Sympathomimetics Lecture Notes PDF

# Introduction to Sympathetic Nervous System & Sympathomimetics ## Dr Christine Muasya ## Lecturer ## Clinical Pharmacology ## UoN # Introduction to SNS * The SNS originates in the thoracolumbar part of the spinal cord * It is an important regulator of the activities of organs such as the h...

# Introduction to Sympathetic Nervous System & Sympathomimetics ## Dr Christine Muasya ## Lecturer ## Clinical Pharmacology ## UoN # Introduction to SNS * The SNS originates in the thoracolumbar part of the spinal cord * It is an important regulator of the activities of organs such as the heart & the peripheral vasculature, especially in response to stressful situations, e.g., trauma, hypoglycemia, fear, cold, & exercise. * It prepares the body for emergencies * It mediates the "fight-or-flight" response by increasing the BP & directing blood to skeletal muscles and other tissues that must work hardest in the face of impending danger * Adrenaline is the neurotransmitter (NT) of the SNS * The fibers of the SNS are said to be adrenergic * The actions of adrenaline (epinephrine) in the bloodstream complement those of noradrenaline (norepinephrine) released by sympathetic nerves. # Sympathomimetics * **Drugs that mimic stimulation of the SNS** # Classification of Sympathomimetics * **By chemistry** * Catecholamines * Non-catecholamines * **By mode of action** * Direct acting * Indirect acting * **By spectrum of action** * The spectrum of receptors that they act on ## Fig 1: Classification of Sympathomimetic Agents by Mode of Action A tree diagram showing: * **Sympathomimetic agonists** * Direct-acting * Alpha (α) agonists * Beta (β) agonists * Dopamine agonists * Indirect-acting * Releasers * Reuptake inhibitors ## Classification by Mode of Action 2 * The indirect acting agents may have either of 2 different mechanisms of action: * Releasers, which displace (or release) stored catecholamines from adrenergic nerve terminals (step 3) e.g. * Amphetamine & its derivatives e.g. Methamphetamine * Ephedrine * Tyramine * Reuptake inhibitors, which inhibit reuptake of catecholamines by the Norepinephrine transporter (NET) in nerve terminals (step 6) * They increase the synaptic activity of released transmitter e.g. * Cocaine * Tricyclic antidepressants (TCAs) * Atomoxetine * Duloxetine ## Fig 2: Mechanism of Norepinephrine Release & Recycling A diagram showing a schematic representation of a neuron and the steps involved in norepinephrine release and recycling: * **Axon Varicosity** * MAO * Tyrosine * NE * **Axon** * Action potential * Voltage-gated Ca2+ channel * Ca2+ * NE * Exocytosis * **Active transport** * **Blood Vessel** * NE * **Adrenergic receptor** * Response * **Effector cell** **Key** * NE (norepinephrine) **Steps** 1. Action potential arrives at the varicosity 2. Depolarization opens voltage-gated Ca2+ channels 3. Ca2+ entry triggers exocytosis of synaptic vesicles 4. NE binds to adrenergic receptor on target 5. Activity ceases when NE diffuses away from the synapse 6. NE is transported back into the axon 7. NE can be taken back into synaptic vesicles for re-release 8. NE is metabolized by monoamine oxidase (MAO). ## Classification by Mode of Action 3 * The indirect acting agents may have either of 2 different mechanisms of action: * Releasers, which displace (or release) stored catecholamines from adrenergic nerve terminals (step 3) e.g. * Amphetamine & its derivatives e.g. Methamphetamine * Ephedrine * Tyramine * Reuptake inhibitors, which inhibit reuptake of catecholamines by the Norepinephrine transporter (NET) in nerve terminals (step 6) * They increase the synaptic activity of released transmitter e.g. * Cocaine * Tricyclic antidepressants (TCAs) * Atomoxetine * Duloxetine # Classification by Spectrum of Action * An Adrenoceptor is a receptor that binds & is activated by one of the endogenous catecholamine transmitters i.e., norepinephrine (NE), epinephrine (EP), or dopamine & related drugs. * Adrenoceptors are classified as α, β, or Dopamine receptors. ## Classification cont. * α receptors are further subdivided into α₁ & α₂ receptors * β receptors are further subdivided into β₁, β₂ & β₃ receptors * Dopamine receptors are further subdivided into D₁-D₅ receptors ## Classification of Direct-Acting Sympathomimetics by Spectrum of Action A tree diagram showing: * **Alpha agonists** * α₂-selective * α₁-selective * Nonselective * **Dopamine agonists** * Nonselective * **Beta agonists** * β₂-selective * β₁-selective * Nonselective # Receptor Selectivity of Sympathomimetics * Receptor Selectivity means that a drug may preferentially bind to one subgroup of receptors at a concentration (conc) too low to interact with another subgroup * However, none of these drugs is perfectly selective & at higher concentrations related classes of receptors may also interact with the drug * e.g., at high doses β₁ selective drugs have β₂ effects & vice versa # Alpha (α) Agonists * Alpha₁ - selective agonists (α₁ > α₂ >>>> β) * Phenylephrine * Methoxamine * Midodrine * Alpha₂-selective agonists (α₂ > α₁ >>>> β) * Clonidine * Oxymetazoline * Clenbuterol * Methylnorepinephrine # Beta (β) Agonists * Beta₁ - Selective Agonists (β₁ > β₂ >>>> α) * Dobutamine * Xamoterol * Beta₂ - Selective agonists (β₂ >> β₁ >>>> α) * Albuterol (salbutamol) * Ritodrine * Terbutaline * Salmeterol * Metaproterenol * Formoterol * Non-selective β agonists (β₁ = β₂ >>>> α) * Isoproterenol # Non-Selective Agonists (Mixed α & β Agonists) * Norepinephrine (α₁ = α₂; β₁ >> β₂) * Epinephrine (α₁ = α₂; β₁ = β₂) * Epinephrine is a prototype agonists with effects at α₁, α₂, β₁, β₂ & β₃ receptor types # Dopamine Agonists * Dopamine (D₁ = D₂ >> β >> α) * Fenoldopam (D₁ >> D₂) * Dopamine is a potent dopamine receptor agonist * When given as a drug it can also activate β receptors (intermediate doses) and α receptors (large doses) # Receptor Selectivity 3 * The distribution of these receptors & their actions is shown in table 1 (table 9-3 Katzung 13th/14th Ed) ## Table 1: Types of Adrenoceptors, Peripheral Tissues in which they are Found and their Major Effects | Type | Tissue | Actions | |---|---|---| | α₁ | Most vascular smooth muscle | Contracts (↑ Vascular resistance) | | α₁ | Pupillary dilator muscle | Contracts (mydriasis) | | α₁ | Pilomotor smooth muscle | Contracts (erects hair) | | α₁ | Heart | ↑ force of contraction (+ve Inotropic effect) | | α₁ | Prostate | Contraction | | α₂ | Adrenergic & cholinergic nerve terminals | Inhibits transmitters release | | α₂ | Platelets | Stimulates aggregation | | α₂ | Some vascular smooth ms | Contracts | | α₂ | Fat Cells | Inhibits lipolysis | | α₂ | Pancreatic β cells| Inhibits insulin release | | β₁ | Heart | ↑ses rate & force of contraction | | β₁ | Juxtaglomerular cells | Stimulates renin release| | β₂ | Airways, uterine & vascular smooth ms | Relaxes | | β₂ | Liver | Stimulates glycogenolysis | | β₂ | Pancreatic β cells | Stimulates insulin release | | β₂ | Somatic motor neuron terminals (voluntary muscle) | Causes tremor | | β₃ | Fat cells | Stimulates lipolysis | | β₃ | Bladder| Relaxes detrusor muscle | | Dopamine₁ (D₁) | Renal and other splanchnic blood vessels | Dilates (↓ resistance) | | Dopamine₂ (D₂) | Nerve terminals | Modulates transmitter release | # Chemistry & Pharmacokinetics (PK) * The endogenous adrenoceptor agonists (EP, NE & dopamine) are catecholamines. * If used as drugs, they are inactive by the oral route. * They must therefore be given parenterally * They are rapidly metabolized by Catechol-O-methyltransferase (COMT) & Monoamine oxidase) MAO. ## PK 2 * When released from nerve endings, they are subsequently taken up into nerve endings (step 6) & into peri-synaptic cells. * This uptake may also occur with EP, NE and dopamine given as drugs * The catecholamines have a short duration of action. ## PK 3 * When given parenterally, catecholamines do not enter the CNS in significant amounts * Isoproterenol, a synthetic catecholamine, similar to the endogenous transmitters. * It is not readily taken up into nerve endings ## PK 4 * Phenylisopropylamines, e.g., amphetamines are resistant to MAO. * Most of them are not catecholamines & are therefore also resistant to COMT * They are orally active. * They enter the CNS * Their effects last much longer than those of catecholamines ## PK 5 * Tyramine * Is a phenethylamine * It is rapidly metabolized by Monoamine Oxidase (MAO) except in patients who are taking a MAO inhibitor (MAOI) drug. # Mechanism of Action (MoA) * All adrenoceptors are G-protein coupled receptors. ## Alpha₁ Receptor Effects * α₁ receptor effects are mediated when G-proteins couple α receptors to phospholipase C. ## Alpha₁ Receptor Effects 2 * This leads to activation of the phosphoinositide cascade which causes release of Inositol- 1,4,5-trisphosphate (IP3) & Diacylclycerol (DAG) from membrane lipids. * Calcium is subsequently released from stores in smooth muscle cells, & enzymes are activated ## α₂ Receptor Effects * α₂ receptor activation results in inhibition of adenylyl cyclase & decreased cAMP formation. ## Beta Receptor Effects * Beta receptors (β₁, β₂ and β₃) stimulate adenylyl cyclase, causing increased cAMP conc in the cell. ## Dopamine Receptor Effects * Dopamine D₁ receptors activate adenylyl cyclase in neurons & vascular smooth muscle. * Dopamine D₂ receptors decrease the synthesis of cAMP. # Clinical Uses of Sympathomimetics ## Anaphylaxis * Epinephrine is the drug of choice (DOC) for immediate Rx of anaphylactic shock * It is a potent vasoconstrictor & cardiac stimulant ## CNS * The phenylisopropylamines, such as amphetamine, are widely used & abused for their CNS effects. * Legitimate clinical indications of amphetamine & its derivatives * Narcolepsy (irresistable urge to sleep, sleep paralysis & hallucinations at onset of sleep). * Attention deficit hyperactivity disorder (ADHD) * Weight reduction (with appropriate controls) * However, these drugs are abused or misused for * Deferring sleep & * Their mood elevating (euphoria-producing) action. * MAOIs may be used in the Rx of depression * Levodopa is a dopamine agonist used for Rx of Parkinson's disease ## Eye * The α agonists, especially phenylephrine, are often used topically: * To produce mydriasis (dilatation of pupils) & facilitate examination of the retina. * Rx of conjunctivitis to decrease conjunctival itching & congestion caused by irritation or allergy. * α₂ agonists used for Rx of glaucoma include: * Apraclonidine * Brimonidine * Phenylephrine ## Bronchi * The β₂ - selective agonists are DOCs in the Rx of acute asthmatic bronchoconstriction. ## CVS Applications * Conditions in which an increase in blood flow is desired. * In acute heart failure & Cardiogenic shock, an increase in cardiac output (CO) & blood flow to the tissues is required. * Beta₁ agonists (Dobutamine & dopamine) are used. ## CVS Applications 2 * Conditions in which a decrease in blood flow or increase in BP is desired. * α₁ agonists are useful in situations where vasoconstriction is appropriate. These include: * Inducing local vasoconstriction * Epinephrine is used to prolong effects of local anesthetics (LAs) * α agonists may be mixed with LAs to decrease the loss of anesthetic from the areas of injection into the circulation. * Nasal Decongestants * Phenyleprine * Pseudoephedrine * Xylometazoline * Oxymetazoline * Spinal shock. * NE or phenylephrine are used for temporary maintenance of BP to help maintain perfusion of the brain, heart, & kidneys. * Emergency management of cardiac arrest * Epinephrine. ## CVS Applications 3 * Conditions in which a decrease in blood flow or increase in BP is desired. * α₁ agonists are useful in situations where vasoconstriction is appropriate. These include: * Inducing local vasoconstriction * Epinephrine is used to prolong effects of local anesthetics (LAs) * α agonists may be mixed with LAs to decrease the loss of anesthetic from the areas of injection into the circulation. * Nasal Decongestants * Phenyleprine * Pseudoephedrine * Xylometazoline * Oxymetazoline * Spinal shock. * NE or phenylephrine are used for temporary maintenance of BP to help maintain perfusion of the brain, heart, & kidneys. * Emergency management of cardiac arrest * Epinephrine. ## CVS Applications 4 * Chronic postural (orthostatic) hypotension due to inadequate sympathetic tone can be Rx with * Oral ephedrine or * The orally active α₁ agonist, midodrine. * Rx of hypertension * α₂ selective agonists: Clonidine, Methyldopa, Guanfacine, Guanabenz * Fenoldopam: D₁ agonist Used IV ## Genitourinary Tract (GUT) * Beta₂ agonists (ritodrine, terbutaline) are sometime used to suppress premature labor. * However, the cardiac stimulant effect may be dangerous to both the mother & fetus. * Long-acting oral sympathomimetics e.g., ephedrine are sometimes used to Rx Incontinence in children with enuresis & in the elderly. * This action is mediated by α receptors in the trigone of the bladder &, in men, the smooth ms of the prostate. # Adverse Effects (AEs) ## Catecholamines * Because of their limited penetration into the brain, these drugs have little CNS toxicity when given systemically. ## AEs of Catecholamines 2 * In the periphery, their AEs are extensions of their pharmacologic alpha or beta actions & include: * Excessive vasoconstriction * Cardiac arrhythmias * Myocardial infarction * Hemorrhagic stroke * Pulmonary edema or hemorrhage ## Other Sympathomimetics * The phenylisopropylamines may produce mild to severe CNS toxicity, depending on dosage. * In small doses, these induce nervousness, anorexia, & insomnia. * In higher doses, they may cause anxiety, aggressiveness, or paranoid behavior. * Convulsions may also occur. ## AEs of Phenylisopropylamines 2 * In higher doses, they may cause anxiety, aggressiveness, or paranoid behavior. * Convulsions may also occur. ## AEs of Peripherally Acting Sympathomimetics * Peripherally acting agents have toxicities that are predictable on the basis of the receptors they activate as follows: * α₁ agonists cause hypertension * β₁ agonists cause sinus tachycardia and serious arrhythmias * β₂ agonists cause skeletal muscle tremor ## AEs of Peripherally Acting Sympathomimetics 2 * Cocaine is an important drug of abuse: * Its major toxicities include cardiac arrhythmias, myocardial infarction & convulsions. * A fatal outcome is more common with acute cocaine overdose than with any other sympathomimetic.