• reaccumulation in presynaptic neuron via norepi. transporter
• 90% of released NE reaccumlated by the transporter

• epi- from adrenal medulla
• norepi- from postganglionic sympathetic R's

• neurons in CNS (precursor to NE in postgang symp. NS)

1. Tyr to DOPA via Tyr hydroxylase (coenzyme: tetrahydrobiopterion)
2. DOPA to dopamine via aromatic L AA decarboxylase (coenzyme: pyridoxal phosphate)
3. dopamine to norepi via dopamine hydroxylase (coenzyme: ascorbate)
4. norepi to epi via methyltransferase (coenzyme: SAM)
   • this step only in adrenal medulla

1. AP invades, opening Ca channels
2. cause NE release to stimulate alpha and beta receptors
3. NE acting at presynaptic alpha 2 receptor cause feedback inhibition of further release

• enzyme: MAO, COMT
  • what normally metabolizes epi
• location
  • liver
  • kidney
  • GI tract
• MAO is located presynaptically

• any NE that is not in a vesicle is broken down by MAO's into metabolites

• it will change direction, and be transported OUT of presynaptic neuron via facilitated exchange difusion
• if MAO inhibited, this could happen

• alters ionic permeability (ex: stim. beta1 R's in heart)
• activate cAMP signaling
  • beta1 and beta 2 is via G_s stimulation increases cAMP
  • activating alpha two is via G_i and decreases cAMP
  • activating alpha one is via G_q which activates PKC and increase calcium

• activates hepatic glycogen phosphorylase
• inhibit hepatic glycogen synthase
• phosphorylates phosphohlamban and troponin (in heart)

• decrease activity of glycogen synthase (decrease activity)
• phosphorylates ion channels, pumps, ion exchangers

1. enters via NET
2. uncouples the AP from Ca entry
3. begins to concentrate in the vesicles
   • now we cant store norepi
   • deplete norepi, LOWER BP

1. enters terminal
2. blocks VMAT (this is what takes norepi into vesicle)
3. deplete NE, so LOWER BP

• accumulation of intracellar NE
• increase synaptic NE levels
• TREAT DEPRESSION
• ex: tranlycypromine

1. Amphetamine is a substrate for NET
2. goes into vesicle
3. kicks norepinepherine out of vessicle
4. NE goes to NET and released into post syn. R
5. sympathomimetic effects

• if you have too much tyramine intake in the diet, you end up sending it to CNS
• it will displace NE from vesicles
• NE gets released, you could have HTN crisis if patient is on MAOI
• sympathomimetic effects

Must avoid wines, cheese, beer, and fava beans

• blocks the NET (reduced reuptake)
• increase synaptic NE

cocaine

imipramine

atomoxetine

alpha 1

beta 1

• at low conc.
  • beta 1 and beta two
• at high conc.
  • it hits everything

• it is selective for increasing contractility without affecting rate

• alpha: epi more than NE
  • HOWEVER, they normally get NE because thats what is released from post syn. nerves
• beta 2: epi MUCH MORE than NE
• beta 1: epi = NE

Isopreteronol has higher affinity for beta receptors than the endogenous compounds

• maximum alpha nad beta activity conferred by 3,4 position alpha groups
• CNS penetration is increased by removal of hydroxyl group from the ring

• non-catecholamines are not metabolized by COMT
• sustitution of alpha carbon blocks MAO metabolism

• heart (via beta 1)
  • increase automaticity
  • increase HR
  • increase conduction velocity
  • increase CO
    • increase contractility
    • slight relaxation of bv's due to beta two stim. at therapeutic doses
  • increase oxygen consumption
  • decrease efficacy

• via beta 2 and alpha 1
• decrease at low doses (via beta 2)
• increases as doses increase and alpha 1 receptors become occupied
  • if alpha one and beta two occupied, alpha one predominates (at high doses, bp increases)

• beta 2 and alpha one
  • dilate bronchioles (beta 2)
    • most prominant when muscle contricted due to drugs/disease
  • secretion decrease (alpha one)

• increase glycogen breakdown (beta 2)
• decrease glycogen synthesis (alpha 1)
• decrease insulin secretion (alpha 2)
• increase free FA's (beta 3)

• anaphylactic shock
• asthma
• hypersensitivity reactions
• topical hemostasis
• cardiac arrest
• support bp (not first line, try dopamine first)

• arrhythmias
• CVA
• less serious, but predictable
  • anxiety
  • fear
  • headaches
  • palpitations
  • tremors

• heart- direct effects same as epi (beta 1)
• bp- increased systolic, diastolic, and mean (alpha 1)
• CO- no change or slightly decrease (alpha mediated constriction of bv's)
• metabolism- decrease glycogen synthase activity via alpha 1

• sometimes used in shock
• neurogenic shock assoicated with spinal anesthesia

• beta two opens airways
• beta two suppress release of histamine, leukotrines via inhibiting degranulation
• alpha one stimulate elevates bp

• heart direct effects same as epi (beta one)
• decrease bp (beta 2)
• resp. tract (beta 2)- relaxes bronchi

• stimulate heart in emergeency (ex: heart block, stimulating rate, prepare to insert pacemaker)
• relax bronchi (but prefer beta 2 agonist)

fatal arrhythmias

tachycardia

palpitation

anginal pain

• dopamine receptors activated first (then beta 1, 2, and alpha one at high doses)
• HR increase (beta one stim)
• bp decreased by dopamine receptor activation in renal and mesenteric beds
  • decrease bp by beta two receptor activation
  • increase at VERY HIGH doses by alpha one receptor activation

• excessive symp. stim.
  • tachycardia
  • anginal pain
  • arrhythmias
• DA receptor stimulation of chemotrigger zone (CTZ)
  • nausea
  • vomiting
• DA does NOT cross BBB, so no CNS effects

• heart
  • selective for beta 1 receptors
  • greater inotropic (contractility) than chronotropic (rate) effects
  • at high doses, increase automaticity
• bp- high doses increase bp via alpha 1

• heart failure associated with open heart surgery or acute MI

• arrhythmias
• dont cross BBB, so no CNS effects

• decong. mucous mem
• raise bp
• dilate pupil
• eye drops

• ephedrine- weak alpha and beta agonist, release NE, CNS stimulant used for decongestant and pressor agent
• phenylpropanolamine- OFF SHELVES due to CV incidents
• phenyephrine- decong., pupillary dilator

• bronchial asthma (beta 2 stimulation opens airways)
• anaphylactic shock (beta 2 stimulation inhibits release of mediators of allergic response from mast cells)
• relax pregnant uterus (beta 2)

• due to less than total selectivity of beta 2
• high doses can activate beta one receptors on heart

• ephedrine (weak beta agonist)- nasal decongestion, pressor agent
• albuterol and terbutaline (beta 2 selective agonist)- better than non selective beta agonist for asthma
• active enantiomer for albuterol, levalbuterol
• new formoterol (COPD)
• ritordrine (relatively beta 2 selective)- used to delay premature labor (can also use terbutaline)

• narcolepsy
• weight reduction
• ADHD

• amphetamine and methamphetaime
• mech.- release NE from nerve terminal by facilitated diffusion

• methylpenidate (widely prescribed as fast, slow release, or patch)
• lisdexamfetamine dimesymalte (prodrug form)
• atomoxetine (selective NE reuptake inh.)

• excessive CNS stim.
• prepipheral CV effects
• risk of abuse (except atomoxetine)

• dont bind beta receptors
• elevate cAMP
• competitve antagonists at adenosine receptors, leading to CNS stimulation

• CNS- coritcal areas sensitized
  • large doses sensitive resp. area to CO2, causing increase resp. rate
• CV
  • HR, contractility increased
  • systemic bv's dilated
  • TPR decreased
  • cerebral bv's constricted
• resp.- bronchi relaxed

• bronchial asthma
  • ex: theophyline in form of aminophylline treats intractable bronchial asthma
• prophylactic management
  • ex: theophylline used with inhaled beta 2 agonist to manage chronic bronchial asthma