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Pharm 2015 > Adrenergic > Flashcards

Adrenergic Flashcards

1
Q

Adrenergic Neurotransmission

A
  • Synthesis of Catecholamine NTs:
    1) *Tyrosine (amino acid) Enters Neuron via Active Transport.

2) => Rate-Limiting Step
@ Cytosol, *Tyrosine Hydroxylase Converts Tyrosine to DOPA

3) *DOPA Decarboxylase Converts DOPA into *Dopamine (DA).
4) DA is Actively Transported into Storage Vesicles.

5) DA is Converted to *Norepinephrine (NE) by Dopamine-Beta-Hydroxylase.
(This is the End Product in Sympathetic Nerve Terminals.)

6) @ *Adrenal Medulla: *NE is Converted to Epinephrine (Epi) by PNMT
* Storage of Norepinephrine:

Norepinephrine is Stored in *Vesicles that are bound to ATP @ End of Nerve Terminals.
_Vesicles are “Leaky.” NE must be pumped back in.
_NE is in Equilibrium with Cytosolic (Extragranular) (Extravesicular) NE.
(Most of NE is in Vesicles.)

  • Release of Transmitter and Autoregulation:
    1) Arrival of Action Potential @ Sympathetic Neuron causes Depolarization.

2) *NE is *Released from the Storage Vesicles via *Exocytosis.

3) *Feedback Mechanisms using *Autoreceptors Regulate NE Release.
_NE can Activate *Presynaptic *Alpha-2 Adrenergic Receptor to Inhibit Further Transmitter Release.

Note:
Tyrosine = Hydroxyphenylalanine

DOPA = Dihydroxyphenylalanine

PNMT = Phenylethanolamine N-methyltransferase

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2
Q

Differentiation of Adrenergic Receptors

A

Isoproterenol (Iso):
(Almost Exclusively a Beta Agonist)
_Very Little Alpha Stimulation.
_Very Good Beta Stimulation.

Epinephrine:
_Stimulates Alpha and Beta

Norepinephrine:
_Mostly an Alpha Agonist

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Alpha-1:
_Generally Post-Synaptic,
_Excitatory: @ Smooth Muscle
_ Epi Greater than or Equal to NE.
_Iso Very Little
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Alpha-2:
_Generally Pre-Synaptic,
_Inhibitory: @ Nerve Terminals, CNS
_NE Greater than Epi
_Iso Very Little
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Beta-1:
_Generally Post-Synaptic,
_Excitatory: @ Heart, Kidney
_Iso Greater than Epi
_Epi Greater than or equal to NE
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Beta-2:
_Generally Post-Synaptic,
_Inhibitory: @ Smooth Muscle
_Iso Greater than or equal to Epi
_Epi Much Greater than NE
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Beta-3:
_Generally Post-Synaptic,
_Excitatory: @ Fat Cells
=> Promote Lipolysis
_Iso equal to Epi
_Epi Greater than NE
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3
Q

Actions of Adrenergic Receptor Stimulation

A

Alpha-1:
_Generally Post-Synaptic,
_Excitatory: @ Smooth Muscle
1) Radial Muscle Contraction: Dilation of Iris (Mydriasis)
2) GI and Bladder Sphincters Contraction
3) Vasoconstriction @ Skin and Splanchnic Vessels
4) Apocrine (Stress) Sweat Glands:
(@ Palms, Soles, Axilla)
5) Pilomotor Smooth Muscle
(hair standing on end)

________________
Alpha-2:
_Generally Pre-Synaptic,
_Inhibitory: @ Nerve Terminals, CNS

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Beta-1:
_Generally Post-Synaptic,
_Excitatory: @ Heart, Kidney
1) Increase Contractility 
(Positive Ionotropic)
2) Increase Heart Rate
(Positive Chronotropic) 
(@ SA Node)
3) Increase Kidney Renin Secretion
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Beta-2:
_Generally Post-Synaptic,
_Inhibitory: @ Smooth Muscle
1) (Far Vision) Relaxation of Ciliary Muscle (Accommodation)
2) Bronchodilation
3) Vasodilation @ Vessels in Skeletal Muscle
(Drops Blood Pressure)
4) Relaxation of GI Walls
(Decreases GI Motility)
5) Relaxation of Bladder Wall
6) Relaxation of Uterine Wall 
7) (Gluconeogenesis in Liver)
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Beta-3:
_Generally Post-Synaptic,
_Excitatory: @ Fat Cells
1) Promote Lipolysis
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4
Q

Adrenergic Receptor Mechanisms

A

Alpha-1: *Gq Receptor
_Activates Phospholipase C (PLC), which cleaves PIP2 into
*DAG and *IP3 (Second Messengers).

(DAG activates Protein Kinase C, PKC.)
(IP3 causes Increase of Cytosolic Ca2+ from ER.)

Alpha-2: Gi (Inhibitory) Receptor
_Inhibitory!
_Reduces Levels of *cAMP.

All Beta: Gs Receptor
_Activate Gs
_Increase *cAMP Levels (Gs converts ATP to cAMP)

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5
Q

Termination of Adrenergic Transmitter Response

A

1) *Reuptake into NE Neuron:
_(70-80%)
_Most Important Mechanism

2) *Active Transport into Effector Cells:
_(10-20%)

3) *Passage into Circulation and *Enzymatic Destruction by *MAO and *COMT.

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6
Q

Enzymatic Metabolism of Catecholamines

A

MAO (Monoamine Oxidase):

Location in Cell:
_@ Mitochondrial outer membrane

Location in Body:

1) *MAOa: @ *Peripheral *Sympathetic Nerve
2) *MAOb: @ *Brain

Effect of Inhibition on NT Levels:
1) MAOa Inhibition: 
_Increased NE Level @ Sympathetic Neuron
2) MAOb Inhibition:
_Increased DA Level @ Brain
(Therapeutic in Parkinson's)

_____________
COMT:
(Catechol-O-methyl transferase)

Location in Cell:
_ @ Cytosol

Location in Body:
_ @ Effector Tissues
(Not in Sympathetic nerves)

Effect of Inhibition on NT Levels:

1) No Effect on Peripheral NE
2) Increases DA @ Brain

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7
Q

Types of Sympathomimetic Drugs

A

Direct-Acting:
_Bind to Alpha and/or Beta Receptors and Activate them Directly.
(e.g. Epi, NE)

Indirect-Acting:
_Release NE from Sympathetic Nerve Terminals
(e.g. Tyramine, Amphetamine)

Mixed Acting:
_Have both direct and indirect activity
(e.g. Ephedrine)

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8
Q

Catecholamine Sympathomimetics

A

Norepinephrine (Noradrenaline):
@ *Alpha

e.g. Levophed: no longer used; was used to treat shock by Vasoconstriction, but also Constricted Renal Vessels, causing Renal Failure by Kidney Shock.

______________
Epinephrine (Adrenaline):
@ *Alpha, *Beta-1, *Beta-2

1) DOC: *Acute Hypersensitivity Reactions
(e.g. *Anaphylactic Shock)
Via injection primarily.
(Beta1: Stimulate Heart,
Beta2: Bronchodilation,
Alpha1: Vasoconstriction to Elevate Blood Pressure)
(Note: High Doses of Epi, or Epi given to a Hypotensive person will cause greater Alpha

2) *Heart Block and Cardiac Arrest (Emergency Use)

3) *Vasoconstrictor in *Local Anesthetic Preps
(e.g. Novocaine)
(Alpha1 Vasoconstriction)
(Keeps the anesthetic localized for longer, preventing systemic toxicity)

______________
Dopamine:
(precursor of NE and Epi)
@ Alpha-1, Beta-1, DA

*Important Drug for Shock:
_Maintains Renal Blood Flow!
_While Stimulating Heart and Vasoconstriction.

(DA treats shock while protecting Kidney;
NE treats shock while shocking Kidney.)
(D1 Receptor: Renal Arterial Dilation)

______________
Isoproterenol:
@ *All Beta Receptors
(Non-selective Beta Agonist)

_Used to be used to treat Asthma via Bronchodilation, but had Adverse Effects: Stimulation of Heart: Arrhythmias and Heart Attacks at young age.

(It has helped us Distinguish Alpha from Beta Receptors.)

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9
Q

Direct-Acting Sympathomimetics

Beta-2 Agonists

A

Direct-Acting Sympathomimetics

  • *Major Drugs in Class:
    1) *Albuterol (Ventolin)
    2) *Salmeterol (Serevent, in Advair),
    3) *Ritodrine (Yutopar)

Therapeutics:
1) Asthma (Bronchodilation)
2) Premature Labor
(Uterine Relaxation)

Adverse Effects:
1) *Tremors 
(*Beta-2 @ Skeletal Muscle)
2) *Cardiac Stimulation 
(*Beta-1)
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10
Q

Direct-Acting Sympathomimetics

Beta-1 Agonists

A

Direct-Acting Sympathomimetics

Dobutamine (Prototype Drug)

Therapeutics:

1) *Cardiovascular Effects
2) Cardiac Decompensation,
* Acute CHF (Beta-1, Alpha-1)

Adverse Effect (Same Mechs):

1) *Arrhythmia (Beta-1)
2) *Hypertension (Alpha-1)

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11
Q

Direct-Acting Sympathomimetics

Beta-3 Agonist

A

Mirabegron (Myrbetriq)

Option if Muscarinic Blockers don’t work or can’t tolerate side effects.

Use:
1) Treat Overactive Bladder
(Beta-3: Relaxes Smooth Muscle @ Bladder)

Adverse Effects:
1) Mild Cardiovascular Stimulation (Beta-1)

Most Beta-3 mediate Metabolic effects: Lipolysis @ Adipose tissue

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12
Q

Direct-Acting Sympathomimetics

Alpha-1 Agonists

A

1) *Phenylephrine (NeoSynephrine)
2) *Oxymetazoline (Afrin)
3) *Pseudoephedrine (Sudafed)

Therapeutics:

1) *Nasal Decongestant
2) *Pressor (Increase BP)

Adverse Effects:
1) *Hypertension with *Reflex Bradycardia
(Reflex via baroreceptors in Carotid Sinus and Aortic Arch)

2) *Rebound Congestion
(rhinitis medicamentosa)

3) *Urinary Retention
(Urinary Sphincter Contraction)
(esp. Middle-aged/Older Males or if have enlarged prostate)

4) * CNS Stimulation:
e. g. *Insomnia

(Vasoconstriction in Nasal Mucosa, decreasing blood flow, which decreases leakage of fluids into tissues)

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13
Q

Direct-Acting Sympathomimetics

Alpha-2 Agonists

A

1) *Clonidine (Catapres)
2) *Tizanidine (Zanaflex)

Therapeutics:
1) *Hypertension
(Acts centrally in Medulla of Brainstem to inhibit Sympathetics there)

2) *Glaucoma
(Reduces Formation of Aqueous humor, reducing intraocular pressure)

3) *Spasticity due to Neuropathy
(e.g. Cerebral Palsy)
(Acts in Spinal cord to reduce firing to motor neurons there)

4) *ADHD
(Not first-line. Aren’t as effective as Central Stimulants.)

Adverse Effects:

1) *Sedation
2) *Muscle Weakness
3) **Rebound Hypertension
4) Inability to Ejaculate

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14
Q

Indirect-Acting Sympathomimetics

A

Mechanisms:

1) Stimulate Release:
* Amphetamine, *Methamphetamine
* Ephedrine
* Tyramine (in *Foods)

2) Inhibit Reuptake:
* Cocaine
* Tricyclic Antidepressants

3) Inhibit Metabolism:
MAO Inhibitors
_Selegilline Type B
*COMT Inhibitors

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15
Q

Indirect-Acting Sympathomimetics

Stimulate Release

A

Note:
***Interaction of These with MAO Inhibitors can cause Hypertensive Crisis!!!

*Tolerance Development: Tachyphylaxis
= Rapid Tolerance with Repeated administration of drug
_Due to Depletion of NE and Rapid Desensitivity of the Receptors on the postsynaptic/effector cell.

________________

  • Amphetamine,
  • Methamphetamine (Greater CNS Activity)

Therapeutics:

1) *Narcolepsy
2) *ADHD

Adverse Effects:

1) *Cardiovascular: Hypertension, Tachycardia
2) *Tremor
3) *Convulsions
4) *Dependence (chronic use)
5) *Psychosis (chronic use)

Tolerance Development: Tachyphylaxis

________________
*Ephedrine:

*Mixed Action:
_Direct Action @ Alpha and Beta
_AND Indirect Action to Release NE
_Similar to Amphetamines, but milder.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
*Tyramine:
_*Found in Food
(e.g. beer, brewer's yeast, red wine, aged cheeses, smoked or pickled fish, fermented sausage such as pepperoni and salami)
_Not a pharm drug
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16
Q

Indirect-Acting Sympathomimetics

Inhibit NE Reuptake

A

(NE Reuptake by Neuron is 70-80%)

1) *Cocaine (Also Inhibits *Dopamine Reuptake)

2) *Tricyclic Antidepressants
_Uses: Depression, Pain Syndromes.

17
Q

Indirect-Acting Sympathomimetics

Inhibit Metabolism

A

*MAO Inhibitors:
1) *Selegiline:
*Inhibits MAO-b.
Increases DA in Brain.

Uses:
_Depression (isozyme A)
_Parkinson’s (isozyme B)

*COMT Inhibitors:
Uses: Parkinson’s
Increases DA in Brain.

18
Q

Effects of NE, Epi, Iso on

Blood Pressure,
Pulse Rate,
Peripheral Resistance

A 
BP = CO x TPR
CO = SV x HR
CO = Cardiac Output
SV = Stroke Volume
TPR = Total Peripheral Arterial Resistance
Norepinephrine: Alpha mostly
1) Peripheral Vasoconstriction
=> Increases Peripheral Resistance
=> Increases Blood Pressure
=> Increases MAP
(Mean Arterial Pressure)
2) Results in Reflex Bradycardia (Baroreflex)
Isoproterenol: 
1) Beta-2 Vasodilation
(particularly @ Skeletal muscle bed, which is a very large vascular bed)
=> Decreases Peripheral Resistance (Markedly)
=> Decreases Diastolic BP
=> Decreases MAP 
(Mean Arterial Pressure)
2) Beta-1 Cardiac Stimulation
=> Increases Heart Rate
=> Increases Cardiac Output
=> Initial Increase in Systolic BP (transient)
3) => Overall Decreases in BP
Epinephrine:
1) Beta-2 Vasodilation (Skeletal muscle bed is large vascular bed)
=> Decreases Peripheral Resistance
=> Decreases Diastolic BP
2) Beta-1 Cardiac Stimulation
=> Increases Heart Rate
=> Increases Cardiac Output
=> Increases Systolic BP
3) Overall No change in MAP
(Mean Arterial Pressure)
19
Q

Denervation Supersensitivity

A

e.g. *Post-Ganglionic Horner’s Syndrome

Diagnostic use to determine if Horner’s is Pre-Ganglionic or Post-Ganglionic.

1) **Indirect-Acting Agents:
=> Effects will be **Reduced (or absent)

2) **Direct-Acting Agents:
=> Effects will be **Enhanced

No Drug:
1) Affected Eye: 
=> Constricted Pupil
2) Normal Eye:
=> Normal
Indirect-Acting Drug:
1) Affected Eye:
=> No Effect
2) Normal Eye:
=> Dilated Pupil
Direct-Acting Drug:
1) Affected Eye:
=> SUPER Dilated Pupil
2) Normal Eye:
=> Dilated Pupil

Mechanism:
1) Damaged Pre-Ganglionic neuron stops making NT, so Nerve Endings become Depleted of NE.

2) Post-Ganglionic Receptors become Super-Sensitive.
3) Constricted Pupil results because now Parasympathetic predominates due to Loss of Sympathetic action.

20
Q

Beta Antagonists

Beta Blockers

A

1) *Propranolol (Non-Selective) (prototype)
2) *Metoprolol (Beta-1 Selective)
3) *Atenolol (Beta-1 Selective)

Therapeutics:
1) Hypertension (Chronic)
_Less Effective in Black patients
_First-line for uncomplicated Essential Hypertension

2) Arrhythmia (Metoprolol)

3) Angina (Atenolol)
_*Pindolol (non-selective, partial agonist): Less Rebound Angina upon abrupt cessation of treatment

4) *CHF (Chronic, Stable type)
5) *Post-MI

6) Tremor of Peripheral origin
(Blocks Beta-2 @ Skeletal Muscle)
(Propranolol most frequently used)

7) Glaucoma (Timolol, non-selective)
(Reduce Aqueous Humor Formation)

8) *Migraine Prophylaxis (Propranolol)

9) Hyperthyroidism:
(Propranolol)
_Blocks the associated Arrhythmias due to Beta Receptor Supersensitivity

Adverse Effects:
1) *Bronchoconstriction 
(Beta-2 Blockage)
(Propranolol)
_*Asthma Patients: 
Prefer Beta-1 Selective agent

2) Hypoglycemia
(Compensatory hyperglycemic effect of Epinephrine in insulin-induced Hypoglycemia is Blocked by Beta-2 Blockage @ Liver
_Sweating is the Only symptom of Hypoglycemia that Remains.
(Lose symptoms of tremor, palpitations)
_Beta-1 Selective agents preferred in Diabetic patients.)

3) Nightmares/Sleep Disturbances, Fatigue, Sedation
_Propranolol has High Lipid Solubility. Atenolol has less.

4) Contraindicated in Unstable/Decompensated CHF or Acute CHF
_Will exacerbate it

21
Q

Effects of Propranolol in Hypertensive Patients

A

Mechanism Unclear.

*Decreases Renin Release.
(Beta-1 Blockage)

CNS Effects or Peripheral Effects to Decrease Sympathetic Tone.
_Less Effective in Black Patients.

Decreased Peripheral Resistance

Decreased Cardiac Output

Result: Long-term Decrease in BP

22
Q

Alpha-1 Antagonists

A

1) *Prazosin (Prototype)
2) *Tamsulosin (Selective Alpha-1)
3) *Labetalol

Therapeutics:
1) Chronic Hypertension
(Prazosin) (p.o.)
(emergency: inj.)

2) Benign Prostatic Hypertrophy (BPH):
(Tamsulosin)
_Relax Urinary Sphincter, Promote Urine Flow

Adverse Effects:
1) *Postural Hypotension
(Very Marked)
_Due to Blockage of Reflex Vasoconstriction

2) *Reflex Tachycardia

3) Impaired Ejaculation
(More of an issue in Middle-aged men)

4) Nasal Stuffiness
_Due to Dilation of Nasal Mucosal Vessels)

23
Q

Drugs That Decrease NE @ Nerve Terminal

A

1) *Direct Inhibition of NE Synthesis

2) Inhibition of Intra-Neuronal Storage of Catecholamines:
_Reserpine: Inhibits Transport of NE from Cytosol to Vesicle. Leads to Gradual Depletion of NE (and 5-HT) Stores.
_Antihypertensive, but little use now.
Major side effects: lethargy, diarrhea, depression (very long lasting)

3) *Prevention of Normal Transmitter Release

Pharm 2015 (22 decks)

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