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8/6/2019 Pharma Ans3
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Steps in Neurotransmission:1. Axonal conduction2. Junctional transmission
a. release of neurotransmitterb. interaction with receptorsc. 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% Epinephrineo 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
Subject: Pharmacology Topic: ANS3Lecturer: Dr. Dela CruzDate of Lecture: August 05, 2011
Transcriptionist: Agaw- buhay x_XEditor: Ms. PAOerfulPages: 16
SY 2011-2012
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Stress Glucocorticoid secretion Synthesis of Phenylethanolamine-N-methyltransferaseIncrease Synthesis of Epinephrine
Presynaptic Adrenergic receptorsRecept
orSite
Gprotein
Second MessengerSystem
Action
2 CNS
Gi c AMP Inhibit NE release
CNS Gs c AMP Stimulate NE releaseD2 CN
SGi c AMP Stimulate Dopamine
release
Postsynaptic Adrenergic receptorsReceptor
Gprotein
Enzyme SecondMessenger
1 Gq Phospholipase C
IP3 and Ca ++
2 Gi Adenylylcyclase
Cyclic AMP
1 Gs Adenylylcyclase Cyclic AMP
2 Gs Adenylylcyclase
Cyclic AMP
3 Gs Adenylylcyclase
Cyclic AMP
D Gi Adenylylcyclase
Cyclic AMP
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Termination of Neurotransmitter ActionI. Reuptake into the nerve terminal
a. Active transport of NE across the axoplasmic membrane from the extracellular fluidto the cytoplasm mediated by Norepinephrine transporter (NET)
b. Active transport of NE from the cytoplasm into the storage vesicles mediated byVesicular Monoamine Transporter (VMAT-2)
II. Uptake 2- Extraneuronala. 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 Transformationa. Monoamine Oxidase (MAO) - metabolizes transmitter within the nerve terminalb. 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
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Adrenergic AgonistsNeurotransmitters 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: PhenylethylamineCatecholamines (0-dihydroxybenezene)
Non - Catecholamines
Benzene ring Benzene ringEthylamine side chain, terminal aminogroup
Ethylamine side chain
OH group in positions 3 and 4 absence of both -OH group in Carbon 3and 4 of the benzene ring
* Chocolate also containsphenylethylamine
orally active
resistant to COMTlonger duration of actionincrease CNS distribution
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Classification of Adrenergic AgonistsBasedonStructure
Catecholamines- Norepinephrine- Isoproterenol- Epinephrine- Dobutamine- Dopamine
Non-Catecholamines- Ephedrine- Amphetamine- Phenylephrine- Tyramine- Phenylpropanolamine- Salbutamol
BasedonModeof Action
Direct-acting- Norepinephrine- Epinephrine- Isoproterenol- Phenylephrine- Dobutamine- Terbutal ine
Indirect acting- Drugs that Displace NE from Storage Vesicles
o Amphetamineo Tyramine
- Drugs that Block NE Uptakeo Cocaine
- Drug/s that Inhibit Monoamine Oxidaseo Pargyline
- Drug/s that Inhibit COMTo Entacapone
Mixed Acting- Dopamine- Ephedrine- Clonidine
BasedonReceptorActiva
ted
Nonselective and agonists
- Norepinephrine- Ephedrine- Epinephrine
- Pseudoephedrine- Dopamine- Phenylpropanola
mine
Nonselective agonist
- Isoproterenol
Selective 1 agonists- Methoxamine- Phenylephrine- Imidazoline
derivatives:o
Naphazolineo Tetrahydrozoline
o Oxymetazoline
Selective 2agonist
- Clonidine- Guanfaci
ne
- Methydopa- Guanabe
nz
Selective 1agonists
- Dobutamine
- Prenalter
ol
Selective 2agonist
- Terbutal ine- Salbutamol /
Albuterol
- Metaproterenol- Ritodrine- Salmeterol- Fomoterol
DopaminergicAgonists
- Dopamine- Bromocripti
ne
- Fenoldopam
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o Xylometazoline
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Mode of action of Sympathomimetics
Major Classification of AdrenergicReceptors
Agonist Selectivity at Adrenoceptors
* MOA of 1 agonist
* MOA of 1 and 2 agonist with 2 agonist
Pharmacologic Actions1. Peripheral Excitatory Action- 1 receptor
blood vessels supplying skin and mucous membrane and kidneys Vasoconstriction salivary glands increase secretion
1 2 1 2
Norepinephrine
+++
- +++
+
Epinephrine +++
- +++
+++
Ephedrine +++
- +++
+++
Isoproterenol
- - +++
+++
Phenylephrine
++ - - -
Clonidine + +++
- -
Salbutamol - - + +++
Dobutamine - - +++
+
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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 + andwater 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
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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
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Comparison of Effects on Blood PressureNOREPINEPHRINE EPINEPHRINE ISOPROTERENOL PHENYLEPHRINE
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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 attentiono mood elevationo insomnia, euphoriao apprehension, restlessnesso headache, tremorso psychotic behavior
appetite suppression
8.Other Actions aqueous humour secretion
o 2 inhibits secretion decrease IOPo increase secretion increase IOP
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DRUG DESCRIPTION PHARMACOKINETICSEPINEPHRINE - unstable in alkaline solution and in the presence of air and light
- concentration for injection (subcutaneous and intravenous) is 1:1000 or1:10,000- concentration for inhalation is 1:100- inadvertent injection of 1:100 solution can be fatal
- not suitable for oral administration- administered topically, by inhalation andparenterally ( subcutaneous, intravenous)- absorption from SC is slow- very short duration of action- not distributed to the brain
NOREPINEPHRINE - 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
ISOPROTERENOL - 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 syndromeDOPAMINE - 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 D 1 receptors in renal, mesentericand coronary beds vasodilatation- activation of D I receptors in the kidneys produce an increase in GFR,renal blood flow and Na + excretion- at high concentration activates b 1 receptor positive Inotropic effect- at higher doses activates vascular a 1 vasoconstriction- given only intravenously- during IV infusion, monitor myocardial function, perfusion of vital organssuch as the brain and urine output- short duration of action
DOBUTAMINE - synthetic catecholamine- direct acting- relative selectivity for b 1 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
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- 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.)
PHENYLEPHRINE - pure a 1 agonist- non-catecholamine- directly-acting, synthetic- commonly used as a Mydriatic, and nasal and conjunctival decongestant- poor oral bioavailability
EPHEDRINE - 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
OXYMETAZOLINE - prototype for Imidazoline- direct-acting a agonist
- used as topical mucosal decongestant- larger doses produce hypotension due to central Clonidine-like effectsAMPHETAMINE - 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
METAMPHETAMINE - 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
METHYLPHENIDATE
- 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
PHENYLPROPANOLAMINE
- 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 increasein 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 likelyto suffer hemorrhagic stroke
CLONIDINE - presynaptic a2 agonist
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- 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
TERBUTALINE - with other selective b 2 agonist, useful in:* Bronchial asthma* Premature labor
- poor substrate for COMTCOCAINE - 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
TYRAMINE - 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
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Characteristics of Adrenergic Receptors1.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 agonisto Tolerance, tachyphylaxis, refractorinesso Mechanisms for Desensitization of Receptors:
sequestration of receptorsDown regulation- decrease in the number of receptorsreceptor phosphorylation resulting to inability of the receptor to couple withG-protein
- Supersensitivityo enhanced responsivenesso may produce exaggerated response (i.e. hypertensive crisis)o Mechanisms for Supersensitization of Receptors:
Pharmacologic sympathectomy Guanethidine
o prevents release of neurotransmitter from the sympatheticnerve ending
Reserpineo inhibits monoamine transport into storage vesicles and leads to
depletion of of catecholamines from sympathetic nerve endingsand in the brain
Up regulation- increase in the number of receptors
Adverse Effects
a 1 receptors a 2 receptors b 1 receptors b 2 receptors
a and b
receptors inthe CNS- hypertension(hypertensivecrisis, stroke)- reboundcongestion- urinaryretention
- dry mouth,sedation- depression- markedbradycardia- sexualdysfunction- reboundhypertensionupon
withdrawal
- palpitation- cardiacarrhythmias(Prematureventricularcontractions,Ventriculararrhythmias)- angina- myocardial
infarction
- skeletalmuscle tremor- tachycardia- hypokalemia- pulmonaryedema- near death ordeath withprolonged use
- depression/stimulation- psychoticsymptoms- euphoria- restlessness,apprehension- convulsion
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Clinical Uses of Adrenergic Agonistsa 1 receptors a 2 receptors b 1 receptors b 2 receptors Others
Vasoconstrictor- Adjunct to
LocalAnesthetics(Epinephrine)
- LocalHemostatic(Epinephrine)
topicalapplication inepistaxis,dentalextractions,ophthalmic
surgery, etc.- Decongestant(nasal andconjunctival)
- Shock(Norepinephrine,Dopamine)
Ophthalmologic- Mydriatic
Paroxysmal atrialtachycardia
- BP reflexvagaldischarge
Antihypertensive- decrease
centralsympathetic outflow
- inhibitionof NErelease
Clonidine- diarrhea in
diabeticpatientswithautonomic
neuropathy- decrease
intraocularpressurein patientswithglaucoma
Congestive heartfailure- (+)inotropic effectComplete heartblockCardiac arrest
- redistributesblood flowduring CPRto thecoronarybeds and thebrain
Bronchodilator- Bronchial
asthma- COPD
Tocolytic- Delay
prematurelabor
- Preventabortion
Hypersensitvity reaction(Epinephrine)
- Anaphylactic shock- by physiologic
antagonismWeight reduction
- Amphetamine andits variants
Narcolepsy- Amphetamine- Dextroamphetamin
eAttention DeficitHyperactivity Disorder
- Methylphenidate- Pemoline
* please read your books if you still have time and if you have a book..hahahaha!!!!
~~Happy Studying!
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