Subject: Pharmacology Topic: ANS3 Lecturer: Dr.

Dela Cruz Date of Lecture: August 05, 2011 Transcriptionist: Agaw- buhay x_X Editor: Ms. PAOerful Pages: 16

Steps in Neurotransmission: 1. Axonal conduction 2. Junctional transmission a. release of neurotransmitter b. interaction with receptors c. production of response 3. Destruction or dissipation of neurotransmitter

Synthesis of Neurotransmitter

Norepinephrine is the neurotransmitter in postganglionic sympathetic fibers In the adrenal medulla, catecholamines are stored in the chromaffin granules o 80% Epinephrine o 10-20% Norepinephrine Glucocorticoid secreted by the adrenal cortex is a major factor that controls the rate of synthesis of Epinephrine

Release of Norepinephrine presence of action potential increase influx of Ca++ fusion of vesicles with cell membrane release of NE by exocytosis

SY 2011-2012
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Stress Glucocorticoid secretion Synthesis of Phenylethanolamine-N-methyltransferase Increase Synthesis of Epinephrine Presynaptic Adrenergic receptors Recept Sit G Second Messenger or e protein System 2 CN Gi c AMP S CN Gs c AMP S D2 CN Gi c AMP S Postsynaptic Adrenergic receptors Recept G Enzyme Second or protein Messenger 1 Gq Phospholipas IP3 and Ca++ eC 2 Gi Adenylyl Cyclic AMP cyclase 1 Gs Adenylyl Cyclic AMP cyclase 2 Gs Adenylyl Cyclic AMP cyclase 3 Gs Adenylyl Cyclic AMP cyclase D Gi Adenylyl Cyclic AMP cyclase Action Inhibit NE release Stimulate NE release Stimulate Dopamine release

Termination of Neurotransmitter Action I. Reuptake into the nerve terminal a. Active transport of NE across the axoplasmic membrane from the extracellular fluid to the cytoplasm mediated by Norepinephrine transporter (NET) b. Active transport of NE from the cytoplasm into the storage vesicles mediated by Vesicular Monoamine Transporter (VMAT-2)

II. Uptake 2- Extraneuronal a. Uptake at extraneuronal sites mediated by extraneuronal transporter (ENT or OCT3), Organic cation transporters (OCT1 and OCT 2) III. Diffusion out of the junctional cleft into the circulation IV. Metabolic Transformation a. Monoamine Oxidase (MAO)- metabolizes transmitter within the nerve terminal b. Catechol-O-Methyltransferase (COMT)- metabolizes endogenous circulating and administered catecholamines particularly in the liver reuptake of approximately 87% of released NE via NET 5% by ENT 8% by diffusion VMAT-2 has a higher affinity for NE than MAO over 70% of recaptured NE is sequestered into storage vesicles

Metabolism of Catecholamines 1

Adrenergic Agonists Neurotransmitters in the Sympathetic Nervous System 1. Norepinephrine (Noradrenaline) main neurotransmitter in postganglionic sympathetic fiber 2. Epinephrine (Adrenaline) main catecholamine secreted by the adrenal medulla 3. Dopamine main neurotransmitter in the nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular systems Structure Activity Relationship: Phenylethylamine Catecholamines (0Non - Catecholamines dihydroxybenezene)

Benzene ring Ethylamine side chain, terminal amino group OH group in positions 3 and 4 * Chocolate also contains phenylethylamine

Benzene ring Ethylamine side chain absence of both -OH group in Carbon 3 and 4 of the benzene ring orally active resistant to COMT longer duration of action increase CNS distribution

Classification of Adrenergic Agonists Based Catecholamines on - Norepinephrine Struct - Isoproterenol ure - Epinephrine - Dobutamine - Dopamine Based on Mode of Action Direct-acting - Norepinephrine - Epinephrine - Isoproterenol - Phenylephrine - Dobutamine - Terbutaline

Non-Catecholamines - Ephedrine - Amphetamine - Phenylephrine - Tyramine - Phenylpropanolamine - Salbutamol Indirect acting Mixed Acting - Drugs that Displace NE from Storage Vesicles - Dopamine o Amphetamine - Ephedrine - Clonidine o Tyramine - Drugs that Block NE Uptake o Cocaine - Drug/s that Inhibit Monoamine Oxidase o Pargyline - Drug/s that Inhibit COMT o Entacapone

Based on Recept or Activa ted

Nonselective and agonists - Norepinephrine - Ephedrine - Epinephrine - Pseudoephedrine - Dopamine - Phenylpropanola mine

Nonselective agonist - Isoprotere nol

Selective 1 agonists - Methoxamine - Phenylephrine - Imidazoline derivatives: o Naphazoline o Tetrahydrozol ine o Oxymetazolin e

Selective 2 agonist - Clonidine - Guanfaci ne - Methydo pa - Guanabe nz

Selective 1 agonists - Dobutami ne - Prenalter ol

Selective 2 agonist - Terbutaline - Salbutamol / Albuterol - Metaprotere nol - Ritodrine - Salmeterol Fomoterol

Dopaminergic Agonists - Dopamine - Bromocripti ne - Fenoldopa m

Xylometazolin e

Mode of action of Sympathomimetics

Major Classification of Adrenergic Receptors 1 2 1 2 Norepinephr ine Epinephrine Ephedrine Isoproteren ol Phenylephri ne Clonidine Salbutamol Dobutamine ++ + ++ + ++ + ++ + ++ + ++ + ++ + ++ + ++ + + ++ + + ++ + ++ + ++ + ++ + +

Agonist Selectivity at Adrenoceptors

* MOA of 1 agonist

* MOA of 1 and 2 agonist with 2 agonist

Pharmacologic Actions 1. Peripheral Excitatory Action- 1 receptor blood vessels supplying skin and mucous membrane and kidneys Vasoconstriction salivary glands increase secretion 1

localized sweat glands palms of hand adrenergic sweating

piloerector muscles contraction goose flesh radial muscles of the iris mydriasis sex organs ejaculation Rank order of potency for a1 receptors: Epinephrine Norepinephrine >> Isoproterenol bladder base, urethral sphincter, prostate urinary retention

increase renal vascular resistance decrease renal blood flow by as much as 40% increase secretion of renin decrease excretion of Na+, K+ and Cl-

2. Peripheral Inhibitory Action - 2 receptor smooth muscles of the: gastrointestinal tract decrease motility and transit time bronchi bronchodilatation uterus relaxation blood vessels supplying skeletal muscles vasodilatation

Other b2 receptor mediated action in the Respiratory Tract: inhibits release of chemical mediators from mast cells enhance mucociliary action decrease bronchial secretions possible inhibition of Phospholipase A2 Rank order of potency at 2 receptors: Isopoterenol > Epinephrine >> Norepinephrine

3. Prejunctional Action- 2 receptor inhibition of NE release decrease central sympathetic outflow

inhibition of Ach release in the GIT relaxation of GIT smooth muscles increase Na+ and water absorption ciliary body decrease aqueous humor production

4. Cardiac Excitatory Action 1 receptor Increase force of myocardial contraction (+) inotropic effect Increase pacemaker activity (+) chronotropic effect Increase conduction velocity in the A-V node and shortened refractory period (+) dromotropic effect

Rank order of potency at 1 receptor: Isoproterenol > Epinephrine Norepinephrine effect on blood pressure Determinants of blood pressure: Cardiac output Total peripheral resistance

Comparison of Effects on Blood Pressure

Comparison of Effects on Blood Pressure NOREPINEPHRINE

EPINEPHRINE

ISOPROTERENOL

PHENYLEPHRINE

5. Metabolic Actions 2 receptor mediated increase rate of glycogenolysis and gluconeogenesis in the liver and muscle enhance uptake of K+ into the cells decreasing extracellular K+ levels 3 receptor mediated increase lipolysis

6. Endocrine Actions- Insulin secretion 2 - inhibits insulin secretion hyperglycemia (predominant) 2 - stimulate insulin secretion hypoglycemia Renin secretion mediated by 1 receptors in the juxtaglomerular cells receptor mediated increase secretion of aqueous humor 7. Actions on the Central Nervous System mediated by both a and b receptor respiratory stimulation mild alerting to stimulation o improved attention o mood elevation o insomnia, euphoria o apprehension, restlessness o headache, tremors o psychotic behavior appetite suppression 8. Other Actions aqueous humour secretion o 2 inhibits secretion decrease IOP o increase secretion increase IOP

DRUG EPINEPHRINE

DESCRIPTION - unstable in alkaline solution and in the presence of air and light - concentration for injection (subcutaneous and intravenous) is 1:1000 or 1:10,000 - concentration for inhalation is 1:100 - inadvertent injection of 1:100 solution can be fatal

PHARMACOKINETICS - not suitable for oral administration - administered topically, by inhalation and parenterally (subcutaneous, intravenous) - absorption from SC is slow - very short duration of action - not distributed to the brain

NOREPINEPHRINE

ISOPROTERENOL

DOPAMINE

DOBUTAMINE

- ineffective when given orally - poor absorption from subcutaneous sites - rapidly inactivated in the body - necrosis and sloughing at site of IV injection due to extravasation - limited therapeutic use - given by intravenous infusion and by inhalation - metabolized primarily by COMT - poor substrate for MAO - longer duration of action than Epinephrine - may produce locked-lung syndrome - immediate metabolic precursor of Norepinephrine and Epinephrine - central neurotransmitter - ineffective when administered orally - inactivated by MAO and COMT - exogenous Dopamine has no central effects - at low concentrations activate vascular D1 receptors in renal, mesenteric and coronary beds vasodilatation - activation of DI receptors in the kidneys produce an increase in GFR, renal blood flow and Na+ excretion - at high concentration activates b1 receptor positive Inotropic effect - at higher doses activates vascular a1 vasoconstriction - given only intravenously - during IV infusion, monitor myocardial function, perfusion of vital organs such as the brain and urine output - short duration of action - synthetic catecholamine - direct acting - relative selectivity for b1 receptors * positive inotropic effect * positive chronotropic effect - more prominent inotropic effects (used in the tx of CHF & to improve hemodynamics) - less effect on heart rate - half-life is 3 minutes

PHENYLEPHRINE

EPHEDRINE

OXYMETAZOLINE

AMPHETAMINE

METAMPHETAMINE

METHYLPHENIDAT E PHENYLPROPANOL AMINE

CLONIDINE

- steady state is attained within 10 minutes after start of infusion - tolerance to its effects occur with prolonged use - worsen long term outcome with chronic use in patients with heart failure (do not use >72 hrs.) - pure a1 agonist - non-catecholamine - directly-acting, synthetic - commonly used as a Mydriatic, and nasal and conjunctival decongestant - poor oral bioavailability - has been used in China for almost 200 years - introduced to western medicine in 1924 - first orally active sympathomimetic drug - poor substrate for COMT and MAO - Herbal preparation Ma-huang contains ephedrine-like alkaloids - weak base; renal excretion is enhanced by urine acidification - prototype for Imidazoline - direct-acting a agonist - used as topical mucosal decongestant - larger doses produce hypotension due to central Clonidine-like effects - not used as a drug - important primarily because of misuse and abuse as a CNS stimulant - similar pharmacokinetic profile as Ephedrine - marked CNS stimulant effects - marked appetite suppressant effects - N-methyl amphetamine - SHABU, poor mans cocaine - compared with Amphetamine, has higher central than peripheral effects - CNS actions attributed to release of Dopamine and Norepinephrine - an amphetamine variant - evidences show that it is a more potent Dopamine transport inhibitor than Cocaine - proven efficacy in children with Attention deficit hyperactivity disorder - one of most prescribed drugs for children - non selective adrenergic receptor agonist - can induce release of NE from adrenergic nerve ending - used as a nasal decongestant and appetite suppressant - common component of over-the counter Cold preparations and weight reducing pills - a five year study by scientists at Yale University, reported that it was associated with a small but significant increase in risk of stroke among young women - In the New England Journal of Medicine women aged 19-49 who took the drug, as much as 15 times are more likely to suffer hemorrhagic stroke - presynaptic a2 agonist

TERBUTALINE

COCAINE

TYRAMINE

postsynaptic effects in blood vessels similar to a1 agonist well absorbed after oral administration, almost 100% bioavilability maximal hypotensive effect in 1-3 hours mean half-life 12 hours with other selective b2 agonist, useful in: * Bronchial asthma * Premature labor poor substrate for COMT binds to the monoamine reuptake transporter and prolongs CNS and peripheral action of monoamines readily enter the CNS and produce CNS stimulation used as a local anesthetic for surgical procedures in the eye, ear, nose and throat heavily abused drug smoked, snorted in the nose and injected for rapid onset of effect produce, euphoria, hallucinations, delusions and paranoia causes of death from overdosage: * convulsion, coma * fatal cardiac arrhythmias * myocardial infarction * hyperthermia * respiratory depression normal by-product of tyrosine metabolism in the body not clinically useful also found in high concentrations in fermented food (cheese, beer, red wine, etc) cause release of stored catecholamines enters the nerve terminal and displaces stored NE direct actions are similar to Norepinephrine readily metabolized by MAO concomitant administration with MAO-A Inhibitors will greatly intensify its effect

Characteristics of Adrenergic Receptors 1. Selectivity - preferential affinity for a specific receptor type/subtype - relative rather than absolute - higher drug concentration decreases selectivity Receptor Regulation - Desensitization o decrease responsiveness with continuous exposure to the agonist o Tolerance, tachyphylaxis, refractoriness o Mechanisms for Desensitization of Receptors: sequestration of receptors Down regulation- decrease in the number of receptors receptor phosphorylation resulting to inability of the receptor to couple with G-protein - Supersensitivity o enhanced responsiveness o may produce exaggerated response (i.e. hypertensive crisis) o Mechanisms for Supersensitization of Receptors: Pharmacologic sympathectomy Guanethidine o prevents release of neurotransmitter from the sympathetic nerve ending Reserpine o inhibits monoamine transport into storage vesicles and leads to depletion of of catecholamines from sympathetic nerve endings and in the brain Up regulation- increase in the number of receptors Adverse Effects a1 receptors - hypertension (hypertensive crisis, stroke) - rebound congestion - urinary retention a2 receptors - dry mouth, sedation - depression - marked bradycardia - sexual dysfunction - rebound hypertension upon withdrawal b1 receptors - palpitation - cardiac arrhythmias (Premature ventricular contractions, Ventricular arrhythmias) - angina - myocardial infarction b2 receptors - skeletal muscle tremor - tachycardia - hypokalemia - pulmonary edema - near death or death with prolonged use a and b receptors in the CNS - depression/ stimulation - psychotic symptoms - euphoria - restlessness, apprehension - convulsion

Clinical Uses of Adrenergic Agonists a1 receptors Vasoconstrictor - Adjunct to Local Anesthetics (Epinephrine) - Local Hemostatic (Epinephrine) topical application in epistaxis, dental extractions, ophthalmic surgery, etc. - Decongestant (nasal and conjunctival) - Shock (Norepinephri ne, Dopamine) Ophthalmologic - Mydriatic Paroxysmal atrial tachycardia - BP reflex vagal discharge

a2 receptors Antihypertensive - decrease central sympathet ic outflow - inhibition of NE release Clonidine - diarrhea in diabetic patients with autonomic neuropath y - decrease intraocular pressure in patients with glaucoma

b1 receptors Congestive heart failure- (+) inotropic effect Complete heart block Cardiac arrest - redistributes blood flow during CPR to the coronary beds and the brain

b2 receptors Bronchodilator - Bronchial asthma - COPD Tocolytic - Delay premature labor - Prevent abortion

Others Hypersensitvity reaction (Epinephrine) - Anaphylactic shock - by physiologic antagonism Weight reduction - Amphetamine and its variants Narcolepsy - Amphetamine - Dextroamphetamin e Attention Deficit Hyperactivity Disorder - Methylphenidate - Pemoline

* please read your books if you still have time and if you have a book..hahahaha!!!! ~~Happy Studying!