resulting in the ability to see far objects, and inability to see near object clearly, Cycloplegia with accompanying mydriasis (loss of adaptation) can be induced pharmacologically by Muscarinic antagonists.
The ophthalmologists use Atropine like drugs not Atropine itself, because the effect of atropine lasts for days, but Atropine like drugs have less effect when used for eye examination, so Atropine induce cycloplegia and Mydriasis more than other drugs and will not seen for days after an eye drop, so cycloplegia is a problem, and that's why they use drugs with less effect. Prototype: The first Used for any Group.

The Prototype at the Muscarinic Receptor Blocking is Atropine. Atropine Therapeutic Uses: 1-Treatment and Management of colic. (Renal, Intestinal, Biliary Colic).

Due to the relaxation and paralysis of Muscles, especially smooth muscles and This cause reduction in the motility such as Intestinal Colic. 2- Pre-operative Medication: Mediaction Before Major Surgeries, When we do a Surgery we have two types of Drugs that induce Anesthesia. *Drugs induce Anesthesia *Drugs for maintenance of Anesthesia.

So in Pre-operative Anesthesia we use either Atropine, or Anti-Muscarinic Drugs. They will reduce the Bronchial and GIT secretions. (This is an aim of use also). 3- Relief Bronchial spasm (Bronchodilators). The drug used for relieving bronchial spasm and Treating Bronchial Asthma is Ipratropium. Ipratropium: is an anticholinergic drug used for the treatment of chronic obstructive pulmonary disease and acute asthma. It blocks the muscarinic acetylcholine receptors in the smooth muscles of the bronchi in the lungs, leading to bronchodilation (Taken By Inhalation). Why Ipratropium is preffered more than Atropine to Relief Bronchial spasm ?! Both of these drugs has the Same effect on releiving Bronchial spasm, But Ipratropium has less Adverse effects. Why? Because it is an ionized Drug, carrying a charge, Water soluble, so it is polar, it fully penetrates the membranes, so it has low systemic adversed effect. So Ipratropium and Atropine has the same effect, But adversed effect is less in ipratropium. Minimal chance to produce Tachycardia, Constipation, Mydriasis; Because poor solubility to Lipids. 4- Atropine is used as Antidote for cholinergic antagonists.

Because cholinergic antagonists overdose in the case of Organophosphate poisoning. 5- Treatment of Parkinson Disease.

To overcome this problem, we must Increase Dopamine and decrease Ach, and we can decrease Ach By Muscarinic Blocker by Benzatropine, Benzatropine antagonizes the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early Parkinson disease. We could use dopamine to increase the Dopamine in CNS, But patients with P.D and schizophrenia has high Dopamine levels, though we can't give them dopamine, so we use Benzatropine (Anti-cholinergic Drug). Tremor and rigidity is eliminated more using Anti cholinergic drug, and not all symptoms relieved by dopamine like drugs, But Bradykinesia is controlled by dopamine like drugs, so sometimes we make a combination between drugs according to the patient's condition. So in CNS, Atropine produces CNS excitation followed by CNS depression which leads to death. Atropine Adverse side effects are Constipation , Dry mouth, Urinary retention, Confusion, Mydriasis and Blurred vision. Hyoscine (Scopolamine): These are the Generic name, and it is a drug that is used as Antispasm drug especially for intestinal colic. Differs from Atropine that low doses from it will cause CNS depression,But High doses of Atropine only case CNS depression. Hyoscine causes loss of short memory (Amnesia), due to that Medical students reject to take Hyoscine. Therapeutic Uses :*Commonly used as Pre-operative Medication because it induces Amnesia (loss of short memory). *Controlling and preventing vomiting during motion sickness. Atropine and similar drugs should not be given to patients with .? + Hypertension, because Atropine induce Tachycardia. + Conditions when Cholinergic Antagonists are indicated and Muscarinic Antagonists are contraindicated.
Parkinson disease is an immune-degenerated disorder caused by the imbalance between Ach and dopamine in the CNS, High levels of Ach and Low levels of dopamine, commonly seen in elder patients such as Mohammad Ali clay, Yassir Arafat This disorder characterized by Muscle rigidity and Bradykinesia, Tremor in lips, hands and legs.

+ Hypoplasia, especially in Males. + Palitic Elias. Loosing Intestinal Motility and it will be worse and paralyzed.
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Atropine is used for the treatment of flat line ECG , means there is no Heart rate, and by atropine we can initiate cardiovascular contraction with C.P.R, because atropine is responsible of increasing heart rate and reach 60 beats/min so C.P.R + Atropine For Cardiopulmonary Resuscitation ..

A revision to remind you that Cholinergic Antagonists are either Muscarinic or Nicotinic, presented either at the level of -Neuromuscular Junction or Ganglia. B- Neuromuscular Blocker: is a Nicotinic Blocker, Blocking neuromuscular transmission at the Neuromuscular Junction and prevent Ach effect from Nicotinic Receptor, and Block the Nicotinic Receptor inducing Muscle relaxation. These Blockers are presented in two main Types. Depolarizing Blockers. Blockers. Non-Depolarizing
Cardiopulmonary resuscitation (CPR) is an emergency procedure which is performed in an effort to manually preserve intact brain function until further measures are taken to restore spontaneous blood circulation and breathing in a person in cardiac arrest.

Depolarizing means There is an Action potential and activation. Depolarizing Blocker. Ex, Succinylcholine (Suxamethonium), a drug that has a rapid onset and short duration of action, It's mechanism of action is binding to Nicotinic receptor at Neuromuscular Junction and they cause muscular fasciculations (a sudden twitch just before paralysis occurs) while they are depolarizing the muscle fibers then binding to Ach and activating it causes Muscle Paralysis. The drug attaches to the nicotinic receptor & act like Ach to depolarize the junction, but it is not destroyed by cholinesterase, so the continued binding of depolarizing agent renders the receptor incapable of transmitting further impulses. With time, membrane is repolarized but receptor is desensitized to affect of Ach. Depolarizing Blocker is Mainly used in * Endotrachial intubation during surgeries. * Elecrtoconvulsive Therapy. (ECT) We will produce electricity to treat a condition .Electrode gives electricity to Brain and make seizures, there is a mild controlled electricity to CNS, this is used to treat Mental disorders such as severe depression associated with suicide attempts. Electrode is used with Muscle

relaxant (succinylcholine) to prevent Muscle Complication such as Muscle pain, Bone Dislocation, Bone fracture. Adverse Side Effects: Apnea in patients who has genetic defect in the plasma cholinesterase. Apnea is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged when prolonged Respiratory Muscles paralysis, and that may cause death. Non-Depolarizing Blockers: Responsible to induce Muscle Relaxation, Bind Muscarinic Receptor and presented as Neuromuscular Junction, prevent Ach from binding and prevent its Action. Ex.Tubocurarine. Tubocurarine: is Mainly used in anesthesia to induce Skeletal Muscle relaxation During major surgeries.

Now We will begin with the new Subject

Sympathetic Nervous system

Sympathetic Nervous system: Released on stressful situations, its general action is to mobilize the body's nervous system fight-or-flight response. It is, however, constantly active at a basic level to maintain homeostasis. We have two types on Neurotransmitters released Norepinephrine which is mainly released from Sympathetic Nerve Endings. Epinephrine which is mainly released from adrenal medulla *Sympathomimetic Amines such As Epinephrine and Norepinephrine, Dopamine and Isoproternol are all called Catecholamines, and They share the same properties: Structure (Benzene ring ). Rapid Inactivation by MOA and COMT enzymes. But the primary process to terminate NE effect is the Re-uptake process. NE is released from Sympathetic nerve fibers which after a while NE effect is terminated by different Mechanisms. Re-uptake to its stored vesicles in the pre-synaptic neurons. Metabolize by Two enzymes either by *MOA enzyme in the pre-synaptic neurons. Or by *COMT enzyme in the synapse. ------------------------------------------------------- Penetrate to CNS, because they are polar and poor lipid solubility Orally inactive, destroyed by walls of the mouth. Brief duration of action, (They act on adrenergic Receptors so there is a difference in their to affinity to type of Receptor).
EEpinephrine NE Norepinephrine

--------------------------------------------------------------Types of adrenergic receptors Alpha Receptors 1 and 2 receptors, and they are stimulated by NE and E. The image below shows the synaptic cleft, presynaptic and postsynaptic membranes. Alpha 1 receptors are located on the postsynaptic membrane of effector organs. Alpha 1 is postsynaptic but Alpha 2 is pre-synaptic. Alpha 1 activation by NE and E. Activation of 1 receptor causes *Mydriasis (Dilatation of the pupil) *Urinary retention *increase vascular smooth muscle contraction, producing increases in blood pressure(Vasoconstriction).* increase the closure of internal sphincter of bladder. Alpha 2 receptors Activation will inhibit further release of Neurotransmitters from the Presynanptic neurons. (Auto-inhibitory Mechanism), E and NE bind to the receptor and this will inhibit the release of Neurotransmitters, this is good for relieving Hypertnsion.

Beta Receptors 1 and 2 and 3, 1 and 2 are stimulated by E and isoprenaline. NE stimulates 1 only. So 2 stimulated by E and Isoprenaline, and this will cause Bronchodilations, Vasodilation and increase in blood Glucose vessels ( by increasing the production of Glucose in liver), and Finally Relaxation of the Uterine Smooth muscle.

In which case we can use a 2 receptor antagonists?! "Drug that stimulate 2" Ans: for Treatment Bronchial spasm, Some drugs under this category include: salbutamol *NE can't be used as a treatment for local asthma, because it doesn't Stimulate 2 and 2 is the receptor that cause bronchodilator.

Uterine contraction Drugs that bind to Beta 2 receptors (Beta 2 agonists) are used in the treatment of premature labor, this clinical application illustrates how Beta 2 receptors mediate tocolysis on the uterine muscle. Ritodrine is an example of a tocolytic drug. --------------------------------------------1 stimulated by E and NE and Isoprenaline, and this will affect the heart compulsive by increasing Heart Rate, and also increasing Cardiac Output. In the Renal system , 1 stimulating will cause release of Renin, this enzyme will activate the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE,
Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure.

Beta 1 receptors are mainly located in the heart and kidneys. Stimulation of beta1-adrenergic receptors on the myocardium, AV node, and SA node results in CARDIAC STIMULATION: Increased force of contraction (positive inotropic effect) Increased heart rate (positive chronotropic effect)

-----------------------------------------------------------Classification of Sympathomimetics/Adrenomimetics Sympathomimetic drugs mimic the effects of transmitter substances of the sympathetic nervous system such as catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine , etc. Such drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor. Direct Acting Sympathomimetics. Drugs directly stimulate the adrenergic receptor (e.g. epinephrine, norepinephrine) ,Selective and Non-Selective. Indirect Acting Sympathomimetics. Drugs that Stimulate the release of Nicotinic receptors, Or Inhibit the re-uptake of Nicotinic receptor, and re-uptaking terminates Nicotinic receptor. Ex amphetamine.

 Mixed-Acting sympathomimetics (both direct and indirect acting)

Sympathomemtic Drugs

Epinephrine (E). Actions 1. Increase the heart rate and force of contraction.(destroyed by mouth Enzymes), caused by 1. 2. Bronchodilation caused by 2. 3. Increase Glucose level caused by 2 4. Eye Mydriasis caused by 1 5. Increase the Systolic Blood pressure and minimal change in Diastolic Blood pressure. Why E affects the systolic Bp more than Diastolic Bp ? Systolic Bp is increased due to increased Heart rate and force of contraction by 1, but minimal change is Diastolic, because 1in blood will lead to Vasoconstriction but in opposite there is 2 cause Vasodilation. Therapeutic uses Anaphylactic shock When histamine is released (released from mast cells) this causes vasodilation, this will lead to some symptoms like hypotension and flushing. In this Case Epinephrine should be administrated I.M not I.V.( I.V is avoided because it is dangerous more than the shock). Stimulates the heart in cardiac arrest Can be used to prolong local anesthetic action --------------------------------------------------------Can be prepared synthetically . Orally Inactive. Secreted from adrenal Medulla.

Nor-Epinephrine (NE) 2 receptor causes increase in the systolic & 1 causes increase Diastolic blood pressure. Uses: Treatment of shock ( BP) given by I.V. infusion, but because of its effect (vasoconstriction) it blood flow in essential organs tissue damage Necrosis.

Good luck Done by Maher.khatib Excuse me for the delay in this script !! The delay was to make sure that the information in this script is Accurate. Hope you will enjoy reading it as I enjoyed writing it .