Pharmacology Exam 1

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Pharmacology Exam 1
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2013-09-20 07:03:15
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Medicine Pharmacology Carver College
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First Carver College of Medicine Pharmacology Exam
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  1. Endobiotics
    Agents normally produced within the body that are used therapeutically
  2. Xenobiotics
    Agents not normally produced within the body (such as foreign chemicals)
  3. Therapeutics vs Pharmacology
    • Pharmacology: The study of how drugs affect biological systems
    • Therapeutics: The treatment of disease
  4. Pure Food and Drug Act Year
    1906
  5. Harrison Narcotic Act Year
    1914
  6. Food, Drug and Cosmetic Act Year and Amendments
    • 1938
    • Durham-Humphrey made legend drugs, which cannot be dispensed without a prescription, and OTC drugs in 1951
    • Kefauver-Harris amendments in 1962
  7. Controlled Substances Act Year and Concepts (schedules)
    • 1970
    • Schedule I: Drugs without legal medial use
    • II: Drugs with highest abuse potential
    • III-V: Decreasing abuse potential
  8. How are drugs developed and marketed? (Phases of trials)
    • Preclinical studies
    • Clinical studies
    • Phase I: Initial dose range and safety
    • Phase II: Efficacy in disease and effective dose
    • Phase III: Compare with best treatment
    • Phase IV: Post-marketing monitoring of new drugs
  9. Categories of OTC drugs
    • Category I: Safe and effective
    • Category II: Not safe, not effective, or both
    • Category III: Inconclusive data
  10. Dietary Supplement Health and Education Act Year and Information
    • 1994
    • FDA doesn't regulate vitamins, minerals, herbals, botanicals, amino acids and metabolites, extracts and constituents
  11. Describe the Phases of Drug Action
    • Administration
    • Pharmaceutical phase: Disintegration of dosage
    • Pharmacokinetic phase: Absorption, distribution; metabolism and excretion is also included
    • Pharmacodynamic phase: Drug-receptor Interation and effect
  12. General Routes of Administration
    • Enteral: Oral, sublingual, rectal
    • Parenteral: subQ, im, iv, ia, intraspinal
    • Pulmonary: Inhilation
    • Dermal: Topical and transdermal
  13. When pKa = 1, what percentage of the drug is ionized?
    50%
  14. Henderson-Hasselbalch
    • Acids
    • pH = pKa + log([ionized]/[non-ionized])
    • Ka = [H+][A-]/[HA]
    • Bases
    • pH = pKa + log([ionized]/[non-ionized])
  15. pH Partition Hypothesis
    The non-ionized, more lipid-soluble form crosses biomembranes much more readily than does the ionized, more water-soluble form
  16. How are most drugs transported through biological membranes?
    • Via active transport through:
    • ABC transporters (contain ATPase) that are generally efflux transporters or
    • Solute-carrier (SLC) transporters (have an indirect energy source of the chemical gradients) that are generally influx transporters
  17. What factors affect the distribution of drugs? (4)
    • Blood flow (differs for tissues)
    • Ease of drug crossing membrane barriers (includes effects from pKa of drug, pH of compartments, and concentration gradients)
    • Polarity of drug (non-polar drugs go to brain and adipose tissue)
    • Binding to plasma proteins
  18. How can plasma protein binding affect drug dosage and toxicity when another drug is given?
    Drugs that are highly bound to plasma proteins may displace one another from binding sites, resulting in greater biologic effects, metabolism, and toxicity
  19. Describe the blood-brain barrier
    • It is made of tight junctions between endothelial cells, resulting in greater permeability to lipid-soluble drugs than water-soluble ones
    • It is NOT fully developed at birth
  20. What are the two classifications of drug responses?
    • Quantal: Arrhythmias, convulsions, death
    • Graded: Blood pressure, plasma glucose
  21. Efficacy versus potency
    • Efficacy: Change in the maximal effectiveness (Emax)
    • Potency: Change in the effective dose (ED50); need more drug to get the same response
    • A potency ratio can be obtained by dividing effective doses for different drugs. Tells us this drug is __x's more potent than this drug
  22. Therapeutic index
    • A ratio of two doses, the toxic or lethal dose 50 and the effective dose 50
    • Tells us how far apart the response curves are, and how safe the drug is
  23. Agonist
    A drug that, by itself, produces a response
  24. Antagonist
    A drug that, by itself, produces no response but prevents the agonist response by interacting with the receptor
  25. Partial agonist
    Any drug that produces a response less than a full maximal efficacy
  26. Inverse agonist
    A drug that, by itself, produces a response to suppress endogenous agonists
  27. Types of antagonists
    • Pharmacological Antagonists
    • Competitive: Bind at the same site on the receptor; effects can be overcome by giving more agonist (no change in maximal effectiveness, but ED50 changes)
    • Noncompetitive: Effects cannot be overcome because binding is irreversible (there is a change in maximal effectiveness, but no change in ED50)
    • Partial agonists: Can be antagonists when given with an agonist; this is because it is decreasing the full agonist activity due to competition for receptor binding
    • Chemical Antagonists
    • Physiological Antagonists
  28. Receptor Specific Versus Receptor Selective
    • Specific: Interacts with only one receptor subtype
    • Selective: interacts with several receptor subtypes but has a preference for one of them
  29. Idiosyncratic Drug Response
    Unusual or atypical response in a small percent of individuals
  30. Tolerance
    A decreased response that takes hours to develop
  31. Tachyphylaxis
    Decreased response that develops in minutes
  32. Refractoriness
    Decreased response or no response
  33. Differences in Side, Adverse, and Toxic Effects
    • Side: Minor, undesired
    • Adverse: Major, serious medical consequences
    • Toxic: Very serious adverse effects
  34. The Four Basic Sources of Side/Adverse Effects
    • Chemical properties of the drug
    • Drug that interacts with multiple receptor types (dirty drugs)
    • Drug that interacts with single receptor type but multiple subtypes of that receptor
    • Drug that interacts with single receptor subtype but receptor is in multiple tissues or acts vial multiple receptors
  35. Termination of Drug Action Process
    • 1: Redistribution
    • 2: Biotransformation
    • Phase 1 - Drug becomes more polar due to addition or unmasking of an -OH, -NH2, or -SH. Oxidations (P450s, CYPs, or monoamine oxidases), reductions (oxidoreductases), and hydrolysis (cholinesterases) are included
    • Phase 2 - Drug becomes conjugated and very polar by addition of an endogenous polar substance such as glucuronic acid, sulfate, an amino acid, or GSH (transferases)
    • 3: Excretion
  36. P450 Mixed Function Oxidase System
    R-H + O2 + NADPH ----> R-OH + H2O + NADP
  37. Types of Phase II Biotransformation Reaction Enzymes
    • They are all transferases
    • Glucuronyl Transferases (UGTs 1, 2, or 8): First, substrate is activated to make UDPGA, and then a GA is transferred to the R group and leaves UDP
    • Sulfotransferases (ST 1 or 2): Also happens in two steps, annd makes a sulfate (SO4) added onto R group from PAPS
    • Catechol-O-methyltransferase (COMT)
    • Acetyltransferases
    • Glutathione transferases
  38. Active Metabolite
    A drug metabolite that has significant activity (sometimes greater than the parent compound)
  39. Prodrug
    Inactive or relatively inactive precursor that is converted by metabolism to a more active compound
  40. Reactive Metabolite
    Very toxic compound produced by biotransformation of a relatively inert substance
  41. Inhibitors of Drug Metabolism and Effect on Drug-Drug Interactions
    • Cimetidine (an imidazole), erythromycin (an antibiotic), grapefruit (part of the bioflavonoids), an proadifen (SKF 525-A) all decrease metabolism and increase drug levels
    • Different CYPs are inhibited, usually directly
    • Common site of drug-drug interaction
  42. Activators of Drug Metabolism and Effect on Drug-Drug Interaction
    • Ethanol, phenobarbital, phenytoin, and DDT all activate metabolism and decrease drug levels
    • Different CYPs are affected to enhance synthesis, reduce degradation, or directly activate enzymes
    • Common site of drug-drug interaction
  43. Routes of Drug Excretion
    • Major: Kidney, liver, GI tract, lungs
    • Minor: Mammary gland, tears, saliva, sweat
  44. If a deficiency in a drug's primary route of excretion occurs, what happens?
    Increased plasma concentration and enhanced drug effects!
  45. Methods of Excretion and Where They Occur
    • Filtration
    • Kidney glomerulus
    • Liver when under 200MW
    • Passive Diffusion
    • Kidney
    • Active Secretion
    • Proximal tubules of kidney by organic anion/cation transporters, MRPs, P-glycoproteins, or conjugates
    • Liver also has OATs/OCTs, MRPs, and transporters for bile salts and steroids
    • OATs are inhibited by probenecid and OCTs are inhibited by cimetidine
  46. Css
    The average steady-state plasma concentration of a drug that we desire. It's right smack in the therapeutic range
  47. Bioavailability (F)
    • The fraction of the administered drug reaching the systemic circulation in its active form
    • On a graph of drug concentration and time, bioavailability is the area under the curve
  48. Volume of distribution (Vd)
    • The apparent volume in which a drug distributes. It's a proportionality factor, not a real value.
    • = Amount of drug in body / Concentration in plasma
    • To determine the plasma concentration at time zero, plot multiple over time as a log and extrapolate Cp
  49. Clearance (CL)
    • Removal of drug from a volume of plasma in a given time
    • = Rate of elimination / Cp
    • = Clearance volumes add up for all systems (renal, liver) and include elimination by excretion and metabolism
  50. Elimination processes are limited by capacity or delivery
    • 1st Order Elimination: Delivery-limited; rate of elimination depends on plasma concentration; clearance is constant; a fixed percentage of drug is removed per unit time
    • Oth Order Elimination: Capacity-limited; rate of elimination is independent of plasma concentration; clearance is variable; a fixed amount of drug is removed per unit time; when concentration gets really low, 1st order occurs
  51. Clearance of an organ
    • CLorgan = Q x ER / dt
    • Q: Blood flow
    • ER: Extraction ratio
    • Extraction ratio = Ci (entering) - Co (exiting) / Ci
  52. Loading dose (DL)
    • = Css X Vd / F
    • The steady-state plasma concentration times the volume of distribution over the fraction of the administered drug reaching the systemic circulation in its active form
  53. Maintenance dose (DM)
    • = Css x CL x dosing interval / F
    • Dependent upon rate of elimination (Cp x CL)
  54. Dosing frequency determination
    • Dependent on clearance and thus, drug half-life (t1/2)
    • t1/2 = 0.693 x Vd / CL
    • Half-life is a good interval to use initially and then alter after 4-5 doses (plateau effect)
  55. If a drug is given orally and a patient develops hepatic disease, what happens to the bioavailability of the drug?
    • It increases, because the "first-pass" effect is lessened due to the hepatic disease
    • We also need to remember that plasma proteins are decreased
  56. Parasympathetics exit the CNS through what nerves?
    CN III, VII, IX, X and S2-4
  57. Sympathetics exit the CNS through what nerves?
    T1-12 and L1-3
  58. On what nerves is myelin present?
    The preganglionics for both sympathetic and parasympathetic nerves and somatic motor nerves to skeletal muscles
  59. What neurotransmitters are used in the autonomic nervous system?
    • Acetylcholine: All parasympathetics, all somatic nerves, all preganglionic sympathetic nerves, and some postganglionic sympathetic nerves (about half of them to sweat glands--the thermoregulatory ones)
    • Norepinephrine: Most postganglionic sympathetic nerves (non-thermoregulatory sweat glands also)
    • Epinephrine: Released by the adrenal medulla directly into the bloodstream
    • Dopamine: Some postganglionic sympathetic nerves (smooth muscles of renal and splanchnic vasculature)
  60. Cotransmitters
    • Packaged with primary transmitters and are released into the synapse
    • My be a primary NT in noncholinergic/nonadrenergic nerves
    • Ex: purines (adenosine, ATP), peptides (cholecystokinin, somatostatin, substance P, neuropeptide Y, vasoactive intestinal peptide), or nitric oxide
  61. Acetylcholine interacts with what kind of receptors?
    • Two cholinergic receptor subclasses
    • Nicotinic (ligand-gated ion channels)
    • N1: Sympathetic and parasympathetic ganglia
    • N2: Neuromuscular junction (somatic nervous system)
    • Muscarinic (G protein-coupled receptors) - Mimic the parasympathetic nervous system
    • M1: Ganglia and secretory glands
    • M2: Smooth muscle and cardiac muscle
    • M3 and M4: Smooth muscle, secretory glands, and endothelium
  62. Acetylcholine receptor locations and mechanisms
  63. Muscarinic receptor description and mechanism
    • 7-transmembrane receptors coupled to G proteins
    • M1 receptors: Bind Gq/11, and when activated, cause activation of phospholipase C, DAG, and IP3
    • M2 receptors: Bind Gi/0, and cause inhibition of cAMP production and K+ channel activation
    • M3 receptors: Just like M1
  64. Parasympathetic nervous system activation causes what general effects?
    • Eye
    • Sphincter muscle: Contraction
    • Ciliary muscle: Contraction
    • Heart (Decreased blood pressure!)
    • SA node: Decreased heart rate
    • Atria: Decreased contractile strength, decreased refractory period
    • AV node: Decrease conduction velocity, increased refractory period
    • Ventricles: Small decrease in contractile strength
    • Blood Vessels: Dilation via EDRF of both arteries and veins; constriction occurs when a high dose is directly applied
    • Lung
    • Bronchial muscle: Contraction
    • Bronchial glands: Stimulation
    • GI Tract: Increases motility, relaxes sphincters, and stimulates secretions
    • Urinary Bladder: Contraction of detrusor muscle; relaxation of trigone and sphincter
    • Glands: Secretion from sweat glands, salivary glands, lacrimal glans, and nasopharyngeal glands

    • Decreased blood pressure
    • Constriction of bronchi
  65. Pseudocholinesterase
    Found throughout the body (plasma, liver, glial cells, satellite cells) to break down released ACh by hydrolysis
  66. Norepinephrine interacts with what kind of receptors?
    • Adrenergic receptors (which are all G protein-coupled receptors) at sites innervated by postganglionic sympathetic nerves
    • 1: Smooth muscle (activation of phospholipase C)
    • 2: Postganglionic sympathetic nerve terminals and presynaptic adrenergic nerve terminals (inactivation of adenylate cyclase)
    • 1: Cardiac muscle and presynaptic adrenergic and cholinergic nerve terminals (activation of adenylate cyclase)
    • 2: Smooth muscle, cardiac muscle, adipose tissue (activation of adenylate cyclase)
  67. Dopamine interacts with what kind of receptors?
    Dopamine receptors on some postganglionic sympathetic nerve terminals and at postjunctional sites on renal vascular smooth muscle
  68. How are sweat glands innervated?
    • The stress-responding sweat glands (non-thermoregulatory) are innervated by sympathetics, but about half of these nerves release ACh instead of NE
    • "Cholinergic sympathetic" nerves are the ones that release ACh, and it acts upon muscarinic receptors (those are parasympathetic-like)
  69. How is the adrenal medulla innervated?
    • By sympathetic nerves which have no postganglionic fibers, and therefore use ACh as the neurotransmitter, just as all other preganglionic sympathetics do
    • The chromaffin cells release epinephrine (80%) and norepinephrine (20%) into the venous circulation
  70. What organs receive only sympathetic innervation?
    Blood vessels, liver, spleen, adrenal medulla, and sweat glands
  71. Cholinergic drugs cause stimulation of what?
    The parasymphathetic nervous system via muscarinic receptors
  72. ACh synthesis
    • Occurs in the nerve terminal, and is limited by the rate of choline uptake
    • Choline uptake occurs via sodium-dependent choline high affinity transport (CHT)
    • Choline acetyltransferase (ChAT) makes ACh on the surface of vesicles, which is then transported into synaptic vesicles
  73. What happens to inactivate ACh after it is released in the synapse?
    • It is hydrolyzed at the ester linkage by acetylcholinesterase in a 2-step reaction, with acetylated AChE as a transient intermediate
    • About 50% of the remaining choline molecules are taken up by the CHT mechanism and the rest diffuse away
  74. How can drugs mimic the parasympathetic system?
    • 1: Directly stimulating the muscarinic receptors [acetylcholine, bethanechol, carbachol, methacholine, pilocarpine]
    • 2A: Inhibiting acetylcholinesterase competitively [edrophonium, tacrine, donepezil demecarium, neostigmine, physostigmine, pyridostigmine]
    • 2B: Inhibiting acetylcholinesterase noncompetitively [organophosphate derivatives such as insecticides and nerve gases, malathion, parathion, sarin, soman]. These are irreversible and are highly toxic! Only echothiphate is used clinically for glaucoma. May be reversed with pralidoxime
  75. Symptoms of intoxication by organo-phosphte AChE inhibitors
    • Excessive parasympathetic stimulation
    • SLUD: Salivation, lacrimation, urination, defecation
    • Depressed heart rate and arterial pressure
  76. How is organo-phosphate intoxication overcome?
    • Atropine may be given to antagonize muscarinic receptors
    • Norepinephrine may be given to activate adrenergic receptors, since we want to decrease parasympathetic activity and increase sympathetic
    • Pralidoxime can be given to reactivate AChE (before it has reached the "aged" stage)
  77. For what are anticholinergic drugs used clinically?
    • Peripheral: Mydriasis (to dilate the pupil); cycloplegia (to lose accomodation of the lens); to decrease secretions of the respiratory tract before giving inhalant anesthetics; to calm hyperactive smooth muscle, GI, or genitourinary incontinence; when patient has excess bradycardia and hypotension (can be from cardiac catheterization, excessive vagal activity, muscarinic drugs, and inhibitors of AChE), poisoning with organo-phosphates, poisoning with muscarine-containing mushrooms; or as preanesthetic medications to ellicit amnesia (can be given for amnesia post-operatively also)
    • Central: Anti-Parkinson, anti-motion sickness, induction of amnesia prior to surgery
  78. What properties allow anticholinergic drugs to cross the blood-brain barrier?
    • Non-quaternary amines will cross the BBB, causing therapeutic actions or side effects
    • Tertiary amines are also good at crossing mucous membranes and for topical use in the eye
  79. Anticholinergics often cause what side effects?
    • Peripheral: Photophobia (mydriasis/dilation), cycloplegia, xerostomia (dry mouth), tachycardia, difficult urination, red skin ("atropine flush"), increase in skin temperature, decreased sweating
    • Central: Sedation or excitement, amnesia
  80. What kinds of receptors do anticholinergics block?
    • Muscarinic receptors or nicotinic
    • We only use antimuscarinics clinically, since antinicotinics would block parasympathetic and sympathetic ganglia and skeletal muscle
  81. In general, what happens when the parasympathetic division is inhibited?
    • Increased heart rate
    • Increased blood pressure
    • Inhibition of GI movements
    • Failure to empty bladder and rectum
    • Inhibition of mucosal cells and salivary/lacrimal glands
    • Dilation of bronchi
  82. Muscarinic antagonist receptor selectivity
    • Muscarinic antagonists competitively bind muscarinic receptors
    • However, at high dosages, a partial blockage of autonomic ganglia occurs, even though they are nicotinic receptors
  83. "Atropine fever"
    • Atropine blocks muscarinic receptors, thereby blocking the "cholinergic sympathetic" sweat glands, which are thermogenic
    • This results in an increased body temperature due to impaired ability to sweat
  84. Parkinson disease treatment
    • In Parkinson disease, excess cholinergic activity results in tremor and rigidity
    • This occurs due to a loss of dopamine-producing cells
    • Treat with levodopa (dopamine precursor) and anticholinergic drugs that are tertiary amines
  85. Tertiary versus quaternary amines
    • Tertiary: Can cross BBB and mucous membranes; good for use in the eye
    • Quaternary: Cannot cross BBB due to poor lipid solubility from charged ammonium group; very bad absorption following oral administration; also poorly absorbed across the conjunctiva
  86. Ganglionic agents
    • Ganglionic stimulants: Amplify stimulation of both sympathetic and parasympathetic divisions of the ANS by stimulating N1 receptors
    • Ganglionic blockers: Inhibit neurotransmission by N1 receptors with equal potency and efficacy in both sympathetic and parasympathetic ganglia; such a broad effect, are difficult to use clinically
    • Clinical uses: Adjunct therapy for severe hypertension and severe peripheral vascular disease
  87. Importance of nicotine
    • Nicotine causes: Increased cardiac rate, vasoconstriction, and plasma levels of epinephrine from stimulation of adrenal medulla; decreased mucociliary movement in lungs; and mild CNS stimulation
    • Also causes small cell carcinoma of the lung and cardiovascular disease
    • Lethal dose: 40mg (same as cigar), but bioavailability is very low
    • Keep in mind that nicotine also stimulates N2 receptors in addition to N1
    • Chronic nicotine toxicity from smoking is the largest single preventable cause of illness and premature death (4/5 leading causes of death)
  88. Ganglionic blockers use and effects
    • Used for increasing blood flow to peripheral organs, increasing nutrient absorption from GI tract due to decreased motility, or for decreasing blood pressure to lessen bleeding
    • Blocks adrenergic control of blood vessels, resulting in dilation and decreased blood pressure
    • Side effects from blocking sympathetics: Postural hypotension, tachycardia, decreased cardiac output, decreased total peripheral resistance, fainting, no sweating (both non- and thermoregulatory sweat glands controlled by sympathetics)
    • Side effects from blocking parasympathetics: Dry mouth, urinary retention and constipation, mydriasis and cyclopegia, prevention of erection and ejaculation, and decreased GI motility/secretions
  89. When a ganglionic blocker is used, what is the main effect on major organ systems?
  90. What happens to denervated skeletal versus smooth muscle?
    • Denervation supersensitivity: The threshold dose of ACh needed to trigger a response is significantly reduced, due to increased N2 receptor expression on the muscle surface in a disorganized pattern
    • Skeletal: Muscle atrophy
    • Smooth: Muscles do not atrophy
  91. How is relaxation of skeletal muscles induced?
    • Competitive inhibitors of acetylcholine: Drugs that compete with acetylcholine for N2 receptor sites
    • These are reversed by use of AChE inhibitors
    • Noncompetitive depolarizing agents: These drugs depolarize the end-plate region; cause contraction first, followed by persistent relaxation and inhibition
    • These are augmented by use of AChE inhibitors (they are susceptible to breakdown by AChE)
  92. Describe flaccid paralysis from neuromuscular blockers
    • Competitive inhibitors of acetylcholine: Cause total flaccid paralysis by the fine motor function loss first, followed by limb/neck/trunk muscle function, and finally by loss of intercostal muscles and diaphragm contraction
    • Noncompetitive depolarizing N2 inhibitors result in:
    • Phase I block: Results in flaccid paralysis due to inability to repolarize; AChE inhibitors augment this effect
    • Phase II block: Desensitizing block, because repolarization occurs, but the membrane is resistant to any further depolarization
  93. Side effects and contraindications of noncompetitive depolarizing neuromuscular blocking agents
    • Excessive loss of K+ ions from skeletal muscle that can lead to cardiac arrest (CHF patients, burns, trauma)
    • Contraction of extra-ocular muscles that could cause eye damage in glaucoma patients
    • May produce prolonged Phase II (desensitizing) inhibition of neuromuscular transmission for many hours [maybe due to plasma cholinesterase inhibition by O-P and continued action of succinylcholine or due to a genetic defect in plasma cholinesterase]
    • Contraindications: Liver/renal dysfunction; hypotension may occur due to blockage of N1 receptors or histamine release; antibiotics may potentiate blocking; patients with myasthenia gravis; patients with decreased AChE
  94. Neuromuscular (N2) blockers clinical uses
    • Relaxation of skeletal muscle for surgery, intubation, control of ventilation, or treatment of convulsions
    • Prevention of broken bones during electroshock therapy
    • Relaxation of spastic muscles (rare)
    • Remember to: Check respiration
  95. Reversal of neuromuscular blockers
    • Transmission can be increased by inhibiting acetylcholinesterase [neostigmine]
    • Ephedrine also enhances muscle contraction, but its mechanism is unknown
  96. Dibucaine test
    • A test for genetic variations of the AChE gene
    • These patients may respond to succinylcholine with an even longer neuromuscularblockade
  97. Alpha-1 adrenergic receptors
    • Location and Role: Contraction/constriction of arteries & veins, iris radiator muscle (to cause mydriasis), ejaculation, piloerection; glycogenolysis (liver); and relaxation of GI smooth muscles
    • Receptor Mechanism: G protein-coupled; agonists bind Gq; results in activation of phospholipase C
    • Major Stimulants: Phenylephrine, methoxmine
    • Epinephrine and Norepinephrine: Agonists
    • Dopamine:
    • Remember big picture - Found at postganglionic sympathetics
  98. Alpha-2 adrenergic receptors
    • Location and Role: Postganglionic sympathetic nerve terminals; presynaptic adrenergic nerve terminals to allow for negative feedback to decrease NE release from terminals
    • Receptor Mechanism: G protein-coupled; agonists binds Gi; results in inhibition of adenylate cyclase
    • Major Stimulants: Clonidine, methyl-NE
    • Epinephrine and Norepinephrine: Agonists
    • Dopamine:
    • Remember big picture - Found on postganglionic sympathetic terminals
  99. Beta-1 adrenergic receptors
    • Location and Role: Heart and adipose tissue; results in increased heart rate, contractile force, cardiac output, and lipolysis; also found at presynaptic adrenergic and cholinergic nerve terminals
    • Receptor Mechanism: G protein-coupled; agonists bind Gs; results in activation of adenylate cyclase
    • Major Stimulants: Dobutamine, isoproterenol
    • Less-strong stimulants include albuterol, terbutaline, metaproterenol
    • Epinephrine and Norepinephrine: Agonists
    • Remember big picture - Found at postganglionic sympathetics
  100. Beta-2 adrenergic receptors
    • Location and Role: Vasodilation of skeletal muscle; relaxation of myometrium and intestines; dilation of bronchioles; reducing intraocular pressure
    • Receptor Mechanism: G protein-coupled; agonists bind Gs; results in activation of adenylate cyclase
    • Major Stimulants: Isoproterenol, albuterol, terbulatine, metaproterenol
    • Less-strong stimulants include Dobutamine
    • Epinephrine and Norepinephrine: Agonists
    • Remember big picture - Found at postganglionic sympathetics
  101. Beta-3 adrenergic receptors
    Location and Role: Increased glycogenolysis in liver and skeletal muscle
  102. Dopamine D1 adrenoreceptors
    • Location and Role: Renal and mesenteric vasodilation
    • Receptor Mechanism: G protein-coupled; agonists bind Gs; result in activation of adenylate cyclase
    • Major Stimulants: Fenoldopam
    • Dopamine: Agonist
    • Remember big picture - Found at postganglionic sympathetics
  103. Dopamine D2 adrenoreceptors
    • Location and Role: Presynaptic nerve terminals; allow for negative feedback to decrease neurotransmitter release
    • Receptor Mechanism: G protein-coupled; agonists bind Gi; results in inhibition of adenylate cyclase
    • Major Stimulants:
    • Less-strong stimulants: Fenoldopam (has a higher affinity for D1)
  104. Catecholamine biosynthesis
    • Tyrosine made into DOPA by tyrosine hydroxylase
    • DOPA to dopamine
    • Dopamine to norepinephrine
    • Norepinephrine to epinephrine (in adrenal medulla)
    • The rate is controlled by neuronal firing frequency: The higher the frequency, the more NT made
  105. Catecholamine metabolism
    • COMT: Transfers a methyl group onto catecholamine
    • MAO: Deaminates catecholimine
    • These enzymes render catecholamines inactive, and can do their reactions in either order
    • Methoxyhydroxyphenylglycol (MHPG) and vanillylmandelic acid (VMA) are metabolic products
  106. Adrenergic receptor agonists
    • Natural: Norepinephrine, Epinephrine, and Dopamine
    • Substitutions to Amino Group
    • Have greater beta activity
    • Isoproterenol
    • Dobutamine (slightly greater affinity to B1)
    • Terbutaline (greater affinity to B2)
    • Substitutions to Benzene Ring
    • Decreased potency with longer duration of action (since COMT cannot metabolize efficiently)
    • Metaraminol
    • Phenylephrine (slightly greater affinity to A1, then A2>>>>B)
    • Ephedrine
    • Substitutions to Alpha Carbon
    • Block oxidation by MAO and have prolonged activity
    • Also are able to displace NE from adrenergic storage vesicles
    • Metaraminol
    • Ephedrine
  107. Amine I transporter (NET)
    • Reuptake system for norepinephrine found at the terminal of postganglionic sympathetics
    • Amine I transports about half of norepinephrine back into nerve terminal for reuse (rest is diffused or metabolized by MAO or COMT)
    • Repackaged into vesicles via vesicular monoamine transporter (VMAT)
    • When this is inhibited [cocaine and tricyclic antidepressants], synaptic norepinephrine levels rise, resulting in sympathetic effects
  108. A2 and D2 receptor blockers
    • When these receptors, found on terminal of postganglionic sympathetics, are blocked, sympathetics are stimulated
    • This is because A2 and D2 receptors are activated by norepinephrine and dopamine, respectively, and turn off norepinephrine release
    • By blocking them, we get greater amounts of norepinephrine in the synapse and a greater sympathetic response
    • D2 blockers are antipsychotic agents [haloperidol, chlorpromazine]
  109. Norepinephrine releasing agents
    • Taken up by amine I (NET) transporter
    • Phenylethylamine derivatives: Dopamine, tyramine, ephedrine, amphetamine
  110. Pheochromocytoma
    • Tumor of the adrenal gland
    • Characterized by very elevated relase of epinephrine (and norepinephrine) into venous circulation and catecholamine excess excreted into the urine
    • Symptoms: Severe tachycardia, hypertension, headaches, increased sweating (due to nonthermoregulatory apocrine sweat glands)
  111. Hypertension can be treated with what classes of drugs?
    • Hyptertension can be treated by blocking the sympathetic nervous system
    • Presynaptic Nerve Terminal
    • Stimulation of A2 [clonidine, guanabenz, a-methyldopa; ] or D2 receptors results in decreased norepinephrine release
    • Stabilization of the nerve terminal membrane interferes with norepinephrine release
    • Inhibiting synthesis, storage, or release of norepinephrine
    • "False" neurotransmitters
    • Postsynaptic Receptors
    • Blocking A1, B1 (and B2 if nonselective), or D1 receptors
  112. A2 receptor agonists
    • Include guanabenz, clonidine, and a-methyldopa
    • Cause inhibition of norepinephrine release, and thereby inhibit the sympathetic nervous system
    • Used to treat hypertension
    • Side Effects: Sedation, xerostomia, anorexia, fluid retention, vivid dreams, & CNS stimulation
  113. D2 receptor agonists
    • Includes bromocriptine
    • Causes inhibition of norepinephrine release, and thereby inhibits the sympathetic nervous system
    • Used as anti-Parkinson agent (targets post-synapted D2 receptors in CNS)
    • Side Effects: Postural hypotension, development of cardiac arrhythmia
  114. Norepinephrine depleting agents
    • Prevent transport of norepinephrine, epinephrine, serotonin, and dopamine into storage vesicles by VMAT
    • Side Effects: Sedation, depression, Parkinsonian symptoms, increased GI motility & ulcers
  115. A1 adrenergic blockers
    • Used to lower MAP by inhibiting constriction/contraction, resulting in vasodilation
    • Competitive: Prazosin, phentolamine
    • Noncompetitive: Phenoxybenzamine
  116. B adrenergic blockers
    • Most are pure antagonists
    • Used for hypertension therapy, often with diuretics and other agents
    • B1/B2 Blockers: B2 blockade may inhibit dilation of bronchioles, which may be significant for patients with asthma; they also lower intraocular pressure following corneal application [propranolol, pindolol, timolol, nadolol]
    • Selective B1 Inhibitors: Effective hypotension agents; less prone to induce constriction of bronchial smooth muscle in patients with asthma [betaxolol, atenolol, metoprolol]
    • Adverse Effects: Must be used with great caution in patients with cardiac insufficiency
  117. Clinical uses for adrenergic blockers
    • Pheochromocytoma
    • Hypertension
    • Ischemic heart disease
    • Glaucoma to lower intraocular pressure by reducing production of aqueous humor
    • Urinary obstruction, such as BPH

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