DRUGS AFFECTING AUTONOMIC NERVOUS SYSTEM by: Ms. Jovelyn May C.

Dimco Nervous System: CNS & PNS PNS: Somatic (SNS) & Autonomic (ANS) ANS: Sympathetic, Parasympathetic, Enteric Enteric Nervous System- controls GIT -maintains secretion and motility of intestines -independent from SNS, ANS -Auerbach plexus & Meissner plexus -Neurotransmitters: Noncholinergic Nonadrenergic Ex: Neoropeptide Y, substance P, adenosine triphosphate SOMATIC Voluntary/under volitional control 1-neuron system No ganglia vs AUTONOMIC Involuntary/autonomic 2-neuron system Presence of ganglia PARASYMPA (CHOLINERGIC) NS

**How is message transmitted? SYMPATHETIC NS(ADRENERGIC) I.Anatomical Difference roots/origin Thoracolumbar roots (T1-T12; L1-L5) location of ganglia Length of fiber: Preganglionic fiber Postganglionic II. Neurotransmitters Preganglionic Postganglionic III.Receptors Ganglionic End organ IV. Organ Responses General Heart Eyes Blood vessels Bronchi GIT: sphincters GIT: intestinal walls GUT: bladder walls GUT: sphincters Near spinal cord Short Long

Craniosacral (cranial nerves 3,7,9,10; S2-S4) Near the organs innervated Long Short

Acetylcholine NE, Epi, Dopamine Nicotinic , , dopamine receptors Fright, flight, fight Chronotropic, inotropic, dromotropic Pupillodilation = mydriasis *radial muscles Vasoconstriction Bronchodilation Closure/contraction Dilation/relaxation(constipation) Relaxation (urinary retention) Closure

Acetylcholine Acetylcholine Nicotinic Nicotinic & muscarinic Rest & digest bradycardia Pupilloconstriction = miosis *ciliary muscles Vasodilation Bronchoconstriction Opening/relaxation Contraction (bowel movement) Contraction Opening

Sweat glands Reproductive system

Apocrine=increase sweating Ejaculation

Eccrine= sweating Erection

increase

Sympathetic Nervous System: Steps in the biosynthesis of NT: NE Site: presynaptic postganglionic sympathetic fiber 1.Active uptake of TYROSINE into presynaptic fiber 2.Tyr DOPA enzyme:tyrosine hydroxylase *rate-limiting step DOPA- dihydroxyphenylalanine 3.DOPA dopamine enzyme: dopa decarboxylase (-) Reserpine (-) Metyrosine Drugs

4.storage/ uptake of dopamine to presynaptic vesicle Site: presynaptic vesicle 5.Dopamine NE (stored/protected from degradation) enzyme: dopamine hydroxylase

6.action potential; influx of Ca ++; fusion of vesicle to cell membrane 7. exocytosis/release of NE (-) Bretyllium, Guanethidine (+) Ephedrine, Amphetamine, Shabu, Angiotensin II, Tyramine 8. Fate of NE a)diffuse into the synapse; destroyed by COMT *COMT- catechol-o-methyltransferase b)bind to postsynaptic , , dopamine receptors; intracellular response; destruction by COMT c) bind to presynaptic 2 receptor; Negative feedback effect d) Re-uptake into presynaptic nerve fiber; 70% of NE lost; conservation *most important mechanism of loss (-) Cocaine, TCAs (-) Pyrogallol (-) Pyrogallol

***MAO = monoamine oxidase enzyme found inside the presynaptic fiber = destroys NE, DOPA, dopamine ** Tyramine-rich foods: cheese, red wine, beer, fermented products, yeast products, chicken liver

Effects of Sympathetic Stimulation: Receptors 1 Location Blood vessels Radial muscles of the iris Sphincter muscles of GIT & urinary bladder Pilomotor smooth muscle Presynaptic nerve terminal Postsynaptic nerve fiber: BV, muscles Heart JG apparatus Bronchial smooth muscles Intestinal smooth muscles Uterine smooth muscles Vascular smooth muscles Skeletal muscles Heart Adipose tissues Renal and sphlanchnic circulation CNS Response Vasoconstriction Mydriasis Constriction/closure GIT: constipation Bladder: urinary retention Contraction/erection of hair Vasodilation ciliary Vasoconstriction Chronotropic, Dromotropic, Inotropic RAAS, secretion and synthesis of rennin Bronchodilation Relaxation Uterine relaxation (tocolytic effect) Vasodilation Fasciculations, tremors, palpitation Tachycardia Lipolysis Vasodilation Stimulation of CNS

2 1 2

3 D1 D2,D3,D4

Sympathetic agonists/ Sympathomimetic drugs/ Adrenergic Agonists: I.Direct-acting II.Mixed acting III. Indirect-acting A. Non-selective -Metaraminol A. Releasers -Epi -Ephedrine -Amphetamine -NE - shabu -Dopamine - Tyramine - AII B. Selective B. Re-uptake Inhibitors -1 -cocaine -2 - TCA -1 -2 - nonselective MOA: Direct-acting Drugs drugs directly activates alpha, beta or dopamine receptors Indirect-acting Drugs drugs increase/enhance the release of NE Epinephrine Uses: 1) primary cardiac stimulant (for cardiac rescucitation) -ACLS (Advanced Cardiac Life Support) -max. dose: none until heart starts pumping again -(dose: 1-3 mg every 3-5 mins)

2) DOC: mx of anaphylactic shock AS: most severe form of allergic reaction due to excessive release of histamine from mast cells. s/sx: generalized rash, flushing, hypotension, bronchospasm MOA of EPI: 1 = vasoconstriction 2 = bronchodilation, inhibition of histamine release 3)Anesthetic adjunct for local vasoconstriction 4)as Dipinefrin (pivalic ester of EPI)- for glaucoma Toxicity: darkening of fingertips Synthesis: adrenal medulla Norepinephrine (no 2 effect) Uses: 1) cardiac stimulant 2) mx of septic shock Dopamine Dose-dependent effect: D1 induce dieresis (for urinary retention ex. BPH) -improve renal perfusion 1- inotropic for septic shock- DOC 1-vasoconstricting dose- raise BP in hypotensive states 1-selective Effect: vasoconstriction Uses: -Decongestants: nasal & ophthalmic -Raise BP in hypotensive states SE: 1) may worsen HPN 2)urinary retention in males with BPH 3) rhinitis medica mentosa- nasal sprays: < 3 days 4) tolerance PO > 5days CI: HPN, BPH Ex: 1) Phenylephrine 2) Propylhexedrine 3) Oxymetazoline 4) Tetrahydrozoline 5) Xylometazoline 6) Methoxamine 2-selective Effect: vasodilation Uses: anti-HPN presynaptic: vasodilation Decongestant postsynaptic: vasoconstriction Drugs: 1) **Methyldopa (Aldomet ) 2) **Clonidine (Catapress) 3) Guanfacine 4) Guanabenz 1-selective Drug: Dobutamine- use DOC for mx of cardiogenic shock 2-selective Effect: bronchodilation, uterine relaxation (tocolytic effect) Uses: 1) Bronchial asthma 2)Tocolytic effect: Terbutaline, Ritodrine, Isoxuphrine, Salbutamol

3)for bradycardia 4)for hyperkalemia SE: 1) tolerance- adm on PRN basis only 4)palpitations 2) Muscle tremors 5) hypercalcemia 3)hypokalemia 6)hyperglycemia Drugs: SA Terbutaline, Salbutamol, Fenoterol, Ritodrin, Isoxuphrine LA Formoterol (OXIS), Salmeterol (SEREVENT), Bambuterol (BAMBEC) -nonselective Drug: Isoproterenol- 1st drug available as MDI Toxicity: cardiotoxic Tolerance: to 2 effects Use: cardiac stimulant Releasers = calcium-acting drugs promote NE release D1-selective agonist Drug: Fenoldopam- vasodilator -use: for BPH and urinary retention Cocaine -powerful vasoconstrictor -stimulant TCAs increase NE Centrally-acting Sympathomimetics Effects: 1) CNS stimulation- wakefulness, increased alertness, seizure 2) loss of appetite- anorexiant effect Drugs: 1) Amphetamine- ADHD in children 2) Methamphetamine- shabu 3) Phenmetrazine 4)Methylphenidate 5)Phentermine 6)Fenfluramine 7) PPA Ephedrine stimulates the receptors and the release of NE Uses: 1) nasal decongestant 2) vasoconstrictor to raise BP in surgery which is lowered by anesth 3) used to treat asthma 4) present in fat burners Sympatholytics/ Sympathetic Antagonists/ Adrenergic Antagonists I.-blockers A.Nonselective C.Selective 2 -Phenoxybenzamine -Yohimbine -Phentolamine -Tolazoline B.Selective 1 -Prazosin -Doxazosin -Terazosin

II.-blockers A.Nonselective -Propanolol B.Selective 1 -M- Metoprolol -A Acebutolol -B Betaxalol, Bisoprolol -A- Atenolol -E- Esmolol C. ISA Effect -P- Pindolol -A- Acebutolol -L- Labetalol

D.MSA -P-A-

E. with -blocking effect -Labetalol -Carvedilol

- L-P- Propanolol - M- Metoprolol

Phenoxybenzamine- irreversible/ noncompetitive Uses: 1) preoperative control of HPN in patients with pheochromocytoma 2) control symptoms of Raynauds phenomenon (intermittent claudication) 3) used to control symptoms in carcinoid syndrome **Pheochromocytoma- hypersecretory tumor of the adrenal medulla leading to excessive release of NE &Epi -s/sx: flushing, severe headache, HPN, severe tachycardia, sympathetic sweating **Carcinoid syndrome- cancer of the enterochromaffin cells (storage sites of 5HT) leading to oversecretion of serotonin -s/sx: flushing, severe headache, palpitation Phentolamine- reversible/competitive Uses: 1) pre-op mx of pheochromocytoma; dx of pheochromocytoma 2) for Raynauds phenomenon 3) Intracavenous injection- for penile erection due to erectile dysfunction zosins Uses: 1) 1st line of drugs for essential HPN 2) relief of urinary retention for BPH SE: First-dose Phenomenon- syncope and orthostatic hypotension Yohimbine (experimental drug for impotence) Locally post synaptic 2 = vasodilation Systemically presynaptic 2 = vasoconstriction -blockers Uses: 1) HPN 2) anti-angina 3) anti-arrhythmia 4) migraine 5) Glaucoma- Timolol 6) control sx of hyperthyroidism 7) familial tremors INDERAL SE: 1. Rebound tachycardia and HPN 2. exacerbate bronchospasm in bronchospastic disorders 3. heart block 4. can mask symptoms of hypoglycemia **Diabetic shock