Adrebergic System Flashcards
Possibilities to influence the adrenergic system
Presynaptic stimulation
Postsynaptic stimulation
= sympathomimetics
Presynaptic inhibition
Poststnaptic inhibition
= sympatholytics
Presynaptic stimulation
- synthesis:
- precursor substance = levodopa - release:
- depolarization = 4-aminopyridine/fampiridin
K+ channel blocker
- increased ca2+ concentration
- latrotoxin - explosive release of NE - Presynaptic receptors
- activation of presynaptic stimulatory b2 receptors
- inhibition of presynaptic inhibitory a2 receptors (yohimbine, mianserine)
- activation of presynaptic stimulatory hereroreceptors (AT1) - Indirectly acting sympathomimetics
- thyramine, ephedrine, ampthanine, they promote transmitter release - Reuptake inhibitors
- cocaine, tricyclic antidepressants (amitryptyline, desipramine) - MAO inhibitors
- tranylcypromine, selegiline, moclobemid
Postsynaptic stimulation groups
Direct acting sympathomimetics
- catecholamines
- b1 receptor agonist
- b2 receptor agonist
- a1 receptor agonist
Indirectly acting sympathomimetics
- tyramine
- ephedrine
- amphetamine
Catecholamines
Direct acting sympathomimetics
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Epinephrine/adrenaline
Norepinephrine/noradrenaline
Isoprenaline
Dopamine
Dobutamine and dopexanine
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Epinephrine/adrenaline
Direct acting sympathomimetics
- activate all adrenergic receptors
- vasodilation = b2
- vasoconstriction = a1
— determined by receptor distribution (MAP IS NOT CHANGED)
- positive inotropic and chromotropic actions on the heart
- bronchodilation
- indication; anaphylactic shock, emergency heart block and cardiac arrest, asthmatic state, inhaled E for croup/subglottic laryngitis, reduction of regional blood flows
Norepinephrine/noradrenaline
Direct acting sympathomimetics
- activates a and b1 receptors, but little effect on b2
- vasoconstriction and increased BP
- Compensatory vagal reflexes can overcome its direct positive chronitropic effect on heart
- indication: neurogenic shock, septic shock, cardiogeic shock and locally to reduce blood flow
Isoprenaline
Direct acting sympathomimetics
- potent and selective b receptor agonist
- positive inotropic and chronitropic action on heart
- vasodilation, decreased diastolic pressure, and decreased MAP
- bronchodilation
- indication: bradycardia and AV blocks
Dopamine
Direct acting sympathomimetics
- low dose: d1 receptor
- medium dose: b1 receptor
- high dose: a receptor (act as e)
Indication: cardiogenic shock (low to medium dose).
Adverse effects: tachycardia, tolerance, - bad pharmacokinetics
Selective b1 receptor agonist
Dopamine in medium dose
Dobutamine
Ibopamine
Prenalterol
Indication: cardiogenic shock, limited use in CHF
Adverse effects: tachycardia
Peripheral D receptor agonists
- Dopamine in low dose: dilation of mesenteric and renal blood vessels
- fenoldopam: peripheral vasodilation in mesenteric vascular bed, for severe hypertension
- dopexamine: D, B2, (b1) agonist, reuptake inhibitor
Selective b2 receptor agonist
Main action and indication
- bronchodilation (COPD, asthma)
—SABA; salbutamol, terbutaline, fenoterol, levosalbutamol
—LABA; salmeterol, formoterol, clenbuterol, bambuterol, procaterol, indacaterol, clodaterol, vilanterol
- relaxation of pregnant uterus
— terbutaline, ritodrine
Potential adverse effects
- tremor, tachycardia, hyperglycemia, hypokalemia
No absolute specificity - if possible= topical use
Alpha receptor agonists
- local and systemic use
1.Local use - nasal decongestant; activates a1 and a2
- naphazolin, xylometazolin, oxymetazoline, phenylephrin
— vasoconstriction locally
— side effects: rebound hyperemia, ischemic changes of mucous membranes
- Local use - ophthalmologic use
- decongesion - phenylephrin
- myadriasis - phenylephrin
- glaucoma - apraclonidine, brimonidine a1 - Systemic use
- selectivity is extremely important
- a1 selective agonist = sympathomimetics
—vasoconstriction and increased BP
—phenylephrin, midodrine, methoxamine
- a2 selective agonist = sympatholytic
— due to enhanced negative feedback
— decreased BP (transient increase)
— clonidine, guanfacin
— used as antihypertensive agents
Indirectly acting sympathomimetics
They release NE from nerve terminals, rapid development of tolerance
- tyramine
- ephedrine
- amphetamine
Tyramine
Indirect acting sympathomimetics
- not used as therapeutic agent
- found in cheese, chicken liver, red wine
- metabolized by MAO-a in GI tract and inactivated
- if treated with MAO-a inhibitors= avoid food with tyramine - can cause hypertensive crisis
Ephedrine
Indirect acting sympathomimetics
- alkaloid
- high oral bioavailability,
- long action of duration
- penetrate bbb, mild stimulant
- mixed sympathomimetic mechanism of action: weak receptor activator and release NE
- vasoconstrictor or bronchodilator when weak and prolonged action is needed
- enantiomer- pseudoephedrine= over the counter drug
Amphetamine
Indirect acting sympathomimetics
- orally active compound with long duration
- enters CNS easily and release biological amines and cause a marked stimulant effect on mood and alertness
- euphoria =abuse
- decreased appetite
- periphery= indirectly acting sympathomimetic
- related drugs;
— methylpheridate - ADHD
— MDMA
— methamphetanine
Reuptake inhibitors
Cocaine
TCA and related compound
SNRI, SSNRI
Cocaine
Reuptake inhibitor
- LA
- block NE and D reuptake on periphery and CNS
- sympathomimetics
- euphoria = abuse
TCA and related compounds
Reuptake inhibitors
- desipramadine, amitriptyline
- used to treat mental depression
- block NE reuptake in PNS + CNS
- a and m blockade may complicate their autonomic action - risk of adverse cardinal effects
SNRI, SSNRI
Reuptake inhibitors
- serotinin NE reuptake inhibitors and selective serotonin ne reuptake inhibitors
—reboxetine, venlafaxine
— antidepressant, no receptor blockade
MAO Inhibitors
Irreversible, non-selective
- tranylcypromine, parglycine
- antidepressants- not used due to severe side effects
Reversible mao-a inhibitors
- modobemid
- treat mental depression
Irreversible mao-b inhibitors
- selegiline
- Parkinson’s
Presynaptic inhibition = sympatholytics
- A-methyltyrosine/methyrosine
- blocks tyrosine hydroxylase enzyme - Reserpine
- prevents transmitter release - tetrodotoxin, saxitoxin
- LA
- prevent/block VGSC - Omega-conotixin
- block ca2+ channels - Activation of inhibitory presynaptic a2 autoreceptors
- clonidine, methyldopa - Activation of presynaptic inhibitory heteroreceptors
- m2, d2, h3, etc - Adrenergic neuron blockers
- guanethidin and bretylium
- inhibit transmission release - 6-OH-dopamine
- destroy the nerve terminal
Postsynaptic inhibition
Groups
Decrease sympathetic activity
- Beta-blockers
- non-selective
- cardioselective/b1 selective - A1 antagonist
- selective a1 antagonist
- non-selective a antagonist - A2 receptor agonist
Non-selective beta blockers
Propranolol Pindolol Timolol Sotalol (also: k+ channel blocker) Carvediol (also: a1 blocker) Labetalol (also: a1 blocker)
B1 selective/cardioselective beta blockers
Atenolol Metoprolol Bisoprolol Esmolol Celiprolol Betaxolol Nebivolol Acebutolol
Partial agonistic activity of beta blockers = ISA
intrinsic sympathomimetic activity
Pindolol Acebutolol Oxprenolol Alprenolol Celiprolol- bronchoconstriction
ISA at b2 receptors
Less likely with decreased HR and lipid abnormalities in plasma
Consequence of beta blocking
- negative chronotropic and inotropic actions on heart
- decreases BP (in part due to less renin release) - b1
- bronchoconstriction - b2
- local vasoconstriction - b2
- decreased production of aqueous humor
- impaired recovery from hypoglycemia - b2
- increased VLDL and decreased HDL
Indication of beta blockers
Hypertension Angina pectoris Supraventricular tachyarrhythmias CHF after AMI Hypertrophic obstructive cardiomyopathy Hyperthyroidism Pheochromocytoma Portal hypertension Esophageal varicose Glaucoma Performance anxiety Migraine Essential tremor Proliferating hemangioma (newborn)
Adverse effect of beta blockers
Bronchoconstriction Cardiac decompensation Bradycardia Decreased AV conduction Cold extremities Worsening peripheral vascular disease Uterus contraction in pregnancy Hypoglycemia Hyperlipidemia Increased potassium levels Sleep disturbance Depression
Abrupt discontinuation can give increased risk of ischemic heart disease
Lipid solubility of beta blockers
High lipid solubility:
- propranolol
- nebivolol
Low lipid solubility
- atenolol
- sotalol
- acebutolol
Action of beta blockers on ion channels
Weak LA effect (Na+ channel block):
- propranolol
- pindolol
- metoprolol
- acebutolol
Block k+ channel
- sotalol - antiarrhythmic drug (I and II)
Beta blockers with additional vasodilator effect (3rd gen)
Block of a1
- labetalol
- carvediol
NO- mediated relaxation
- nebivolol
- antihypertensive indication
Half-life beta blockers
Ultra-short acting 1. esmolol — b1 selective — 10 min half life — critically ill patients
Long half life
- Nadolol - 16-20h
- Betaxolol- 14-20h
- Bisoprolol- 10-12 h
- Nebivolol - 10 h
Alpha receptor antagonists
- selective a1 receptor antagonist
- non-selective a receptor antagonist
— synthetic compound: phenoxybenzamine and phentoamine, (tolazoline)
— ergot alkaloids
Therapeutic interest of a receptor antagonist
Smooth muscle relaxation
Antihypertensive action
Peripheral vascular disease
Benign prostate hyperplasia
Selective a1 antagonists cause less tachycardia than the non-selective ones.
A2 receptor agonist
Sympatholytic effects due to negative feedback on autoreceptor
- clonidine
- guanabenz
- Guanfacine
- moxinidine
- rilmenidine
- methyldopa
- dexamedetomidine - sedation
- tizanidine - centrally acting muscle relax
- apraclonidine, brimonidine - glaucoma
Clonidine
A2 receptor agonist
- Sympatholytic effects due to negative feedback on autoreceptor
- imidazoline derivative
- moa: enhances negative feedback on presynaptic a2 autoreceptors, stimulates postsynaptic a2 receptors in medulla (BP regulation) and stimulates imidazoline 1 receptors in the medulla.
- indication: HT (acute, mild to moderate), alcohol and opioid withdrawal, peri anesthetic medication, sedation and analgesia in ICU, diarrhea in DM, ADHD, glaucoma
Adverse effects; sedation, dry mouth, bradycardia, orthostatic hypotension, mental depression.
Abrupt withdrawal can cause HT crisis and increased sympathetic activity
Guanabenz and guanfacine
A2 receptor agonist
- Sympatholytic effects due to negative feedback on autoreceptor
- centrally acting antihypertensive drugs
- clonidine like action but different structure
Moxonidine and rilmenidine
A2 receptor agonist
- Sympatholytic effects due to negative feedback on autoreceptor
- newer imidazoline derivatives with clonidine like structure
- more sensitive to imidazoline receptor 1 in adrenal medulla
- less affinity to a2?
- indication: HT
- sedation and dry mouth occurs less frequently than with clonidine
Methyldopa
A2 receptor agonist
- Sympatholytic effects due to negative feedback on autoreceptor
- false substrate is FOPA-decarboxylase
- methylNE= a2 agonist
- slow onset of action
- indication: mild to moderate HT, and HT in pregnancy
- adverse effects: sedation, dry mouth, hyperprolactinenia, extrapyrimidal symptoms, depression, +Coombs test, immune hemolysis, liver toxicity
Selective a1 receptor antagonists
Prazosin Terazosin Doxazosin Alfuzosin Tamsulozin Silodosin Urapidil Labetalol Carvediol
Non-selective alpha blockers
Phenoxybenzamine
Phentolamine
Tolazoline
Prazosin
Selective a1 receptor antagonist
Indication: chronic treatment of mild to moderate HT, and BPH
- orally active
- short half life: 3x/day
- side effects; first dose phenomenon (HT and syncope) - start treatment at bed time to avoid, mild and non-spesific: dizziness, palpitations
Terazosin and dixazosin
Selective a1 receptor antagonist
- prazosin like with longer half life
- indication; HT and BPH
Alfuzosin, tamsulosin, and silodosin
Selective a1 receptor antagonist
- urinary tract
- BPH
Urapidil
Selective a1 receptor antagonist
- weak a2 agonist, 5-HT1a agonist, and beta antagonistic action
- hypertensive crisis
Labetalol and carvediol
Selective a1 receptor antagonist.
Also beta antagonist
Phenoxybenzamine
Non-selective synthetic alpha blocker
- irreversible a blocker, long duration (14-18h)
- indication: pheochromocytoma
Phentolamine and tolazoline
Non-selective synthetic alpha blockers
- reversible a blocker
- strong
- pheochromocytoma (diagnosis and treat)
Tolazoline - weak, vasodilation
Ergot alkaloids groups
- produced by fungus: claviceps purpurea
- lysergic acid derivatives (LSD)
- 2 major families of natural compounds
1. Amine alkaloids - ergometrine
2. Peptide alkaloids - ergotamine
- ergocryptine
- ergocrystine
- ergocornine
Agonist, partial agonist or antagonist action on several receptors, especially a and 5-HT and D
Main effect of ergot alkaloids
Vasoconstriction
Vasospasm
Powerful stimulation of pregnant uterus
CNS action
Structurally related drugs if ergot alkaloids
Dihydro-derivatives: more selective for a receptors (antagonist)
Methysergid: more selective for 5-HT receptor (antagonist)
Bromocryptine, cabergoline; more selective for D receptors (agonist)
Lysergic acid diethylamine(LSD); peripheral agonist on5-HT in CNS
Therapeutic indication of ergot alkaloids
Postpartum hemorrhage
- ergometrine, ergotamine
- never before delivery
Migraine
- ergotamine
Therapeutic indication of ergot derivatives
Hyperprolactinemia
- bromocryptine
- cabergoline
Parkinson’s
- bromocryptine, cabergoline
Migraine
- dihydro ergotamine
Peripheral vascular disease
- dihydro- derivatives
Side effects of ergot alkaloids
Nausea Vomiting Diarrhea Prolonged vasospasm CNS disturbances
Drugs with alpha blocking side effects
- Several (mostly tricyclic) antidepressants
- amitriptyline
- imipramine - Several antipsychotics
- phenothiazines
- chlorpromazine
May cause HT and reflex tachycardia - Quinidine
- antiarrhythmic drug
- to rapid iv infusion may cause BP fall
Adrenergic neuron blockers
Quanethidine Debrisoquine Bretylium Reserpine Tetrabenazine Methyltyrosine
Quanethidine and debrisoquine
- adrenergic neuron blockers
- inhibit NE release from synaptic nerve terminals
- antihypertensive indication
- adverse effects; postural HT, diarrhea, impaired ejaculation, sodium and water retention, nasal stiffness
Bretylium
- adrenergic neuron blockers
- inhibit release of ne from synaptic nerve terminals
- blocks potassium channels on the heart - antiarrhythmic indication
- adverse effects: initial release of ne can precipitate arrhythmia, sympatholytic action
Reserpine
- adrenergic neuron blockers
- blocks the uptake of biogenic amines into the synaptic vesicles, they are not stored in the vesicles, broken down by MAO
- enters the brain - depletion of me, dopamine, serotonin in both several and peripheral neurons
- theoretical indication; HT And psychosis
- side effects: sympatholytic action, mental depression, Parkinsonism
Tetrabenazine
Adrenergic neuron blockers
Huntington
Tourette
Methyltyrosine
Block the norepinephrine synthesis
Adrenergic neuron blocker
Chronic ergot poisoning
Hallucinations Convulsions Prolonged vasospasm Gangrene Burning pain Abortion in pregnancy
