Autonomic Nervous System: Adrenergic Agonists

Autonomic Nervous System: Adrenergic Agonists (Sympathomimetics)

• The origin of the sympathetic nervous system is from thoracolumbar segments. Thoracic and lumbar segments L1, L2, L3, and L4 are included.
• Short preganglionic fibers relay in sympathetic chain ganglia and release Acetylcholine (Ach).
• Long postganglionic fibers innervate body organs and release Norepinephrine as a neurotransmitter.
• The sympathetic nervous system induces a "stress" state, with pupils dilating and heart rate increasing.
• The parasympathetic nervous system produces a "calm" state, with pupils constricting and heart rate decreasing.

Neurotransmission at Adrenergic Neurons

• Norepinephrine (NE) is synthesized.
• Dopamine (DA) and NE are stored in vesicles.
• NE is released.
• Metabolism: 20% via COMT and 80% via MAO.
• Catechol-o-methyltransferase (COMT) and Monoamine oxidases (MAO) are involved.
• Binding to receptors, and the process of neuronal uptake occurs.

Adrenergic Receptors

• Adrenoceptor subtypes consist of alpha (α) and beta (β) receptors.
• Alpha receptors are divided into α1 and α2 subtypes.
• Beta receptors are divided into β1, β2, and β3 subtypes.

Second Messengers

• α1 receptors activate PLC, leading to IP3 and DAG production.
• α2 receptors inhibit adenylate cyclase, decreasing cAMP levels.
• All beta receptor subtypes stimulate adenylate cyclase, increasing cAMP levels.

Alpha-1 (α1) Receptors

• Alpha-1 receptors are postsynaptic.
• Stimulation causes contraction of the pilomotor muscle.
• Contraction of the dilator pupillae muscle occurs.
• Vasoconstriction (VC) in skin, mm (muscle), and renal vessels increases peripheral resistance.
• Increased viscid salivation occurs.
• Spasm of the GIT and urinary bladder sphincter.
• Contraction of the pregnant uterus.
• NM transmission is facilitated.
• Ejaculation in males is caused.

Alpha-2 (α2) Receptors

• Alpha-2 receptors are presynaptic, postsynaptic, and central.
• Sympathetic outflow from the CNS is inhibited.
• Presynaptic: Auto receptors are present.
• Reduces noradrenaline release.
• Reduces Ach release in enteric ganglia.
• Decreases renin and insulin release.
• Triggers the reduction of lipolysis in fat cells.
• Increase platelet aggregation.

Beta (β) Receptors

• Beta-1 (β1) receptors: Postsynaptic, mainly in the CNS.
• Beta-1 stimulation results in cardiac stimulation, release of renin, and increases in lipolysis and free fatty acids.
• Beta-2 (β2) receptors: Presynaptic and postsynaptic.
• Facilitates release of noradrenaline. Results in vasodilation in skeletal muscle, bronchodilation and glycogenolysis in the liver and skeletal muscle.
• Beta-2 stimulation causes insulin release, relaxation of the GIT and urinary bladder wall, uterus relaxation, and skeletal muscle tremors.
• Beta-3 (β3) receptors: Increase lipolysis and thermogenesis.

Adrenergic Agonists

• Adrenergic agonists are drugs that stimulate adrenoceptors.
• They produce actions similar to sympathetic nerve stimulation.
• Natural agonists: Includes adrenaline, noradrenaline, and dopamine.
• Synthetic agonists: Other synthetic agonists exist.
• Catecholamine agonists: Includes adrenaline, noradrenaline, isoprenaline, dopamine, and dobutamine.
• Non-catecholamine agonists are present.

Classification of Adrenergic Agonists

• Direct-acting adrenergic agonists include selective and non-selective subtypes.
• Mixed-acting adrenergic agonists.
• Indirect-acting adrenergic agonists include releasing agents and uptake inhibitors.
• Direct-Acting (Selective): Phenylephrine (α1), Clonidine (α2), Dobutamine (β1), Salbutamol (β2).
• Direct-Acting (Non-Selective): Adrenaline (α1, α2, β1, β2), Noradrenaline (α1, α2, β1), Isoprenaline (β1, β2).
• Mixed-Acting: Ephedrine
• Indirect-Acting: Amphetamine and Tyramine (releasing agents), Cocaine (uptake inhibitor).

Adrenaline (Epinephrine)

• A sympathomimetic catecholamine present in the adrenal medulla (80%) and CNS tract.
• Unstable in alkaline mediums, and is stored in dark glass ampoules.
• Kinetics:
  • Administered via S.C injection, inhalation, intracardiac injection, or eye drops.
  • It cannot pass the blood-brain barrier (BBB). It is metabolized by MAO and COMT. Only 2% is unchanged in urine.
• Dynamics:
  • Stimulates all adrenergic receptors.

Adrenaline (Epinephrine) Cardiovascular Actions:

• Heart stimulation of β1 receptors increases all cardiac properties
• Increases contractility, heart rate (HR), AV conduction, excitability, and automaticity.
  • May cause arrhythmia.
  • Increases cardiac output (COP) and oxygen needs, potentially causing angina.
• Blood Vessels:
  • Vasoconstriction in skin, mm (muscle), and renal vessels because of α1 effects.
  • Vasodilation in skeletal and coronary blood vessels because of β2 effects.
• Blood Pressure:
  • Increases systolic blood pressure (SBP).
  • Decreases diastolic blood pressure (DBP).
  • Increases pulse pressure.

Adrenaline (Epinephrine) Other Actions

• Respiratory:
  • Bronchodilation through β2 receptors.
  • Decongestion of bronchial mucosa through α1 receptors.
• GIT and Urinary Bladder:
  • Spasm of sphincters is caused by α1 receptors.
  • Relaxation of the wall via β2 receptors.
• Uterus:
  • Variable effects. It is mainly a relaxant.
• Skeletal Muscle:
  • Prevents fatigue, causes VD (β2), and facilitates NM transmission.
• Eye:
  • Vasoconstriction of conjunctival blood vessels and reduced aqueous humor formation.
• Antiallergic: It is a physiological antagonist of histamine.

Adrenaline (Epinephrine) Metabolic and Local Actions

• Metabolism:

  • Increases liver and muscle glycogenolysis (β2).
  • Decreases insulin release (α2).
  • Increases lipolysis (β3).
  • Causes hypokalemia (β2) after hyperkalemia.

• Local Action: It is a local haemostatic, decongestive, and delays the absorption and prolongs the action of drugs when given together S.C, for example, local anesthetics.

Adrenaline (Epinephrine) Uses

• Acute bronchial asthma is treated.
• Anaphylactic shock and urticaria is treated.
• Acute insulin hypoglycemia is treated.
• Cardiac resuscitation in cardiac arrest occurs.
• Contraction ring of the uterus during labor happens.
• Epistaxis is reduced
• Open-angle glaucoma is treated.
• Utilized with local anesthetics to delay absorption and prolong action.

Adrenaline (Epinephrine) Side Effects

• α Effects: Treated by alpha-blockers.
  • Gangrene if injected with local anesthetic around fingers or toes.
  • Hypertension leads to cerebral hemorrhage.
• β1 Effects: Treated by beta-blockers.
  • Tachycardia, palpitation, and angina occur.
  • Cardiac arrhythmia may occur with digitalis or halothane.
• CNS: Anxiety, headache.

Adrenaline (Epinephrine) Contraindications

• Around finger or toe.
• Hypertension, coronary heart disease, arrhythmia.
• Hypotensive shock.
• Pulmonary embolism.
• Thyrotoxicosis.
• With digitalis or halothane.
• With adrenergic neuron depressants: guanithidine.
• With ganglion blockers or MAO inhibitors.

Noradrenaline (Norepinephrine)

• It is a natural sympathomimetic catecholamine.
• Kinetics:
  • Cannot be administered orally, will not pass the BBB. It is given via IV infusion because its fate is similar to adrenaline.
• Dynamics:
  • Stimulates α1, α2, and β1 receptors.
• Cardiovascular (CVS) Actions:
  • Blood vessels: VC leads to increased peripheral resistance.
  • Increases blood pressure (↑BP).
  • It can cause reflex bradycardia and can increase excitability automaticity, also know as arrhythmia.
• Respiration: Can cause reflex apnea.
• GIT: Relaxes wall, spasms sphincters.
• Metabolism: Can Cause hyperglycemia and hyperlipidemia.
• Uterus: Contracts pregnant uterus, leading to abortion.

Noradrenaline (Norepinephrine) Uses

• Treats acute hypotension such as with spinal anesthesia.
• Used with local anesthetics.
• Side Effects:
  • Hypertension leads to cerebral hemorrhage.
  • Can cause bradycardia, palpitation, headache, and anxiety.
  • Abortion.
  • Sudden withdrawal of infusion can cause hypotension.
  • Extravasations' lead to sloughs and necrosis.
• Contraindications:
  • Known hypersensitivity, and injection around finger or toe.
  • Hypertension and Arrhythmia.
  • Shock other than anaphylactic shock.
  • Cardiac dilatation and insufficiency.
  • Ischemic heart disease and Cerebral arteriosclerosis.

Isoprenaline

• Kinetics: It is a synthetic sympathomimetic catecholamine that is a non-selective beta agonist.
• It is not prescribed orally, nor is it prescribed through the BBB. It can be administered sublingually or inhaled.
• Dynamics:
  • Cardiovascular (CVS):
  • Increases all cardiac properties (β1).
    • Generalized VD, leading to decreased peripheral resistance.
    • Causes Hypotension.
  • Respiration: bronchodilation (β2).
  • GIT and urinary bladder: wall relaxation (β2).
  • Metabolism: hyperglycemia (β2).
  • Hyperlipidemia (β3). The uterus relaxes pregnant uterus (β2).
• Uses:
• Treats Heart block.
• Treats Acute bronchial asthma.

Isoprenaline Side Effects and Contraindications

• Side Effects: Tachycardia, palpitation, angina, arrhythmia, tremors.
• Contraindications:
  • Coronary heart disease and Arrhythmia.
  • Thyrotoxicosis.
  • With digitalis and general anesthesia.

Dopamine

• Natural sympathomimetic catecholamine.
• Kinetics:
  • It is not administered orally and does not pass the BBB. It is metabolized by MAO-B and COMT.
• Dynamics: There are both directing and dual processes.
• Direct process:
  • Peripheral actions arise from D1,5.
  • D2,3,4 causes central actions.
  • D3 triggers the presynaptic auto receptor.
• Dual process: Stimulation of α, β.

Dopamine Peripheral and Central Actions

• Peripheral Actions:
  • Small dose: D1 causes VD, which increases Renal Blood Flow (RBF).
  • Moderate dose: D1+β1 causes +ve inotropic effects.
  • Large dose: α1 can cause VC, which leads to increased peripheral resistance.
• Central Actions:
  • Dopamine cannot pass the BBB; l-dopa must pass and convert to dopamine.
  • Euphoria and psychosis can result.
  • It can treat Anti-parkinsonism.
  • Decreases appetite and prolactin secretion.
  • Raises temperature. Chemoreceptor trigger zone (CTZ): Nausea and vomiting.
• Uses:
  • Shock.
  • Treats Resistant heart failure.

Dopamine Side Effects

• Side Effects:
  • Tachycardia, arrhythmia, nausea, and vomiting result.
  • Hypertension also resuts if a large dose is used.

Dobutamine

• Synthetic sympathomimetic catecholamine.
  • Selective β1 agonist with no dopaminergic action.
  • Selective positive inotropic and dromotropic (conduction properties).
  • Minimal tachycardia and minimal change in peripheral resistance.
  • Used by I.V. infusion to treat cardiogenic shock, resistant heart failure, and resistant heart block.

Ephedrine

• Ephedrine is an indirect sympathomimetic non-catecholamine.
• Kinetics:
• Absorption can be oral, transmucosal, or parenteral.
• Distribution occurs all over the body. It can pass the BBB.
• Excretion is excreted unchanged in urine and can be accelerated by acidification of urine.
• Dynamics:
  • Like adrenaline, but is weaker, slower, and longer. Tachyphylaxis (rapid decrease in response to repeated doses over a short time period) occurs.
• Cardiovascular (CVS):
• Increases all cardiac properties such as Heart rate and blood pressure.
  • Hypertension can be abolished by α blockers.
  • Respiration is responsible for bronchodilation (β2) and decongestion (α1).
• GIT and urinary bladder relax the wall and spasm sphincter.
• Causes Antiallergic responses and Skeletal muscle antifatigue, which facilitates NM transmission.
• Actions continue with CNS Stimulation of the Chemoreceptor trigger zone (CTZ) and respiratory center (RC) (analeptic and CNS stimulant). Results in Uterus Relaxation of the human uterus.
• Local Actions: Nose decongestion with rebound congestion due to its irritant action. Eye Decongestion, Active mydriasis occurs.
• Analeptic in toxicity with CNS.

Ephedrine Uses and Side Effects

• Uses: Treats heart block, Hypotension, asthma, and allergy. Mydriatic eye drops treats Nasal decongestion, Treats Nocturnal enuresis and Myasthenia gravis. Is also an Analeptic in toxicity with CNS.
• Side Effects: Causes Insomnia, anxiety, headache, tremors, and convulsion. Also causes Nausea and vomiting, Hypertension, tachycardia, angina, and arrhythmia. Results in Tolerance and tachyphylaxis.

Amphetamine

• Amphetamine is a synthetic sympathomimetic non-catecholamine.
• Kinetics: Similar to ephedrine.
• Dynamics:
• Acts indirectly via release of endogenous noradrenaline.

Amphetamine Actions

• Sympathomimetic: Similar to noradrenaline but weaker, slower, and longer with tachyphylaxis.
• Increases hypertension abolished by α blockers, reflex bradycardia.
• CNS Stimulation: Stronger than ephedrine.
• Anorexogenic, Analgesic, and Analeptic effects.
• Has a Psychic effect that is dose dependent.
• Facilitates (mono & poly) in spinal cord synaptic pathways.

Amphetamine Uses and Side Effects

• Uses:
  • Obesity.
  • Attention-deficit disorders in children.
  • Parkinsonism and Psychic depression.
  • Treats Mental and physical fatigue and Narcolepsy.
• Side Effects:
  • Hypertension or Insomnia, anxiety and anorexia.
  • Hallucination, schizophrenia, hyperpyrexia, and convulsions.
  • Prolonged use leads to physical dependence (addiction).
• Treatment of Acute Toxicity include:
  • Acidification of urine or haemodialysis.
  • Use α-blockers for Hypertension and major tranquilizers for Psychosis. Also use diazepam for Convulsions.

Amphetamine Contraindications

• Hypertension and Coronary heart disease.
• Do not prescribed with Patients that are also taking MAOIs because (as it may produce severe hypertension- Cheese Reaction).
• Psychosis.

Alpha-1 Stimulants used as

• Vasopressors to stimulate α-receptors leading to Vasoconstriction and increase BP.
  • Examples: Phenylephrine, methoxamine, and midodrine.
  • Indications: Treat Hypotension, septic shock, cardiogenic, and hypovolemic shock, locally as nasal decongestants, and in open-angle glaucoma.
  • Can cause Adverse reactions such as hypertension, bradycardia, systemic absorption, and rebound nasal congestion.
• Nasal Decongestants lead to Sympathomimetic vasoconstriction and may promote drainage in nasal passages.
  • Types: Topical (oxymetazoline) and Oral (psuedoephedrine).
  • Uses: Treats allergic congestion and common cold.
  • Side effects: Causes orally (hypertension, repeated use (rebound congestion), chronic use (atrophic rhinitis).

Beta-2 Stimulants

• As Bronchodilators to selectively agonize β2 agonists. Bronchodilatation results from drugs like (salbutamol, terbutaline, and salmeterol) and is used mainly in bronchial asthma (oral or nebulizer).
• Also prescribed as Uterine Relaxants to selectively stimulate β2 agonists e.g. ritodrine during premature labor, dysmenorrhea, and habitual abortion.
• Can also function as vasodilators to stimulate β2-receptors, which produce vasodilation in the skeletal muscle. Also act as uterine relaxants e.g. Ritodrine.
• This function can treat Peripheral vascular diseases. It can also Increase cerebral blood flow in cerebral arteriosclerosis. Aids in delaying premature labor by utilizing tocolytic drugs.