Pharma Ans3

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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Pharma Ans3