Adrenergic Flashcards
Adrenergic Neurotransmission
- 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
Differentiation of Adrenergic Receptors
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
Actions of Adrenergic Receptor Stimulation
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
Adrenergic Receptor Mechanisms
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)
Termination of Adrenergic Transmitter Response
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.
Enzymatic Metabolism of Catecholamines
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
Types of Sympathomimetic Drugs
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)
Catecholamine Sympathomimetics
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.)
Direct-Acting Sympathomimetics
Beta-2 Agonists
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)
Direct-Acting Sympathomimetics
Beta-1 Agonists
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)
Direct-Acting Sympathomimetics
Beta-3 Agonist
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
Direct-Acting Sympathomimetics
Alpha-1 Agonists
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)
Direct-Acting Sympathomimetics
Alpha-2 Agonists
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
Indirect-Acting Sympathomimetics
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
Indirect-Acting Sympathomimetics
Stimulate Release
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
Indirect-Acting Sympathomimetics
Inhibit NE Reuptake
(NE Reuptake by Neuron is 70-80%)
1) *Cocaine (Also Inhibits *Dopamine Reuptake)
2) *Tricyclic Antidepressants
_Uses: Depression, Pain Syndromes.
Indirect-Acting Sympathomimetics
Inhibit Metabolism
*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.
Effects of NE, Epi, Iso on
Blood Pressure,
Pulse Rate,
Peripheral Resistance
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)
Denervation Supersensitivity
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.
Beta Antagonists
Beta Blockers
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
Effects of Propranolol in Hypertensive Patients
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
Alpha-1 Antagonists
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)
Drugs That Decrease NE @ Nerve Terminal
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
