Sympathetic Neurotransmission and Adrenoceptor Agonists Flashcards
alpha1-adrenoceptor - MoA and Location
Phospholipase C activation, increased IP3 and release of Ca
Smooth muscle at sympathetic neuroeffector junctions, exocrine glands, CNS
alpha1-adrenoceptor - Effect
Smooth muscle contraction (vascular, iris dilator, bladder, urethra, prostate), exocrine gland secretion, neuronal excitation
–> Vasoconstriction increased BP
alpha2- adrenoceptor - MoA and Location
Inhibition of adenylyl cyclase and decreased cAMP
Distributed in presynaptic neurons, blood platelets, and tissues (ocular/adipose/intestinal/hepatic/renal/endocrine)
alpha2- adrenoceptor - Effect
Sympathetic postganglionic neurons: Autoreceptors, activation –> feedback inhibition of norepinephrine release from nerve terminals
Blood platelets: platelet aggregation
Pancreas: inh of insulin secretion
Eyes: decreased secretion of aqueous humor
CNS effects
Beta adrenoceptors - MoA
Adenylyl cyclase activation, increased cAMP, protein kinase A activation
–> phosphorylation of other proteins and enzymes.
Beta1- adrenoceptor - Effect
Cardiac stimulation:
Positive chronotropic (increased HR), inotropic (increased contractility), dromotropic (increased impulse conduction velocity).
Kidney:
Increased Renin secretion from juxtaglomerular cells.
Beta2- adrenoceptor - Effect
Smooth muscle:
Relaxation ( bronchi, uterus, vascular)
Skeletal muscle: potassium uptake
Liver: glycogenolysis
Beta3- adrenoceptor - Effect
Adipose: lipolysis
Skeletal muscle: thermogenesis
Smooth muscle: relaxation
D1 receptor - MoA
Increases cAMP by stimulating adenylyl cyclase. cAMP activates protein kinase A –> phosphorylation of other proteins and enzymes.
D1 receptor - Effect
Relaxation of vascular smooth muscle
D2 receptor - MoA
Decreases cAMP, increases K currents, decreases Ca influx
D2 receptor - Effect
Modulation of neurotransmission in the sympathetic and CNS
Imidazoline receptors - MoA and Location
Activated by adrenoceptor agonists that possess an imidazoline structure
CNS, peripheral tissues
Imidazoline receptors - Effect
Natriuresis and decrease of symp outflow from CNS
Catecholamines - Indications
Shock
Hypovolemic shock (inadequate blood V)
Cardiogenic shock (inadequate cardiac function)
Rogenic shock/Neurogenic
Septic shock (massive vasodilation secondary to production of toxins)
Anaphylactic shock (hypotension, difficulty breathing)
Catecholamines - Adverse effects
Excessive vasoconstriction –> tissue ischemia and necrosis.
Excessive doses: reduce blood flow to vital organs such as kidneys or cause excessive cardiac stimulation –>
Tachycardia
Arrhythmias
Beta adrenoceptor agonists can cause:
hyperglycemia, esp diabetes patients.
Direct acting catecholamines
Dobutamine Dopamine (both) Epinephrine Norepinephrine Isoproterenol
Norepinephrine - MoA and Effects
Vasoconstriction and increased BP (alpha1)
Greater affinity for beta1 adrencoceptors then for beta2. –> constricts all blood vessels
Cardiovascular effect: primarly results from activation of alpha1 adrenoceptors. Leads to vasoconstriction and increases peripheral resistance, which in turn increases the systolic and diastolic blood pressure.
Norepinephrine - Indication
Hypotension
Septic shock
Cardiogenic shock when response to dopamine is inadequate or tachycardia
Norepinephrine - Adverse effects
Reflex bradycardia if blood pressure increases sufficiently to activate the baroreceptor reflex.
Epinephrine - MoA and Effects
Potent agonist at all alpha and beta adrenoceptors –> constricts some blood vessels and dilates others.
Increases systolic blood pressure, but can increase or decrease diastolic
Vasoconstriction (alpha1), cardiac stimulation (beta1) and bronchodilation (beta2)
Epinephrine - Indications
Anaphylactic shock
Cardiac arrest
Ventricular fibrillation
Reduction in bleeding during surgery (vasoconstrictor)
Prolongation of action of local anesthetics
Local anesthetic formulation (vasoconstrictor) –> limits systemic absorption of local anesthetic –> increases duration of action + decreases adverse effect
Epinephrine Lower dose VS Higher dose
Lower dose: greater beta2 receptors than alpha1 in vascular beds of skeletal muscle –> vasodilation and decreases diastolic BP
Higher dose: more vasoconstriction –> increases dia and sys BP
Dopamine - MoA and Effects
Activates D1 receptors, beta1 and alpha receptors, unlike the other catecholamines, dopamine also stimulates the release of norepinephrine from sympathetic neurons.
Renal vasodilation (D1), cardiac stimulation (beta1), increased BP (beta1, alpha1)
Dopamine - Indications
Cardiogenic shock Septic shock Heart failure Hypotension Adjunct to fluid administration in hypovolemic shock
Dopamine - Higher dose VS Lower dose
Low doses: dopamine selectively activates D1 in renal and other vascular beds, thereby cause vasodilation and an increase in renal blood flow –> NOT effective in treating/preventing acute renal failure
Higher doses: it activates beta1 in the heart–> stimulating cardiac contractility and increasing cardiac output and tissue perfusion.
At even higher doses: activates alpha1 and causes vasoconstriction
Isoproterenol - MoA and Effects
Selective beta1and beta2 adrenoceptor agonist, because it has little affinity for alpha receptors.
Cardiovascular:
Produces vasodilation and cardiac stimulation (beta1). Lowers diastolic pressure, but it can increase systolic pressure by increasing heart rate and contractility.
Respiratory: bronchodilation (beta2)
Isoproterenol - Indication
Atrioventricular block
Bradycardia
Asthma
Isoproterenol - Adverse effects
Potent chronotropic effect –> Tachycardia, Cardiac arrhythmias
Dobutamine - MoA and Effects
Primarily stimulates beta1 receptor (cardiac stimulation), with smaller effects on beta2 (vasodilation) and alpha receptors.
Cardiovascular:
Selectively increases myocardial contractility and stroke volume while producing a smaller increase in heart rate –> increase CO if heart failure
Reduces vascular resistance by activating beta2, thereby reducing the impedance to ventricular ejection.
Respiratory:vasodilation
Dobutamine - Indication
Short-term management of Acute heart failure
Cardiogenic shock
Cardiac stimulation during heart surgery
Direct - Acting Noncatecholamine
Albuterol Brimonidine Apraclonidine Clonidine Dexmedetomidine Midodrine Oxymetazoline Phenylephrine Pributerol Terbutaline
Phenylephrine - MoA and Effect
Activates alpha1 adrenoceptors and causes smooth muscle contraction. This produces vasoconstriction and increases vascular resistance and blood pressure.
Ocular adm leads to contraction of the iris dilator muscle and dilation of pupil(mydriasis)
Phenylephrine - Indication
Nasal decongestant(inhibits vasodilation) in patient with viral rhinitis Allergic rhinitis Allergic conjunctivitis( used as ocular decongestant) Induce mydriasis (opthalmoscopic examination) Hypotension and shock (IV) caused by decreased peripheral vascular resistance(hypotension by excessive doses of vasodilator drugs, drug induced shock, septic shock, neurogenic shock from spinal cord injury) Maintain blood pressure during surgery.
Brimonidine - MoA
Decreases aqueous humor formation (alpha2)
Brimonidine - Indication
Postop control of intraocular pressure: open-angle glaucoma and ocular hypertension
Midodrine - MoA
Selectively activates alpha1 adrenoceptors in the arteriolar and venous circulation, leading to increased systolic and diastolic BP in the standing, sitting and supine position.
Midodrine - Indication
Postural(orthostatic) hypotension(people who have BP decreased when standing) ex, in diabetic autonomic neuropathy pt)
Hypotension caused by infection in infants or induced by psychotropic agents.
Hypotension in person undergoing renal dialysis.
Midodrine - Adverse effects
Hypertension when persons are supine.
Albuterol, Terbutaline and Pributerol - MoA
Selective beta2-adrenoceptor agonists. Causes smooth muscle relaxation. Produces bronchodilation
Albuterol, Terbutaline and Pributerol - Indication
Asthma
Chronic obstructive lung disease
Terbutaline - Preterm labor –> before 37th week of gestation. Relaxes uterus and maintains pregnancy for 24 to 48h –> Tocolysis)
Albuterol, Terbutaline and Pributerol - Adverse effects and Contraindication
Tachycardia
Muscle tremor
Nervousness
Terbutaline: not used in pregnant women for prevention or prolong treatment –> fatal maternal heart problems
1st group imidazoline drug
Oxymetazoline
Oxymetazoline - MoA
Activates alpha1-adrenoceptors and cause vasoconstriction.
Oxymetazoline - Indication
Topical nasal and ocular decongestant.
Local anesthetic formulation (vasoconstrictor) –> limits systemic absorption of local anesthetic: increased duration of action + decreased adverse effect
Oxymetazoline - Adverse effects
Increased BP
CNS and cardiovascular depression (if absorbed into systemic circulation and distributed to the brain)
Rebound congestion
2nd group imidazoline drugs
Apraclonidine
Brimonidine
Apraclonidine, Brimonidine - MoA
Activate ocular alpha2 –adrenoceptor in the ciliary body and thereby reduce aqueous humor secretion.
Apraclonidine, Brimonidine - Indication
Short-term presurgical and postop control of intraocular pressure.
Open-angle glaucoma and ocular hypertension
Apraclonidine, Brimonidine - Adverse effects
High rate of tachyphylaxis( rapid development of tolerance)
3rd group of imidazoline drugs
Clonidine, Dexmedetomidine
Clonidine, Dexmedetomidine - MoA
Activates alpha2 –adrenoceptors and imidazoline receptors in CNS. Leads to reduction in sympathetic outflow from the vasomotor center in the medulla
Clonidine - Indication
Hypertension
Sedative and analgesic
Pediatric procedures/surgery: Sedation & decreased anxiety and anesthetic requirements
ADHD (attention deficit/hyperactivity disorder) in children and adolescent (by decreasing firing rate of neurons releasing norepinephrine in the prefrontal cortex –> decreases impulsivity and hyperactivity)
Drug dependence (facilitates withdrawal and abstinence from opioids, benzodiazepines, alcohol and cocaine)
Dexmedetomidine - Indication
Sedative and analgesic
Sedation of intubated and mechanically ventilated patients during treatment in an intensive care setting.
Adjunct to anesthesia during surgical procedures (analgesic and sedative effect, prevent delirium during emergence from anesthesia)
What is the advantage of dexmedetomidine?
Does not cause respiratory depression
Mirabegron - MoA and Effect
Selective agonist of beta3-adrenoceptor.
Effect:
Detrusor muscle relaxation –> increased urinary bladder capacity
Mirabegron - Indication
Overactive bladder with symptoms urge urinary incontinence, urgency, and urinary frequency.
Mirabegron - Contraindication and Adverse effects
Contraindication:
Uncontrolled hypertension
Angioedema
increased BP
Droxidopa - MoA
Precursor to norepinephrine and effectively increases the amount of norepinephrine produced and released –> norepinephrine acts on alpha1- receptors in the blood vessels –> vascular smooth muscle constriction –> increased BP
Droxidopa - Indication
Orthotension
Amphetamine - MoA
Increase in NE release, CNS stimulation
Transported into the sympathetic nerve terminal by catecholamine transporter. Once inside the sympathetic neuron, it inh storage of norepinephrine by neuronal vesicles –> increased cytoplasmic concentration of norepinephrine –> reverse transport into synapse by catecholamine transporter.
Amphetamine - Indication and Effects
Narcolepsy, attention-deficit disorder
Effects: vasoconstriction, cardiac stimulation, increased BP, CNS stimulation
Tyramine - MoA and effect
Rapidly degraded by MAO(monoaminooxidase) in the gut and liver.
Sympathomimetic effect: increased BP
Cocaine - MoA
Inhibits catecholamine transporter located in the plasma membrane of presynaptic sympathetic neuron –> decreases neuronal reuptake of norepinephrine and increases its synaptic concentrations
Cocaine - Effects
Acts as local anesthetic Stimulates SNS (by blocking neuronal reuptake of norepinephrine at both peripheral and central synapses) Produces vasoconstriction and cardiac stimulation and elevates BP. Blocks reuptake of dopamine
Cocaine - Adverse effects
Due to vasoconstriction: ischemia, necrosis of the nasal mucosa in people who abuse cocaine. Severe hypertension Cardiac damage(abuse)
Mixed- acting adrenoceptor agonists
Ephedrine, Pseudoepherine, Dopamine
Mixed- acting adrenoceptor agonists - MoA
Indirectly increase synaptic concentrations of norepinephrine in a manner similar to amphetamine.
Mixed- acting adrenoceptor agonists - Indications
Nasal decongestant in the treatment of allergic and viral rhinitis
Mixed- acting adrenoceptor agonists - Contraindication
cough and cold medications should not be used in children under 6yo
Mixed- acting adrenoceptor agonists - Adverse effects
Tachycardia Increased BP Urinary retention Contraction of the sphincter muscle of bladder (esp in men w prostatic hypertrophy) CNS stimulation and insomnia Weight loss, appetite suppressant
Ephedrine and pseudoephedrine - MoA
Activates alpha and beta adrenoceptors by direct and indirect mechanisms. They produce vasoconstriction, bronchodilation.
alpha1: vasoconstriction
beta: broncodilation
Ephedrine and pseudoephedrine - Indication
Nasal decongestant in treatment of colds and allergies –> restricted in many countries due to its usage to make methamphetamine.
Bronchodilation
Hypotension
Ephedra- appetite suppressor
Tizanidine - MoA and Indication
Alpha 2 agonist.
Muscle relaxant, Multiple sclerosis
