3.2 - Sympathetic Drugs Flashcards
Biosynthesis of Catecholamines
- Location
- Steps
- Fate of NE in the cleft
- Drugs that interfere in the biosynthesis, storage, release and fate of Catecholamines
Catecholamines
- NE
- EPI
- Dopamine
Locations
- Sympathetic, post-ganglionic neurons — NE
- Adrenal Medulla — EPI
- CNS — Dopamine
Steps
Tyrosine ➡️1️⃣ L-DOPA ➡️2️⃣ Dopamine ➡️ vesicular transport via VMAT ➡️ formation of NE (DA ➡️3️⃣ NE) ➡️ formation of EPI (NE ➡️4️⃣ EPI)
REMEMBER ‼️
- Tyrosine — Precursor
* L-DOPA — L-dihydroxyphenylalanine)
Prevent premature metabolism by pre-synaptic enzymes
VMAT
– Vesicular Monoamine Transporter
1️⃣
Tyrosine Hydroxylase
— rate-limiting step
2️⃣
L-DOPA decarboxylase
3️⃣
Dopamine-B-hydroxylase
4️⃣
Phenylethanolamine-N-methyltransferase
Fate of NE in the cleft
- Binding to post-synaptic ®
- Metabolism by MAO & COMT
- Reuptake Process
– Major mechanism of excess NE in the cleft (loss)
– Transporter:
— NET (NE Transporter/ Uptake-1 Transporter
Reuptake Process
Drugs that Interfere in the Biosynthesis, Storage, Release and Fate of Catecholamines
- Formation of L-Dopa
- Vesicular Transport via VMAT
- Release of NE
- Reuptake Process
Formation of L-DOPA: INHIBITOR
Metyrosine
— Inhibits tyrosine hudroxylase
Vesicular transport via VMAT: INHIBITOR
Reserpine
Release of NE (exocytosis): STIMULATORS
— TEAAA
- Tyramine
- Ephedrine
- Amphetamine
- Angiotensin II
- a-latrotoxin
Release of NE (expcytosis): INHIBITORS
- Guanethidine
- Guanabenz
- Bretylium
Reuptake Process: INHIBITORS
• TCAs - Inhibits reuotake of NE > 5-HT • Cocaine - Vasoconstriction • NERI (Reboxitine)
Receptors
- Alpha
- Beta
- Dopamine
Alpha
- Alpha 1
* Alpha 2
Alpha 1 Receptors
– Gq linked — CONTRACTION
— Locations & Effects
Alpha 1: Locations & Effects
- Vascular SM
- Bladder Trigone & Sphincter
- Prostatic SM
- Radial Muscle of the 👀
- Pilomotor SM
Vascular SM
Vasoconstriction
— ⬆️ BP
Bladder Trigone & Sphincter
Contraction
— Urinary Retention
Prostatic SM
Contraction
— URinary Retention
Radial Muscle of the 👀
Contraction
— MYDRIASIS
Pilomotor SM
Piloerection
— Goosebumps
Alpha 2 Receptors
- Pre-synaptic a2
* Post-synaptic a2
Pre-synaptic a2
– Gi-linked— ⬇️ CAMP
— Location
— Effect
— Consequencs
Location
Vasomotor Center (Brain) — momentary regulation of BP
Effect
Autoregulation
— stimulation will INHIBIT further release of NE
Consequences
- Central
* Peripheral
Central
Sedation & Depression
Peripheral
Vasodilation
Post-synaptic a2
– Gq-linked — CONTRACTION
— Location
— Effects
Location
Peripheral Blood Vessels
Effect
VasoCONSTRICTION
Beta
– Gs-linked — ⬆️cAMP
- Beta 1
- Beta 2
- Beta 3
Beta 1 Receptors
• Locations & Effects
Heart
- (+) Inotropy — force
- (+) Chronotropy — rate
- (+) Dromotropy — conduction velocity
Kidneys (Juxtaglomerular Apparatus)
Release of the enzyme renin = HTN
Beta 2 Receptors
• Locations & Effects
Locations
- Bronchial SM
- Uterine SM
- Vascular SM
- Skeletal Muscle Cell Membrane
- Neuromuscular End Plates
Bronchial SM
Bronchodilation
Uterine SM
Uterine Relaxation (Tocolysis)
Vascular SM
- Blood vessels that supply skeletal muscles
VasoDILATION
Skeletal Muscle Cell Membrane
⬆️ inward conductance of K ions = HYPOkalemia
Neuromuscular End Plates
Contraction (Tremors)
Beta 3 Receptors
• Location
- Adipose Tissues
• Effect
- LIPOLYSIS
Dopamine
– Gs-linked
- D1 Receptors
* D2 Receptors
D1 Receptors
- Location
* Effect
Renal & Splanchic Blood Vessels
Renal Vasodilation = ⬆️ GFR = ⬆️ diuresis
D2 Receptors
- Peripheral GIT
* CNS
Peripheral GIT
Loss of Peristalsis (Ileus)
— Relaxation
** Antagonist: Metoclopramide
CNS
- Modulates motor activity
* Perception & behavior
Sympathomimetics
— aka Adrenergic Agonists
- Direct-acting
- Indirect-acting
- Centrally-acting
Direct-acting Sympathomimetics
– directly binds & stimulates adrenergic receptors
- Non-selective
* Selective
Non-selective
Directly bind & activate MORE THAN 1 general type of adrenergic receptors (a, B, DA)
Examples:
- Natural catecholamines
- NE
- EPI
- DA
Pharmacodynamics
⬆️ affinity at B receptors than A receptors
• Low Dose: B effect
• Hugh Dose: A effect
Pharmacodynamics
Specific:
• NE: B1 ➡️ A1
• EPI: B2 = B1 ➡️ A1 (anaphylaxis)
• DA: D1 ➡️ B1 ➡️ A1
Pharmacokinetics
- ✖️oral preparations available
* Undergo extensive first pass effect
Route of Administration
- IV
- SQ
- Inhalational
Metabolism (MAO, COMT)
- NE & EPI
* Dopamine
NE & EPI
- 3-methoxy-4-hydroxymandelic acid
* Vanillyl mandelic acid (VMA)
Dopamine
Homovanillic acid
Clinical Uses
- Epinephrine/ Adrenaline
- Norepinephrine/ Noradrenaline/ Levarterenol
- Dopamine
– 1st line: Cardiac stimulant
– 1st line: Mgt of Anaphylaxis
– Local Vasoconstrictor
– Mgt of Glaucoma
Epinephrine/ Adrenaline
Pivalic acid ester of EPI
Dipivefrin
– 1st line: Inotropic agent for SEPTIC shock
– IV infusion
Norepinephrine/ Noradrenaline/Levarterenol
Dopamine
- Effects
* Uses
1-3 ug/kg/min
D1 activation — Renal vasodilation
= ⬆️GFR = ⬆️ diuresis
2-5 ug/ kg/ min
B1 activation — ➕ I, C, D
> 5 ug/ kg/ min
A1 activation — Vasoconstriction
– Mgt of Septic shock
– Mgt of Cardiogenic shock
– Mgt of Acute ❤️ Failure complicated by oliguria & anuria
Dopamine
Oliguria
< 500 ml/ day
Anuria
< 50 ml/ day
Side Effects: Non-selective
- A1 overstimulation
* B1 overstimulation
A1 overstimulation
Digital necrosis
B1 overstimulation
Tachyarrhythmias
Selective
Directly bind and stimulate 1 general type of adrenergic receptors
Selective
- Non-selective B agonists
- Selective B1 agonists
- Selective B2 agonists
- Selective A1 agonists
- Sleective A2 agonists
- Selective D1 agonist
Non-selective B agonists
- Isoproterenol
- Isoprenaline
– Uses
– Hx. Use
Uses
- Alt. during shock states
* Mgt of ❤️ Failure (acute)
Hx. Use
• Mgt of Brochial Asthma
— May cause TACHYPHYLAXIS (rapid dev’t of tolerance to B2 = Tachyarrhythmias)
Selective B1 Agonist
Dobutamine
– 1st line: Mgt of CARDIOGENIC shock
– Pharmacologic Stress Test
Dobutamine
Selective B2 agonists
- SABA
- LABA
- Tocolytics
SABA
– Short Acting B2 Agonists
- Salbutamol/ Albuterol
- Terbutaline — SQ
- Pirbuterol
- Metaproterenol
LABA
– Long Acting B2 Agonists
- Salmoterol — Slow onset
- Formoterol — Fast onset
- Bambuterol — PO
- Indacaterol — COPD
Tocolytics
- Ritodrine
- Isoxsuprine
- Terbutaline
– Mgt of preterm labor
– Mgt of bronchial asthma and COPD
– Adjuncts in the mgt of hyperkalemia
Tocolytics
Mgt of symptomatic bradycardia
Terbutaline
Selective A1 Agonists
- Phenylephrine
- Methoxamine
- Propyhexedrine
- Tetrahydrozoline
- Oxymetazoline
- Nafazoline
Uses:
- Nasal decongestants
- Mgt of HYPOtension
- Local Vasoconstrictors
S/E:
- Intranadal
* Systemis
Intranasal
Rhinitis Medicamentosa
— rebound congestion
** given for NMT 3 days only
Systemic
• Exacerbation of HTN
• Precipitation if Urinary Retention in BPH pts
• Rapid development of Tolerance
** use for NMT 5 days
Selective A2 agonists
- Clonidine
- Methyldopa
- Guanficine
- Guanabenz
Effects:
- Pre-synaptic
* Post-synaptic
Pre-synaptic:
– AUTOREGULATION
- Central: Sedation& Depression
* Peripheral: Vasodilation
Post-synaptic
VasoCONSTRICTION
Effects: Clonidine
- Initial: Vasoconstriction
* Final: Vasodilation
Uses: Clonidine
• Alt. Mgt of HTN • Alt. Mgt of ADHD • Mgt of Clonidine withdrawal-induced HTN (rebound HTN) ** Alt: Labetalol Captopril
Methydopa
— Prodrug
Methyldopa (a-methyldopa) ➡️1️⃣ a-methyldopamine ➡️2️⃣ a-methylnorepinephrine
1️⃣
L-dopa decarboxylase
2️⃣
Dopamine-B-hydroxylase
– False neurotransmitter
– ✖️ B1 & A1 agonist
– ✔️ A2 agonist
a- methylnorepinephrine
Use: Methyldopa
• Mgt of HTN in pregnancy
— FDA Approved
S/E: Methyldopa
- Sedation — most common
- Hepatotoxicity (> 2g/ day) — dose dependent
- ➕ Coomb’s Test — Hemolytic Anemia
Selective D1 Agonist
Fenoldopam
Use: Fenoldopam
Mgt of HTN Crisis (Alt)
Indirect-acting Sympathomimetics
- Releasers
* Reuptake Inhibitors
Releasers
— ⬆️ release of NE
- Tyramine
- Ephedrine
- Amphetamine
– Ma Huang
– Dual Mechanisms:
- ⬆️ release of NE; Direct Action = ⬆️ Sympathetic Effect
Ephedrine
Uses: Ephedrine
- Nasal Decongestant
- Mgt of HYPOtension
- Mgt of Bronchial Asthma (Chinese Med)
S/E: Ephedrine
- Exacerbation of HTN
- Urinary retention (BPH pts)
- Tachyarrhythmias
Reuptake Inhibitors
• TCAs - Inhibit reuptake of NE and 5-HT • Cocaine - Vasoconstriction • NERI (Reboxitine)
Centrally-acting Sympathomimetics
- Phenylpropanolamine (PPA)
- Phentermine
- Phenmetrazine
- Amphetamine
- Methylphenidate
Uses: Centrally-acting Sympathomimetics
- Mgt of ADHD
- Anorexiants
- Mgt of Narcolepsy
1st line: Mgt of ADHD
Methylphenidate
Anorexiants
- PPA
- Phentermine
- Phenmetrazine
Mgt of Narcolepsy
- Amphetamine
* Phentermine
S/E: Centrally-acting Sympathomimetics
- ⬆️ risk if addiction
- ⬆️ risk of hemorrhagic shock
- ⬆️ risk of pulmonary HTN
⬆️ risk of hemorrhagic shock
PPA
⬆️ risk of pulmonary HTN
Phentermine
Sympatholytics
— aka Adrenergic Antagonists
- Alpha Blockers
* Beta Blockers
Alpha Blockers
- Non-selective
- A1-selective
- A2-selective
Non-selective
• Phenoxybenzamine
— irreversible
• Phentolamine
— reversible
A1-selective
— -zosin
- Prazosin
- Doxazosin
- Terazosin
- Alfuzosin
- Tamsulosin
A2-selective
- Yohimbine
* Rauwolscine
Clinical uses: Alpha Blockers
- Mgt of Pheocytochroma
- Mgt of Reynaud’s Syndrome
- Mgt of HTN & Urinary Retention in BPH pts
- Mgt of Erectile Dysfunction
- Ngt of Carxinoid Syndrome
Pheocytochroma
– Tumor in adrenal medulla
– S/Sx:
- HTN, Tachycardia, Palpitations
Tx for Pheocytochroma
- alpha blockers
* beta blockers
Raynaud’s Syndrome
Digital vasospasm due to extreme cold/ stress
Tx for Reynaud’s Syndrome
- alpha blockers — Phentolamine
* CCBs — DHP
Mgt of HTB & Urinary Retention in BPH pts
Alpha 1 blocker —‼️First Dose Phenomenon ‼️"First fall" - Remedies: - Take at bedtime - Start at lower dose
Mgt of Erectile Dysfunction
Phentolamine
Carcinoid Syndrome
Malignancy in the enterochromaffin cells (SI)
— > 90% of 5-HT
S/Sx: Carcinoid Syndrome
– Flushing
– Severe HA
– Watey diarrhea
Tx for Carcinoid Syndrome
Phenoxybenzamine
– Anti-Serotonorgic
Beta blockers
- Non-selective
- B1-selective/ cardioselective
- B blockers with ISA
- B blockers with Membrane Stabilizing Effect
- B blockers with a1 blocking effect
Nonselective
— N S T P
— C/I: Asthmatic pts
- Nadolol
- Sotalol
- Timolol
- Propranolol
B1 selective/ Cardioselective
— C B E A M
- Celiprolol
- Betaxolol
- Bisoprolol
- Esmolol
- Acebutolol
- Atenolol
- Metoprolol
B blockers with Intrinsic Sympathomimetic Activity (ISA)
— C L A P
— Lesser risk of rebound HTN
- Celiprolol
- Carteolol
- Labetalol
- Acebutolol
- Pindolol
- Penbutolol
B blockers with Membrane Stabilizing Effect
— ✔️ local anesthetic effect
— ✖️prepared as ophthalmic drops (corneal damage)
— P A L M
- Propranolol
- Pindolol
- Acebutolol
- Labetalol
- Metoprolol
B blockers witg a1 bocking effect
— ✔️vasodilatory effect
— L C
- Labetalol
* Carvedilol
– B1 blocker
– ✔️vasodilatory effect = ⬆️ levels of nitric oxide — endogenous vasodilator
Nebivolol
Clinical Uses: Beta Blockers
- 1st line: Mgt of HTN in pts with history of post MI
- Mgt: CSAP
- Mgt: Stable HF
- Mgt: Arrhythmia
- Mgt: Glaucoma
- Mgt: Sympathetic sx of hyperthyroidism
- Prophylaxis: Migraine HA
- Mgt: Stage fright
Mgt of Stable HF
- Bisoprolol
- Metoprolol
- Carvedilol
Mgt of Arrhythmia
• Class II
- Penbutolol
- Esmolol
- Acebutolol
Mgt of Glaucoma
- Betaxolol
* Timolol
Mgt of Sympathetic sx of hyperthyroidism
Propranolol
— inhibits peripheral conversion of T4 to T3
Prophylaxis of Migraine HA
Propranolol
Mgt of Stage fright
Propranolol
S/E: Beta Blockers
- Bradycardia
* Mask hypoglycemic sx
C/I: Beta Blockers
- Pts > 65 y/o
- Pts with HR < 60 bpm
- Pts with unstable HF
- Pts with pre-existing ❤️ block
- Concomittant administration with Non-DHP CCB (cardioselective)
- Pts with reduced exercise tolerance
Alt. Mgt of ADHD
Amphetamine