BIO 493 Drugs Nervous System Overview PDF

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BIO 493 -- Integrative Pharmacology -- Fall 2016 -- Professor Banes-Berceli -- Nervous system Lecture ...

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BIO 493: Integrative Pharmacology - Winter 2017 - Professor Banes-Bercelli Nervous System Drugs Overview

Receptors: - five subtypes of Muscarinic receptors M1-M5 - ex. drug pirezipine = muscarinic antagonist - decreases the effect of Ach - more potent at M1 receptors M1 located at autonomic ganglion cells - Agonist: Ach - Antagonist: Atropine M2 located at heart nodes (AV and SA nodes) - Agonist: Ach - Antagonist: Atropine M3 located in eye and smooth muscle - Agonist: Ach - Antagonist: Atropine M4 located in the CNS - Agonist: Ach - Antagonist: Atropine M5 located in the CNS - Agonist: Ach - Antagonist: Atropine Cholinergic Agonists M3 Distigmine, Pilocarpine, Pyridostigmine - Effects: improves muscular contraction - Uses: - Atonic bladder and urinary retention - Postpartum (lots of bleeding) or postoperative (stimulates the GI system)

- Muscular weakness - Myasthenia gravis - Ocular Eye pressure - Glaucoma - Side effects: - Sweating (diaphoresis), headache, urinary urgency, nausea, diarrhea, hypotension, salivation, flushing, abdominal pain and cramps, bronchial spasms (panting), heart palpitations or tachycardia, tremors - Interactions with other conditions: - Asthma, hyperthyroid, hypotension Acetylcholinesterase Inhibitors Donepezil, Rivastigmine, Pyridostigmine, Neostigmine, Galantamine, (Sarin) - Uses: - Cognitive deficit such as Alzheimers - Attention deficit (impaired memory) such as ADHD - Muscular weakness from Myasthenia Gravis - Side effects - Sweating (diaphoresis), headache, urinary urgency, nausea, diarrhea, hypotension, salivation, flushing, abdominal pain and cramps, bronchial spasms (panting), heart palpitations or tachycardia, tremors - Same as cholinergic agonists - Interactions with other conditions - constipation Adrenergic Receptors - Alpha1 class of receptors has 3 iso forms: -Alpha1A -Alpha 1B -Alpha 1D - Alpha2 class of receptors has 3 isoforms: -Alpha2A

-Alpha2B -Alpha2C - Beta class only has 3 receptors (no iso forms) Alpha1 Receptors: found in most vascular smooth muscles and in the pupils of the eyes - when stimulated cause vasoconstriction (dilation of the pupil) Alpha2 Receptors: found int he CNS on presynaptic neurons, some vascular smooth muscle cells, adipose tissue, and platelets - On smooth muscle is most prominent in neonates and small infants - when stimulated they inhibit cAMP ; coupled to GI - Inhibitory Differences between Alpha1 and Alpha2: - Location: Alpha1 is postjunctional, Alpha2 is pre junctional - Function: - Alpha 1 Stimulatory, Vasoconstriction, gland secretion, gut relaxation, glycogenolysis - Alpha 2 inhibition of trasmitter release, vasoconstriction, decreased central sympathetic outflow, platelet aggregation - Agonist: - Alpha 1 = Phenylephrine, methoxamine (OTC cold medicine) - Alpha 2 = Clonodine - Antagonist: - Alpha 1 = Prazosin - Alpha 2 = Yohimbine Properties of Beta1 Adrenergic Receptors - Located in cardiac muscle and kidneys - AV and SA Nodes - controls release of renin in the kidneys - Usually excitatory (activate cAMP) - equal affinity for norepinephrine and epinephrine - Receptors increase heart rate and stimulate renin release

- also increase force of contraction = increase blood pressure - agonist will increase blood pressure - antagonist will decrease blood pressure Properties of Beta2 Adrenergic Receptors - Located in some blood vessels and smooth muscle - usually inhibitory (activate cAMP) - greater affinity for epinephrine than for norepinephrine ** why we give people epi pen not norepi pen for treatment of anaphylactic shock - in the lungs these receptors are located in the bronchial smooth muscle and cause relaxation - ex. Albuterol Properties of Beta3 Adrenergic receptors - located in Adipose tissue - usually excitatory (activate cAMP) - equal affinity for norepinephrine and epinephrine - receptors stimulate pyrolysis by fat cells - release energy into the blood stream - no drugs in use clinically but can be used as a drug for obesity; activates Beta3 receptors Differences between Beta1, Beta2, and Beta3: Location: Beta1: Heart and JG cells Beta2: bronchi, uterus, blood vessels, urinary tract, eye Beta3: Adipose tissue Agonist: Beta1: Dobutamine Beta2: Salbutamol Antagonist: Beta1: Metoprolol, Atenolol

Beta2: Alpha-methyl Propranolol ** Glucocorticoid and mineralocorticoid receptors respond to cortisol - most common non selective reactions that we have due to their structural similarity ** Most drugs bind to Terminal portion on extracellular - don’t need to be lipophilic Drug Actions: - Block transmitter release - Botox - Block transmitter reuptake - cocaine - Block cleft enzymes that metabolize transmitter - Caffeine, neostigmine, MAOIs ** Reuptake really important for catecholamines ** MAOIs degrade all Bioamines Reuptake Mechanisms: - body recycles catecholamines and serotonin - Catecholamines are stored in vesicles and the transporter VMAT-2 (vessicular monoamine transporter) - VMAT-2 responsible for transport into vesicles from the cytoplasm - VMAT-2 will transport Dopamine, 5-HT, Norepinephrine, and epinephrine - VMAT-2 blocked by Reserpine - leads to a depletion of catecholamines - acts as neurotransmitter and CNS depression - leads to decrease in heart rate, mood, activity, respiratory, and even death Transporters: - Norepinephrine transporter (NET) = neuronal membrane transporter - highly selective - picks up norepinephrine from the cleft and puts it back into the presynaptic cell - blocked by cocaine and TCAs (tricyclic antidepressant - imipramine) - Dopamine Transporter (DAT) = neuronal transporter - found in CNS and periphery - particularly the kidney

Degradation of Adrenal Neurotransmitters - All biogenic amines broken down by 2 enzymes - MAO - COMT - 2 isoforms of MAO (MAO-A and MAO-B - most antidepressants that work on MAOs target both isoforms - Selegiline = MAO-B specific drug, irreversible - used to treat parkinson’s disease - COMPT is inhibited by Entacapone and Tolacapone - also treats parkinson’s to protect the neurotransmitter Categories of Action: ADRENERGICS Smooth muscle effects - smooth muscle activation including activation of blood vessel vasculature (skin and kidney) - Activation of glands (salivary and sweat) - Smooth muscle inhibition - including inhibition of smooth muscle of the gut, bronchioles, and skeletal muscle vascular smooth muscle

Cardiac Effects - increased heart rate - positive chronotropic effect - increased contractility - positive inotropic effect Metabolic effects - increase in rate of muscle and liver glycogenolysis - increase in free fatty acid release from fat Endocrine effects - Regulation/modulation of insulin, pituitary, and renin secretion Central Nervous System Effects - Respiratory stimulation - CNS Stimulation

- Appetite attenuation Presynaptic effects - modulation of release of norepinephrine or acetylcholine Epinephrine: - Potent activator of alpha and beta adrenergic receptors - prominent cardiovascular effects Epinephrine and Blood Pressure: - Potent vasopressor - systolic pressure increases more than diastolic pressure does (diastolic pressure may decrease) - pulse pressure widens - Epinephrine increases blood pressure by - enhancing cardiac contractility: positive inotropic effect - Beta1 receptor effects - increasing heart rate: positive chronotropic effect - Beta1 receptor effects - vasoconstriction Alpha1 receptor effects - pre capillary resistance vessels of the skin, veins kidney, and mucosa - If epinephrine is administered relatively rapidly the elevation of systolic pressure activates the baroreceptor reflex system - resulting in a reflex-mediated decrease in heart rate - helps to modulate and stabilize the pressure - reflex initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck - high density of baroreceptors is found in the wall of each internal carotid artery and in the wall of the aortic arch - As pressure rises (especially for rapid increases in pressure) baroreceptor input to the tracts solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers - vasodilation of the veins and arterioles in the peripheral vascular beds

- negative chronotropic and inotropic effects of the heart (slower heart rate with reduced force of contraction) Blood Pressure - Most potent vasopressor known = Endothelin 1 - both systolic and diastolic BP rise - has a characteristic effect on BP: Rapid rise to a peak - direct myocardial stimulation - Inotropic = increased heart rate - Chronotropic - Vasoconstriction which leads to increased peripheral resistance - reflex Bradycardia due to activation of the baroreceptor Question: - all EPI pens contain a warning label that you do not inject the EPI into a finger or thumb, the proper injection site is the thigh muscle - IM administration - if you injected the epi pen into the tip of the thumb there would be effects of necrosis in the tissue because the blood supply is cut off to that area - the receptor responsible for this action is the Alpha1 receptor Drugs Acting on the sympathetic system Sympathomimetics (mimic action of the sympathetic nervous system) - indirectly acting -Ephedrine -Amphetamine -Cocaine - directly acting - Alpha agonists - Alpha1, Alpha2 - Noradrenalin - Adrenalin - Alpha2

- Clonidine (catapress) - Alpha1 - Phenylephrine Adrenergic neuron blockers - Reserpine - Guanethidine Andrenoceptor antagonists - Alpha blockers - Alpha1 and Alpha2 - Phenoxybenzamine - Phentolamine - Alpha1 - Prazosin (Hypovase) Adrenergic (Alpha Blockers) - Alpha 1 antagonists Doxazosin, Guanethidine, Prazosin, Terazosin, Tamsulosin (flomax), Bethanidine, Phenoxybenzamine, Phentolamine - Uses: (to treat) - hypertension - prostatic hypertrophy - relieves constriction of bladder and prostate sphincters - Side effects: - Postural hypotension, Nausea and vomiting, Nasal congestion, Fatigue, headache, poor ejeculation, palpitations (Tachycardia), Oedema - postural hypotension = when you’ve been laying down for a while and stand up too fast and get woozy; blood pools in your legs and your intestinal tract; get a drop in BP Sympathomimetics - Indirectly acting - Ephedrine, Amphetamine, Cocaine, Methamphetamine, Dextroamphetamine, Methylphenidate (ritalin), Modafinil - Uses:

- obesity - somnolence - ADHD - sleep apnea - Fatigue - recreational drugs - Side effects - diaphoresis (sweating), headache, palpitations, fatigue, angina, depression, hypotension, hypertension, dry mouth, nausea and vomiting, poor appetite, diarrhea, abdominal cramps ** these drugs should not be used concurrently with MAOI’s — potentiates the response of these drugs, leftward shift on the dose response curve - Overdose: restless, irritable, insomnia, dizziness, tremors, talkativee, fever, anxiety, panic, confusion, delirium, hallucinations, aggressiveness, psychosis, suicial/homicidal thoughts, convulsions, coma, cerebral hemorrhage Adrenergic Beta Agonists/Antagonists: - Beta agonists - Beta1 and Beta2 - Adrenaline (epinephrine) - Isoprenaline - Beta2 - Salbutamol (Albuterol) - Terbutaline - Beta1 - Noradrenalin - Dobutamine - to treat congestive heart failure, increases heart rate and force of contraction - Beta Blockers - Beta1 and Beta2 - Propanolol (inderal) - Timolol (Meducren)

- Beta1 — Cardioselective - Metoprolol - Atenolol Adrenergic Beta Agonists: Adrenaline, Isoprenaline, Salbutamol, Terbutaline, Noradrenalin, Dobutamine,Xamoterol - Uses: - Congestive heart failure - Bradycardia - Asthma - Anaphylaxis - Side effects: - Tachycardia - Arrhythmias - Hypertension - Angina - ischemia of the heart muscle, heart working harder than oxygen being delivered Beta blockers: Atenolol, propranolol, metaprolol, timolol - Action: cardiac selective and non cardiac selective - beta blockers counteract the action of noradrenalin - reduce the force and speed of the heart beat - non cardiac selective drugs also prevent dilation of blood vessels in the head and extremities - Uses: - hypertension - migraines - hyperthyroidism - angina - myocardial infarctions

- Side effects: heart palpitations — bradycardia, Hypoclycemia (reduced glycogenolysis), Bronchoconstriction, insomnia, nightmare, depression, fatigue, cold extremities, peripheral vascular disease, Reynaud’s syndrom, decreased libdo and ejeculation problems - Contraindications: when you are not supposed to give a drug - Bradycardia, hypotension, metabolic acidosis, peripheral arterial disease, hear bloc/failure, Phaeochromocytosis (tumor on adrenal glad secreting large amounts of epinephrine), bronchial ashthma Adrenaline - Clinical uses - injectable preparations available in dilutions 1/1000, 1/10000, 1/100000 - usual dose .3-.5 mg sc of 1/10,000 solution - used in: - Anaphylactic shock - prolong action of local anesthetics - cardiac arrest - topically to stop bleeding Mucosal Decongestants - Works at alpha1 receptor - nasal and bronchial decongestants are used in allergic rhinitis, colds, coughs, and sinusitis as nasal drops - Sympathomimetic vasoconstrictor with Alpha effects used - Mucosal ischemic damage occurs if used excessively - more often than 3 hourly or for prolonged periods (more than 3 weeks) - rebound congestion leads to overuse — can cause addiction - use ephedrine, phenylpherine, xylometazoline for only a few days since longer application reduces capillary action - Do not use Naphazoline and Adrenaline - Do not use mixtures of vasoconstrictor, antihistaminic, adrenal steroid, and antibiotic - oily drops and sprays may cause lipoid pneumonia - lead to failure of antihypertensive therapy - fatal hypertensive crisis occurs in patients on MAOIs

- will increase blood pressure because they act at the alpha1 receptor Phenylephrine — most commonly seen in OTC cold medicine, has no affect on beta1 receptor on the heart - selective, synthetic, and direct alpha1 agonist - administered parenteral and topically (eye, nose) - long duration of action - resistant to MAO and COMT - peripheral vasoconstriction leads to rise in BP - reflex bradycardia - produces mydriasis and nasal decongestion - used in hypovalaemic shock as pressor agent - Sinusistis and Rhinitis as nasal decongestant - Mydriatic in the form of eye drops and lowers intraocular pressure - Does NOT cross the blood, brain, barrier, NO CNS effects - actions qualitively similar to noradrenaline - ADRs: photosensitivity, conjunctival hyperemia, and hypersensitivity

Ephedrine — causes stimulation of CNS: anxiety, insomnia; Pseudophedrine is similar - plant alkaloid, indirect sympathomimetic actions resembling adrenaline peripherally - Centrally - Increased alertness, anxiety, insomnia, tremor and nausea in adults - sleepiness in children - Effects appear slowly but last longer (half life = 4 hours) - Achyphylaxis on repeated dosing — can develop problems to it with repeated use - Used as bronchodilator, mydriatic, in heart bloc, mucosal vasoconstriction, and in myasthenia gravis - Phenylpropanolamine (PPA) on prolonged administration to women as anorectic causes pulmonary valve abnormality - can damage heart valves and cause anorexia with prolonged use

Beta2 Adrenergic Agonists: Salbutamol (Albuterol, ProAir), Terbutaline, Salmeterol, Isoxsuprine, Ritodrine - short acting: Salbutamol, Metaproterenol, Terbutaline, Pirbuterol - good for inhalers - Selective for Beta2 receptor subtype - used for acute inhalation treatment of bronchospasm - onset of action within 1-5 minutes - bronchodilation lasts for 2-6 hours - duration of action longer on oral administration - directly relax airway smooth muscle - relieve dyspnoea of asthmatic bronchoconstriction - Long acting: Salmeterol, Bitolterol, Colterol Clonidine: - agonist to postsynaptic Alpha 2A adrenoceptors in brain - stimulation suppresses sympathetic outflow and reduces blood pressure - inhibitory; couple to GI - High dose activates peripheral presynaptic auto receptors on adrenergic nerve endings -mediating negative feedback suppression of noradrenaline release - Overdose stimulates peripheral postsynaptic Alpha1 adrenoceptors and cause hypertension by vasoconstriction - Chlonodine reduces blood pressure - treatment for hypertension, shuts down outflow from the sympathetic nervous system Chlonidine - ADRs - Sedation, dry mouth - TCAs antagonize anti-hypertensive action - increase rebound hypertension of abrupt withdrawal - Low dose of Clonidine (50-100 ug/dl) used in migraine prophylaxis, menopausal flushing, and chorea

- Moxonidine, Rilmenidine — Newer Imidazolines Muscarinic receptors: M1 located at autonomic ganglion cells - Agonist: Ach - Antagonist: Atropine M2 located at heart nodes (AV and SA nodes) - Agonist: Ach - Antagonist: Atropine M3 located in eye and smooth muscle - Agonist: Ach - Antagonist: Atropine M4 located in the CNS - Agonist: Ach - Antagonist: Atropine M5 located in the CNS - Agonist: Ach - Antagonist: Atropine Muscarinic Receptor Agonists: - 2 major groups 1. Choline esters - including Ach and synthetic esters 2. Cholinomimetic alkaloids and their synthetic congeners - pilocarpine, muscarine - of all possible agonists investigated only Methacholine, Carbachol, and Bethanechol have clinical applications - Pilocarpine has limited clinical uses - Methacholine (acetyl-meta-methylcholine) = synthetic choline ester - longer duration of action than Ach - methyl group makes it more resistant to acetylcholinesterase - harder to degrade

- acts mostly at muscarinic receptors with minor actions at nicotinic receptors - Carbachol and Methanecol - almost completely resistant to acetylcholinesterase - long half life - Carbachol has nicotinic and muscarinic activity - Bethanecol has mostly muscarinic actions on GI motility and urinary bladder Pilocarpine - has dominant actions at muscarinic receptors and is a partial agonist — mostly dental uses - clinical use as a sialagogue (increases the flow rate of saliva) and as a miotic agent (used in eye drops to treat glaucoma) - Sialogogues used in treatment of xerostomia - subjective feeling of having a dry mouth - stimulates any functioning salivary gland tissue to produce more saliva - Low levels of saliva can result in dental cavities, fungal infections (such as oral candidiasis), tooth enamel demineralization and xerostromia - M3 receptor has been identified as the principle target to increase salivary flow rates - max dose of the drug = 30 mg/day Muscarinic Receptors and Cognition - M1, M2, and M3 receptors may all be involved in the regulation of cognitive function - makes receptors attractive targets in cases of cognitive decline - common disease that includes cognitive decline = Alzheimer’s disease

Alzheimer’s Disease: - neurons associated with the Ach system degenerate in people with Alzheimer’s disease - disease affects 10-15% of people 65+ and 50% of people age 85

- Degeneration of cholinergic neurons - decreased amount of Ach in certain areas of the brain - loss of postsynaptic neurons that would have responded to it - Signs for alzheimer’s victims - declining language and perceptual abilities, confusion, and memory loss - Medication treatments include CHOLINESTERASE INHIBITORS - curb the breakdown of acetylcholine to increase the levels of acetylcholine in the brain (chemical in the brain important for memory and learning) - these drugs slow the progression of symptoms for about half of people taking them for a limited time — about 6-12 months Aricept = only treatment approved for all stages of Alzheimer’s disease (mild, moderate, and severe) - tablets to swallow or tablets to dissolve in mouth Exelon = approved for use in mild to moderate Alzheimer’s dementia - skin patch, capsules, and liquid form Razadyne = approved for mild to moderate Alzheimer’s dementia - extended-release capsule, immediate-release tablet, and liquid forms ** common side effects are usually mild for these medications include diarrhea, vomiting, nausea, fatigue, insomnia, loss of appetite, and weight loss Namenda = approved to treat moderate to severe Alzheimer’s disease - works by a different mechanism - plays a protective role in the brain by regulating the activity of a bra...