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225 Cards in this Set
- Front
- Back
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Acetaminophen Metabolism
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Major route: UDPGA transferase
Other route: Sulfotransferase Minor route: CYP3A4/2E1(alcohol) Toxic metabolite can either react with cellular proteins and have a toxic effect OR with GSH and get excreted |
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Acetylcholine
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-Muscarinic and Nicotinic agonist
-Highly susceptible to cholinesterase -High degree of muscarinic and nicotinic activity -Used for tx of Glaucoma |
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Alkaloids
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-Muscarine
-Pilocarpine -Nicotine -Lobeline |
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Alpha 1 receptor
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stimulation will stim. IP3 and DAG
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Angiotensin II
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Presynaptically acts on AT1 Receptor to facilitate NE release
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Atenolol
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b1 antagonist
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B2 effect: order of potency
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Iso > Epi >> NE
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Beta 1 receptor
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on cardiac muscle
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Beta 2 receptor
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on smooth muscle
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Bethanechol
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-Muscarinic agonist; acts on M1-M3 receptors
-More selective for muscarinic attack due to methyl substitution -Negligible susceptibility to cholinesterase -Less muscarinic action than ACh and Methacholine -NO NICOTINIC action -Used for tx of post-operative and neurogenic ileus as well as urinary retention |
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Botulinum Toxin
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Blocks fusion of vesicles with nerve membrane to allow exocytotic expulsion of ACh and co-transmitters into synaptic cleft
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Butoxamine
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b2 antagonist
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Carbachol
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-Muscarinic and Nicotinic agonist
-Carbamylated (prolonged action, insensitive to AChE) -Negligible susceptibility to cholinesterase -Less muscarinic action than Methacholine -Nicotinic action -Used for tx of Glaucoma |
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Catecholamines
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DA, NE, Epi
Metabolized by MAO and COMT |
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Choline Acetyltransferase
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Synthesizes Acetylcholine in cytoplasm from Choline and Acetyl-CoA
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Choline Esters
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-Acetylcholine
-Methacholine: methyl group in beta position -Carbachol: carbamylated (prolonged action, insensitive to AChE) -Bethanechol: more selective for muscarinic attack due to methyl substitution |
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Cholinoceptor Stimulants
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Drugs fhat affect PSNS
Direct acting and Indirect acting |
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Ciprofloxacin
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Inhibits CYP1A2/3A4 which metabolizes Theophylline into an inactive drug
Impt to consider possibility of drug interaction when two drugs have similar routes of metabolism |
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Clonidine
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a2 agonist, acts on presynaptic a2 receptors which can affect synaptic levels of NE
-Anti-HTN drug, acts centrally to decr. SNS outflow to heart and BVs; lowers BP -Side effects include CNS symptoms |
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Codeine
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Pro-drug, metabolized by CYP2D6 into morphine
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CYP Expression
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Variation in activity results from:
-Environmental factors: inducers, inhibitors, disease -Multiple P450s can catalyze the same rxn/substrate -Single P450 enzyme can catalyze multiple pathways and metabolize many substrates -Several P450s metabolize endogenous substrates (fatty acids, steroids) -Genetic polymorphism (SNP, mutations) 2D6, 2C19, 2C9 have polymorphic distribution |
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CYP Inducers
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-Rifampin (antibacterial): CYP2B6
-Phenytoin (antiepileptic): CYP3A4 -Carbamazepine (anticonvulsant): CYP3A4 -Phenobarbital (CNS depressant): CYP2C9 -Polycyclic Aromatic Hydrocarbons: CYP1A2 -Chronic Alcoholism: CYP2E1; induction promotes 'pharmacokinetic tolerance' and increases risk of acetaminophen hepatotoxicity -Steroids, Anticonvulsants, Antimicrobials, St. John's Wort: CYP3A; induction may increase metabolism of many drugs -Smoking: CYP1A1/1A2; induction leads to more rapid metabolism of theophylline than non-smokers |
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CYP Inhibitors
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-Fluoroquinolones: Ciprofloxacin
-H2Blockers: Cimetidine -Imidazoles: Fluconazole -INH: Isoniazid (pro-drug for tx of tuberculosis) -Ritonavir (anti-retroviral used to inhibit HIV proteases/ to inhibit CYP3A4) |
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CYP Nomenclature
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CYP: cytochrome P450
2: genetic family D: generic sub-family 6: specific gene >40% amino acid identity between family members >55% amino acid identity between subfamily members |
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CYP2C19 Inhibitors
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-Omeprazole
-Isoniazid -Ketoconazole |
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CYP2C19 Polymorphism
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Involved in primary metabolism of:
-Diazepam -Omeprazole -Phenytoin Absent in 3-5% Cauc, 20-30% Asians Inhibited by: -Omeprazole -Isoniazid -Ketoconazole |
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CYP2C9 Polymorphism
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CYP2C9 is involed in primary metabolism of:
-Most NSAIDs -S-Warfarin -Phenytoin Absent in 1% Cauc and African Amer Inhibited by Fluconazole |
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CYP2D6
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-Metabolizes: Carvedilol, Cevimeline, Chlorpheniramine, Efavirenz, Imipramine, Metoprolol, Promethazine, Timolol
-3-10% caucasians have autosomal recessive mutation that makes it abnormal (Debrisoquine Polymorphism) |
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CYP2D6 Deficiency
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-Truncated CYP2D6 is an inactive enzyme; 1-2%non-cauc., 3-10%cauc.
-Altered CYP2D6 has altered activity which leads to ultrarapid metabolism; leads to incr. morphine production from codeine- this amt will not undergo glucourodination and excretion |
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Direct acting Cholinoceptor stimulants
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Directly stimulate muscarinic and nicotinic receptors
-Choline esters -Alkaloids |
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Dobutamine
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b1 agonist
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Dopamine-beta Hydroxylase
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Used for conversion of DA --> NE
Marker for degree of sympathetic activation |
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Drug Toxicity
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Toxic effects of drugs become apparent when drug is overdosed and when alternative detoxification processes are overwhelmed
-Poor drug metabolizers will end up with a build up of drug in their plasma until it reaches toxic levels and a toxic effect is observed |
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Drug-Drug Interactions
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-Co-administration of drugs that are metabolized by the same enzyme; COMPETITIVE INHIBITION- decr rate of metabolism of lower affinity drug
-Induction of one drug metabolism by other-INCR METABOLISM- decr pharmacological effect -Inhibition of one drug metabolism by other-DECR METABOLISM- incr pharmacological effect |
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Drugs with little or no 1st pass effect
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Clonidine (alpha2 adrenergic agonist, anti-HTN)
Flucytosine (antimycotic) Metronidazole (antibiotic) |
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Drugs with major 1st pass effect
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Imipramine (antidepressant)
Lidocaine (local anesthetic) Morphine (opiate analgesic) Propranolol (beta-blocker, anti-HTN) |
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Enterohepatic Circulation
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Drugs --> Liver --> Conjugation --> Absorption into bile --> Transport to small intestine via biliary ducts and common duct --> Hydrolysis --> Reabsorption and Transportation to the liver via portal system
Can result in enhanced effectiveness/ increased toxicity; must be aware of this to adjust dosing |
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Epinephrine
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non-selective a1 agonist, acts on presynaptic a1 receptor, can affect synaptic NE levels
a1, a2, b1, b2 direct agonist -methyl group confers ability to activate b2 receptors -Typical action is to Incr. HR and BP and to Decr. TPR -acts on b1 and decreases threshold of depol. of SA cells and purkinje fibers; this increases conduction velocity and increases HR -acts on beta receptors to produce vasodilation in skeletal m.; if a-blocker is given before Epi, effects of Epi will be prevented? *RESPONSE IS DOSE DEPENDENT |
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Factors that Affect Drug Metabolism
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-Age, Gender
-Genetic Factors -Pathological states -Physiological states -Drug interactions -Diet, Environmental |
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First Pass Effect
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Reabsorption in small intestine
Transportation to liver via portal system Metabolized in the liver Result is lower systemic bioavailability Can be overcome by changing the route of administration i.e inject drug rather than administer orally or by administering it as a pro-drug (inactive) so that it gets activated when metabolized by the liber- leads to greater bioavailability in systemic circulation |
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Fluconazole
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Inhibits CYP2C9
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Genetic Polymorphism
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A trait with differential expression in >1% of the population
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Glutathione Precursor
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N-acetyl-L-cysteine
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Hemicholinium Drugs
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Inhibits Na-Dependent Choline Transporters
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Indirect acting Cholinoceptor stimulants
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Stimulate nicotinic and muscarinic receptors
-AChE inhibitors (reversible and irreversible) -Neostigmine -Carbaryl -Physostigmine -Edrophonium |
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Isoprenaline
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b1, b2 agonist; better b2 than epi
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Methacholine
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-Methyl group in beta position
-Not very susceptible to cholinesterase -Muscarinic action but NO NICOTINIC action |
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Metoprolol
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b1 antagonist
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Mixed Fxn Oxidases
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Cytochrome P450s (NADPH Cytochrome C Reductase); low substrate selectivity, lipophilicity; drugs may be metabolized by more than one CYP
Rxn: RH + O2 + H + NADPH --> ROH + H2O + NADP A P450 enzyme can catalyze multiple pathways and metabolize many substrates; genetic mutations in P450s lead to polymorphisms and individual variation in ability to metabolize drugs |
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Muscarinic Recptors
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-G-protein regulated (7 transmembrane domains; ACh binds between domains 6&7)
-Primarily found in smooth muscle, cardiac muscle, glands and CNS -M1-3 are clinically impt -M1: neural -M2: glandular -M3: cardiac -M1,3,5 stimulate Gq (leads to incr. IP3 and DAG; incr. Ca leads to incr. contraction) -M2,4 stimulate Gi (leads to inhibition of AC and K+ channel opening; inhibition of cAMP) |
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Nicotinic Receptors
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Found in NMJ or autonomic ganglia; embedded in cell membrane- forms cation channel, allows Na influx which causes membrane depol. and initiation of action potential
-Nicotinic muscle receptor: 2alpha, beta, delta, epsilon subunits -Nicotinic nerve receptor: 2alpha, 3beta subunits |
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Norepinephrine
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a1, a2, b1 direct agonist, some b2 but not as good as epi or iso
major NT released from post-ganglionic sympathetic nerves Direct action on B1 receptors produces sinus bradycardia, centricular tachycardia, A-V dissociation Indirectly decreases heart rate by increasing blood pressure via a1 activation; due to deactivation/inhibition of baroreceptor reflex Activation of a1 receptors in peripheral blood vessels leads to vasoconstriction and venoconstriction |
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Oxprenolol
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non-selective beta antagonist
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Oxymetazoline
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a1 agonist
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Parasympathetic Nerves
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-long preganglionic fibers
-short postganglionic fibers -Primary NT is ACh; acts on pre-ganglionic nicotinic recptors and post-ganglionic muscarinic receptors -Parasympathetic NS: directly influences HR -Sparse innervation of peripheral vasculature |
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Phase I Biotransformation Rxns
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-Oxidation (mainly by mixed fxn oxidases)
-Reduction -Hydrolysis Can lead to inactivation, activation or no change in pharmacological potency/activity |
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Phase II Biotransformation Rxns
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-Acetylation (Acetyl-CoA)
-Glucuronidation (Glucoronic acid) -Glutathione conjugation (GSH) -Sulfation (Sulfuric acid) -Methylation (S-adenosyl-methionine) Results in decreased drug potency and half-life; exception is M6G metabolite of morphine which can form in the brain and is 100x more potent than morphine |
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Phase II Enzyme Polymorphism
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N-Acetylation of Isoniazid- mutation in NAT2 enzyme
Inherited autosomal recessive trait Phenotype occurs in 50% Cauc and African Amer |
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Phenoxybenzamine
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non-selective a1 antagonist
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Phentolamine
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non-selective a1 antagonist
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Phenylephrine
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a1 agonist
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Pilocarpine
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Muscarinic Alkaloid Agonist
-Used for tx of Glaucoma and Sjogren's syndrome (M3 selective disease) -Good hypotensive agent when administered IV |
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Prazosin
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-a1b selective antagonist
-Competitive, reversible inhibitor but has some negative side effects (orthostatic hypotension, sexual dysfxn, impotence) -Useful for Tx of Chronic HTN (in PTs who poorly responded to other anti-HTN medications); can cause an initial decr. in BP, must abruptly discontinue to prevent incr. BP in response to endogenous NE -Useful for Tx of Benign Prostatic Hypertrophy -Occasionally useful for Tx of Peripheral Vascular disease |
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Propanolol
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-non-selective beta antagonist; b1 and b2
-results in decr. HR, CO and BP(to a small extent) -blocks effects of Epi in resting animals -developed to treat cardiac arrhythmias but can be problematic when used in cases where you only want to block b1 but not b2 -Can be used to treat ischemic heart disease -Can be used to treat migraine headaches probably due to b2 blocking effects (reduces frequency and intensity of migraines when taken prophylactically) |
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Prostaglandins
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Released in response to stimuli at adrenergic nerve terminals but act as a brake for further release of NE from nerve terminal
PGEs act on EP3 Receptor NSAIDs block PGs- this can facilitate NE transmission |
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Rifampin and Warfarin Interaction
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Certain barbiturates (Phenobarbital) and antibiotics (Rifampin) are CYP inducers
Rifampin induces CYP which will shorten the half-life of Warfarin which will reduce its effectiveness |
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Salbutamol
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b2 agonist
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Salmeterol
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b2 agonist
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Sympathetic Nerves
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-Short pre-ganglionic fibers
-Long post-ganglionic fibers -Derived from thoracolumbar region -Preganglionic NT is ACh (acts on ganglionic nicotinic receptors) -Adrenal gland has no short preganglionic fiber -Primary postganglionic NT is NE -ACh is postganglionic NT that acts on muscarinic receptors on sweat glands -Sympathetic NS influences peripheral vascular resistance, heart rate, contractile force, venous tone, direct modulation of renin production |
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Terbutaline
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b2 agonist
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Theophylline
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Low therapeutic index
Therapeutic dose: 10-20mg/L Used to treat asthma Can participate in different drug interactions to produce toxicity |
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Tyrosine
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AA used for synthesis of catecholamines (DA, NE, Epi)
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Tyrosine Hydroxylase
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Rate limiting enzyme for formation of NE in nerve terminal; important for formation of DOPA
Inhibition can result in production of Tyramine and Octapamine (false NTs) which can have effects on end organs |
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Vagus nerve varicosity
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SA Nodal cells in the heart are innervated by vagus nerve
-ACh is released and interacts with M2 receptor on post-synaptic membrane -Ultimately leads to hyperpilarization of SA Nodal cells (makes it harder for cells to reach thershold therefore, slows firing rate) |
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Vesicle Associated Transporter
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Transports Acetylcholine into storage vesicle; inhibited bu Vesamicol
Storage vesicles contain ACh, Peptides, ATP, Proteoglycan |
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Muscarine
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Quaternary ammonium group; less likely to be absorbed by GI tract or to get into the brain
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Pilocarpine
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No quarternary ammonium group; no barrier to penetration
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Nicotine
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CNS stimulant; gets into the brain
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Dilator muscle in the eye
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Stimulated by alpha receptor mediated incr. in DAG and IP3
Contraction leads to mydriasis (pupil dilates) |
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Sphincter muscle in the eye
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Stimulated by muscarinic receptor activation
Contraction leads to miosis (pupil constricts) Muscarinic agonist activity causes miosis and flattening of the iris (facilitates outflow of aqueous humor which will decrease intraocular pressure) |
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Ciliary muscle in the eye
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Contraction and relaxation change tension of the trabecular meshwork, thereby affects accomodation
Muscarinic receptor effect |
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Ciliary Epithelium
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Transport water and electrolytes from one side of cells to the other; involved in formation of aqueous humor
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Chronotropy
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Rate
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Ionotropy
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Contractility (how forceful)
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Dromotropy
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Activation of SA Nodal cells
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Edrophonium
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-Alcohol Cholinesterase inhibitor
-Half-life: 10-15min (short-acting) -Acts at ANIONIC site on AChE -Used in tx of Glaucoma -Used for Tensilon test (diagnostic test for Myasthenia Gravis) -Previously used to treat supraventricular tachycardias |
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Carbaryl
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Carbamate containing cholinesterase inhibitor
-Moderate duration of action (range from .5-8hrs) -Reversible |
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Phosphate containing Cholinesterase inhibitors
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-Cause irreversible effects to inhibit AChE
-Echothiophate -Parathion -Soman -Paraoxon -Melathion -Malaoxon |
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Physostigmine
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Carbamate containing cholinesterase inhibitor
-Can cross BBB (therefore can produce convulsions and CNS excitation) -Moderate duration of action (.5-2hrs) Acts at ANIONIC site and ESTERATIC site on AChE -Reversible -Used to tx antimuscarinic drug intoxication |
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Neostigmine
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Carbamate containing cholinesterase inhibitor
-Moderate duration of action (.5-2hrs) -Acts at ANIONIC site and ESTERATIC site on AChE -Reversible -Used for tx of Myasthenia Gravis ,urinary retention, post-operative and neurogenic ileus |
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Echothiphate
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Phosphate containing Cholinesterase inhibitor
-Long duration of action (100hrs) |
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Soman
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Phosphate containing Cholinesterase inhibitor
-Poison used for chemical warfare |
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Parathion
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Phosphate containing Cholinesterase inhibitor
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Paraoxon
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Phosphate containing Cholinesterase inhibitor
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Melathion
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Phosphate containing Cholinesterase inhibitor
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Melaoxon
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Phosphate containing Cholinesterase inhibitor
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Pyridostigmine
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Carbamate containing cholinesterase inhibitor
-Moderate duration of action (range from (3-6hrs) -Reversible |
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Ambenonium
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Carbamate containing cholinesterase inhibitor
-Moderate duration of action (4-8hrs) -Reversible |
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Demecarium
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Carbamate containing cholinesterase inhibitor
-Moderate duration of action (4-6hrs) -Reversible |
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Acetylcholine Esterase (AChE)
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-Anionic site: quaternary ammonium group binds and fixes ACh molecule in place
-Esteratic site: involved in cleavage and hydrolysis of ACh molecule |
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Dyflos
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-AChE inhibitor
-Long acting -Acts at ESTERATIC site on AChE |
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Cholinesterase Regenerator Compounds
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-Pralidoxime (2-PAM): nucelophilic agent, prevents aging of phosphate group
-Diacetylmonoxime |
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AChE Inhibitor effects on CNS
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-Low dose: Alerting response
-High dose: Convulsions -Tacrine used for tx of Alzheimer's disease (donepezil, galantamine, rivastigmine are more selective cholinesterase inhibitors) |
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AChE Inhibitor effects on eye, lung, GI tract, urinary tract
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-Mimics effects of direct acting agents since these organs are well innervated by PSNS
-Can cause tracheal secretion and/or paralysis of the diaphragm -Used for tx of Glaucoma (pilocarpine, methacholine, carbachol, physostigmine) -Neostigmine used for tx of urinary retention, post-operative and neurogenic ileus |
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AChE Inhibitor effects on CV System
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-Heart: negative ionotropic, chronotropic, dromotropic effects
-Vascular smooth muscle: little direct effect, may incr. resistance |
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AChE Inhibitor effects on NMJ
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-Low dose: intensifies ACh effects
-Moderate dose: may cause fasciculation -High dose: may cause depolarization block -Neostigmine is used for tx of Myasthenia Gravis |
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Tacrine
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-Anticholinesterase activity
-Cholinomimetic actions -Reported to cause liver toxicity -Less selective inhibitor than donepezil, galantamine, rivastigmine -Use to tx Alzheimer's disease; acts on M4 and M5 in the brain |
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AChE Inhibitor use for Antimuscarinic Drug Intoxication
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-AChE Inhibitor will lead to increased levels of ACh which will compete with muscarinic antagonist (Atropine)
-AChE Inhibitors act as competitive, reversible inhibitors for antimuscarinic drugs -Physostigmine |
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Pilocarpine
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-Muscarinic alkaloid
-Used for tx of Glaucoma, Sjogren's syndrome (M3 selective disorder) |
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Bethanechol
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-Muscarinic agonist; acts on M1-M3 receptors
-Promotes excretion of urine via bladder contraction and sphincter relaxation |
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Nicotine
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-Nicotinic Alkaloid Agnoist at all nicotinic receptors
-Used for smoking cessation tx |
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Cevimline
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-M3 selective Muscarinic Agonist
-Used for tx of Glaucoma |
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Varenicline
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-Partial Agonist at a2, b3 nicotinic receptors in CNS
-Used for smoking cessation tx |
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Rivastigmine
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AChE Inhibitor
-Used for tx of Alzheimer's disease |
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Donepezil
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AChE Inhibitor
-Alzheimer's disease |
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Direct-acting Muscarinic Stimulants
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-Effects are blocked by Atropine
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Direct-acting Nicotinic Stimulants
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Nicotinic stimulatuon of ganglia leads to incr. sympathetic outflow; tx with atropine and anticonvulsants
-CNS stimulant actions can lead to convulsions, coma -Skeletal muscle end plate depolarization leads to depolarization blockade and respiratory paralysis -HTN and cardiac arrhythmia -AChE Inhibitors: parathion, malathion, sarin |
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AChE Inhibitor poisoning pharmacodynamic effects
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-DUMBBELSS
-diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (muscle, CNS), lacrimation, salivation, sweating |
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Cholinergic Drug Effects
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-SLUDGE
-salivation, lacrimation, urinary incontinence, diarrhea, gastrointestinal cramps, emesis |
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Muscarinic Receptor Antagonists
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-Block muscarinic receptors
-Atropine -Scopolamine -Homatropine |
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Atropine
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-Muscarinic antagonist
-Half-life: 7-10days; prolonged duration of action -Dose-dependent effects -Increased doses will cause: decreased salivary, bronchial and sweat secretions, urinary retention, constipation, hyperthermia, tachycardia, palpitations, dryness of mouth, mydriasis, cycloplegia (loss of accommodation), behavioral effects, hallucinations, delirium |
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Scopolamine
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-Muscarinic receptor antagonist with an oxygen group
-Half-life: 3-7days -Causes CNS effects that are associated with delirium -Can be used to prevent nausea and vomiting |
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Homatropine
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-Muscarinic receptor antagonist with a hydroxyl group
-Half-life: 1-3days |
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Cholinergic antagonists
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Useful for treating asthma (ACh causes bronchoconstriction)
-Tiotropium |
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Benztropine
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-Cholinergic antagonist
-Tertiary amine, can cross BBB -Some use in tx of Parkinson's disease -Can reduce secretions in tx of COPD when given via inhalation- selective effect on lung |
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Glycopyrrolate
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Antimuscarinic drug
-Used for tx of GI and genitourinary conditions |
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Pirenzepine
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M1 receptor antagonist
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Darifenacin
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M3 receptor antagonist
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Muscarinic agonist
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Leads to miosis and incr. outflow of aqueous humor via Canal of Schlemm
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Muscarinic antagonist
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Leads to mydriasis, incr. ocular pressure due to occlusion of Canal of Schlemm
-formation of aqueous humor is beta-receptor mediated therefore, beta blockers decr. production of aq. humor |
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Timolol
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-b1, b2 receptor antagonist
-Can be used to treat ischemic heart disease -Ocular application decreases intraocular pressure- used for tx of Glaucoma |
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Tropicamide
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-Antimuscarinic drug
-Short half-life (.25 days) |
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Cyclopentolate
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-Antimuscarinic drug
-Half-life: 1day |
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Dicyclomine
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-Competitive M3 antagonist
-Used for tx of irritable bowel syndrome and diarrhea |
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Ipratropium
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-Muscarinic antagonist
-Used to prevent bronchospasms in asthmatics |
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Oxybutynin
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-Muscarinic antagonist
-Used for tx of incontinence; opposite effects as bethanecol |
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Pralodoxine
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-Regenerates AChE via nucleophilic rxn
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Ganglionic blocking drugs
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-Hexamethonium: double quarternary ammonium
-Decamethonium: stimulant at NMJ -Trimetaphan -Mecamylamine: no charge, antagonist at nicotinic nerve receptor; ganglionic blocker -Hexamethonium -Tetraethylammonium |
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Mecamylamine
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-Ganglionic blocker
-Can cross BBB and cause mental aberrations |
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Ganglionic blocking drugs effects
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-Eye: causes cycloplegia with loss of accomodation
-GI tract: reduced secretions, marked constipation -CV system: BP may fall due to reduced arteriolar and venous tone |
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Trimethaphan
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-Ganglionic blocker; acts at ANS ganglia
-Used for tx of hypertensive emergenics |
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Diphenhydramine
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-Antihistamine effects
-Can cross BBB and dull mental sharpne |
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Antimuscarinic effect
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-Enhances antihistaminic effect
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Total Body Water
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Approx. 42L water in a 70kg person
-3L in plasma -11L in interstitial fluid -28L in cellular fluid |
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Adrenergic Agents
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-Interact with adrenergic receptors on effector cells and can mimic actions of Sympathetic NS
-Can interact specifically with 1 or more receptors -Biological response determined by: a) Type of Receptor it interacts with b) Distribution of receptors w/in target tissue c) Counter-regulatory mechanisms |
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Adrenoreceptors
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-Some are expressed in particular tissues but not in others
-a1, a2, b1, b2, b3, D1, D2 |
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a1 adrenoreceptor: Vascular smooth muscle
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Contraction
-Venoconstriction and decreased venous compliance (increeases VR and CO) -Vasoconstriction (increases TPR and CO) |
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a1 adrenoreceptor: Pupillary dilator muscle
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Contraction --> Pupil dilates
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a1 adrenoreceptor: Pilomotor smooth muscle
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Erects hair
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a1 adrenoreceptor: Rat liver
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Glycogenolysis
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a1 adrenoreceptor: Heart
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Incr. force of contraction
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a2 adrenoreceptor: Post synaptic CNS adrenoreceptors
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Multiple actions
-Activates inhibitory neurons to inhibit sympathetic outflow from vasomotor center -Modulates baroreceptor activity and decreases BP a2 receptors can be expressed pre-synaptically in sympathetic cholinergic post-ganglionic neurons (this is impt for inhibition of AP induced NE release; if blocked, get magnified NE release) |
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a2 adrenoreceptor: Platelets
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Aggregation
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a2 adrenoreceptor: Adrenergic and cholinergic nerve terminals
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Inhibition of transmitter release
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a2 adrenoreceptor: some vascular smooth muscle
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Contraction- especially when skin is exposed to cold (a2 translocate from Golgi --> VSM membrane)
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a2 adrenoreceptor: Fat Cells
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Inhibition of lipolysis
-inhibition of narcoleptic response |
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b1 adrenoreceptor: Heart
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Increases force and rate of contraction
-Decreases refractory period Iso, Epi, Dobutamine all act directly on b1 to incr. force of contraction and incr. heart rate |
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b2 adrenoreceptor: Respiratory, Uterine and Vascular smooth muscle
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Promotes smooth muscle relaxation --> bronchodilation of airways and relaxation of some vascular smooth muscle in the brain
All resistance vessels in systemic circulation express b2 adrenergic receptors |
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b2 adrenoreceptor: Skeletal Muscle
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Promotes potassium uptake, vessels dilate
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b2 adrenoreceptor: Human Liver
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Activates glycogenolysis
-Promotes glycogen breakdown |
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b3 adrenoreceptor: Fat Cells
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Activates lipolysis
-Increases free fatty acids |
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D1 adrenoreceptor: Smooth Muscle
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Dilates renal blood vessels
-Increases blood flow |
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D2 adrenoreceptor: Nerve endings
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Modulates transmitter release
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b1 adrenoreceptor: Kidney
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Secretion of Renin
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Directly acting adrenergic agents
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Interact with 1 or more receptors and produce a biological response
-NE acts directly on post-synaptic receptors (and on a2 presynaptic receptor) -Phenylalanine, Isopreoterenol also act on post-synaptic receptor |
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Indirectly acting adrenergic agents
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Do not interact with receptor but bring about a response that is similar to the response brought about by stimulation of receptors
-Tyramine: enters nerve terminal via NE transporter and displaces NE from binding site, promoting non-exocytotic/ Ca independent NE release into synaptic cleft -Amphetamine, Ephedrine act by blocking NE transporter activity which typically clears NE from extracellular space and terminates its signalling effects; can enter CNS (lipid soluble) -TYRAMINE, AMPHETAMINE, EPHEDRINE -Ephedrine is a direct and indirect agonist |
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Reserpine
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-Prevents DA entry into neruosecretory vesicles in post ganglionic SNS nerves
-Results in decr. NE content in sympathetic nerves; this prevents Tyramine from having an effect (if there is no NE, Tyramine cannot stimulate NE release) -Effective anti-HTN when used with Thiazide diuretic -Side effects: orthostatic hypotension, impotence, depression |
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Tricyclic Antidepressants
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Block NE reuptake which increases sympathetic response because NE remains in synaptic cleft longer
*70% NE that gets released is taken back up |
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Non-lipid soluble adrenergic agents
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NE, Epi, Iso, Phenylephrine, Methoxamine
-Phenylephrine and Methoxamine are not catecholamines |
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Phenylephrine
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Direct acting adrenergic a1 agonist
-No -OH therefore cant activate a2, b1, b2 Increases TPR which increases Syst.BP and Diast.BP and a greater decr. HR than with NE Not a catecholamine (no -OH and not a COMT substrate) -Prolonged duration of action bc it is COMT resistant |
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Isoproterenol
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Direct acting adrenergic b1, b2 agonist
-Isopropyl group prevents it from activating a1 and a2 receptors but increases b-receptor activity Synthetic catecholamine/ b-agonist Activates b1 receptors in heart and produces incr. excitability and automaticity; shortens refractory period which results in incr HR |
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Catecholamines
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NE, Epi, DA, Iso
-Iso is synthetic |
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Result of Decr. TPR
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Decr. BP (particularly diastolic)
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Atropine
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Prevents ACh release from PSNS nerves which prevents decrease in HR
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Clonidine
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Direct acting a2 adrenergic agonist
-activates a2 and b2 -decreases sympathetic outflow from the brain -there is an initial, transient increase in BP due to vasoconstriction brought about by activation of a2 receptos in circulation |
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Dopamine receptor agonists
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-DA (D1, D2)
-Fenoldopam (D1) |
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b2 adrenergic activation
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-Incr. HR and force of contraction
-Activation is linked to vasodilation in skeletal m. (primarily expressed in bronchiolar smooth m.) -Activation in peripheral BVs will decr. TPR, incr. PP (linked to incr. Syst.P due to incr.CO) -Impt for bronchodilation and appropriate airflow |
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a1 adrenergic activation
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-Vasoconstriction
-Incr. BP |
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b1 adrenergic activation
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Incr HR and CO
-b1 blockage and administration of Epi results in hypotensive response without incr. HR |
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GI Tract adrenergic receptors
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a1, a2, b1, b2
-activation of receptors relaxes GI muscles and inhibits motility/tone |
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Metabolic effects of adrenergics
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Diabetes taking b-blockers are at risk of hypoglycemic events; b-blockers prevent incr. HR and mask CV symptoms of hypoglycemia
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alpha adrenergic agonists and shock
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Can be used to maintain BP in different stages of circulatory shock
-Also useful for PT with spinal anesthesia associated hypotension *DONT give a-agonist to a PT in hypovolemic shock bc they already have an overactive SNS and are vasoconstricted |
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Dose dependent effects of Epinephrine
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-Low dose: interaction with a1 results in vasoconstriction and incr. TPR
-Moderate dose: interaction with b2 results in an initial vasodilation and decr. TPR -High dose: interaction with a1; fxns are more "NE-like" -Action on B1 in heart: Incr. HR, CO, Contractility and Syst.BP -Can produce local vasoconstriction when used with local anesthetics |
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Adverse effects of Adrenergic Agonists
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-Tachyarrhythmias: due to b1 agents
-Hypertension: due to a1 agents (excessive vasoconstriction --> HTN) -Localized ischemia: can occur at site of infusion when administering a1 agonists -Precipitous hypotension: can occur with withdrawal of a1 agonist; avoid this by gradually withdrawing -CNS stimulation (nervousness, anxiety, insomia, drug dependence): can result with use of adrenergic agonists that cross BBB i.e. Amphetamines |
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Alpha adrenergic receptor ANTAGONISTS
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-Phenoxybenzamine
-Phentolamine -Prazosin -Tamsulosin *target activity of SNS by preventing generation or release of NE or by preventing NE/Epi from acting on specific receptors *Antagonists have a degree of selectivity for adrenoreceptors which results in fewer side effects |
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Beta adrenergic receptor ANTAGONISTS
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-Propanolol
-Pindolol -Atenolol -Metoprolol -Labetalol -Carvedilol -Nebivolol *Work synergistically to control BP (esp. in PTs with high plasma Renin activity) -beta blockers have cardio-protective fxn since b1-receptor is pro-arrhythmogenic; can be used to treat supraventricular and ventricular arrhythmias |
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Prazosin, terazosin, doxazosin
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-alpha adrenergic antagonists
-much more affinity for a1 receptor than a2 receptor -not as effective at blocking a2 receptor activity |
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Phentolamine
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-non-selective alpha adrenergic antagonist
-affinity: a1=a2 -result of a-receptor blockage: vasodilation, decr. BP assoc. w/ incr. HR, decr. VR and decr. CO due to venodilation -acts on both a1 and a2 therefore, great ability to incr. HR due to a2 effect |
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Yohimbine, Tolazoline
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-alpha adrenergic antagonists
-affinity: a2 >> a1 -will still act on a1 but not as effective as on a2 receptor |
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Labetalol, Carvedilol
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-Synthetic agents, fxn as mixed alpha/beta antagonists
-affinity: b1 = b2 >/ a1 > a2 -Can be used in hypertensive emergencies (short term tx of HTN to decr. BP) |
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Metopropolol, Acebutolol, Alprenolol, Atenolol, Betaxolol, Celiprolol, Esmolol, Nebivolol
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-beta adrenergic antagonists
-affinity: b1 >>>> b2 |
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Propanolol, Carteolol, Penbutalal, Pindolol, Timolol
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-beta adrenergic antagonists
-affinity: b1=b2 |
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Butoxamine
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-beta adrenergic antagonists
-affinity: b2 >>>> b1 |
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Irreversible alpha adrenergic antagonists
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-Non-competitive inhibition
-Longer duration of action bc protein synthesis must occur to generate receptors; cannot reverse effects of these antagonist by increasing [agonist] -Phenoxybenzamine |
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Phenoxybenzamine
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-non-selective alpha adrenergic antagonist
-a1 > a2 -irreversible antagonist; forms covalent bond with receptor -acts on both a1 and a2 therefore, great ability to incr. HR due to a2 effect -useful for tx of Pheochromocytoma |
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Reversible alpha adrenergic antagonists
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-Competitive inhibition- antagonist binds to same site as agonist
-Incr. [agonist] will reverse effects of antagonist binding -Can still achieve max response with high enough [adrenergic] -Phentolamine, Prazosin, Terazosin, Doxazosin, Tamsulosin |
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Pheochromocytoma
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Condition in which there is tumor of adrenal medulla chromaffin cells (release Epi) and Paroxysmal HTN
-symptoms involved overactive alpha and beta receptors Tx: Phenoxybenzamine, Alpha Methyltryosine |
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Hypertensive Emergencies
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Increased BP
Tx: Labetalol, Carvedilol for short term tx |
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Chronic Hypertension
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Tx: Prazosin and Prazosin-like agents
-Prazosin can cause an initial decr. in BP, must abruptly discontinue to prevent incr. BP in response to endogenous NE |
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Peripheral Vascular Disease
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Tx: Prazosin, Phenoxybenzamine -occasionally effective but a1 antagonists are not very effective at increasing blood flow
They are effective in PTs with Raynaud's Syndrome |
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Benign Prostatic Hypertrophy
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Prostate has smooth fibers which have alpha receptors therefore blocking these receptors can prevent contraction and thereby prevent urinary retention
Tx: Tamsulosin, Prazosin and like-acting agents |
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Tamsulosin
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-Reversible, non-competitive a1a, a1b antagonist
-Can be used in tx of Benign Prostatic Hypertrophy |
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Side effects of Alpha adrenergic Antagonists
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-Orthostatic Hypotension: incr. venous capacitance, decr. VR, CO, BP; compromised blood flow to the brain
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Atenolol
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-beta adrenergic receptor antagonist
-b1 > b2 -short acting (half-life = 4-5hrs) |
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Metoprolol
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-beta adrenergic receptor antagonist
-b1 > b2 -Can be used with diuretics to treat HTN; using w. diuretics allows lower dose and therefore results in less side effects -Can be used to treat ischemic heart disease |
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Nevivolol
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-beta adrenergic receptor antagonist
-b1 > b2 -more selective for b1 than atenolol and metoprolol -long acting (half-life = 12+ hrs) -also stimulates No synth. in endothelium -Can be used with diuretics to treat HTN; using w. diuretics allows lower dose and therefore results in less side effects |
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Pindolol
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-beta adrenergic receptor antagonist
-b1 and b2 antagonist when SNS activity is high -can fxn as a partial agonist when SNS activity is low |
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Labetalol
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-b1 and a1 adrenergic receptor antagonist
-Used for tx of acute hypertensive emergencies |
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Carvedilol
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-b1 and a1 adrenergic receptor antagonist
-Used for tx of acute hypertensive emergencies |
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b1 blockage
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-Decr. HR, force of contraction, CO and renin secretion (via decr. stimulatory influence of SNS on renin secretion)
-Decr. aqueous humor production and intraocular pressure -Effects are more apparent in PTs with high levels of SNS activity -Can result in incr. expression of receptor; when withdraw antagonist can get exaggerated b1 adrenoreceptor response due to incr. expression of receptors that resulted from b-block -Effective for tx of Renin-Induced HTN |
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Epinephrine and Beta-Blockers
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-Epi will incr. contractile force if given before b-blocker but will not incr. contractile force if given after b-blocker
-Epi will incr. BP if given before or after b-blocker Effects on BP are related to alpha receptor-stimulatory effects of Epi which are not blocked by beta blockers but the effect of Epi on vasodilation (b2 receptors) is blocked by b-blockers -Epi will incr. HR if given before b-blocker but not if given after |
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Renin Secretion
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-Inhibited by b-adregeric receptor antagonists (b-blockers can treat renin-dep. HTN)
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b2 blockage
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Increase airway resistance- esp. in PTs with bronchial asthma or COPD
-if giving a b-blocker to those PTs, must treat with low dose of selective b1-antagonist |
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b1 AND b2 blockage
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-Hypoglycemia due to lack of glycogen breakdown in response to SNS activation
-SNS activation stimulates heart --> tachycardia and palpitations |
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Ischemic Heart Disease
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-Treat with b1-receptor antagonists which will decr. frequency of angina attacks, decr. cardiac work, decr. o2 consumption
-b1 blockers improve outcome of PTs with MI and reduce incidence of another MI |
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Metoprolol, Bisoprolol, Carvedilol
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beta receptor antagonists that reduce mortality in PTs with chronic cardiac failure
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Glaucoma
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-Incr. intraocular pressure
-Timolol will decr. intraocular pressure |
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Obstructive Cardiacmyopathy
|
Severe L. ventricular hypertrophy occludes/compresses aorta and impeded blood flow out of ventricles
-b-blockers are useful due to actions of incr. stroke vol., slowing ventricular ejection and decr. outflow resistance; decr. HR allows for better filling |
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Hyperthyroidism
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-There is an incr. in SNS activity assoc. with hyperthyroidism which results in tachycardia and tremor
-Symptoms are related to b-receptor over activation therefore, tx with b-blockers is useful |
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Negative effects of Beta adrenergic receptor Antagonists
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-Bradycardia can occur w high concentrations of b-blockers
-Aggravation of pre-existing Asthma with use of b2-blockers -Aggravation of peripheral circulatory dysfxn with use of b2-blockers -Decreased exercise tolerance with use of b1 blockers at high doses -Aggravation of hypoglycemia in diabetic PTs treated with insulin -Incr. Cardiac Responsiveness to SNS if b1-blockers are abruptly stopped |
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Alpha Methyltyrosine
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Inhibits synthesis of adrenergic transmitters
-Competitive inhibitory of Tyrosine Hydroxylase -Inhibits NE synthesis Used in treatment of PTs with Pheochromocytoma |
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Trimethaphan
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Ganglionic blocking drug; blocks ANS
-Disrupt ganglionic transmission -Results in reduced vascular resistance, increased venous capacitance, decr. BP, mydriasis, cyclopegia, decr. GI tract motility, anhydrosis, urinary retention Used to lower and maintain BP in hypertensive PTs undergoing surgical intervention but not in ambulating PTs (risk of orthostatic hypotension) -administered via IV |
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Mecamylamine
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Ganglionic blocking drug; blocks ANS
-Disrupt ganglionic transmission -Results in reduced vascular resistance, increased venous capacitance, decr. BP, mydriasis, cyclopegia, decr. GI tract motility, anhydrosis, urinary retention Limited use in ambulating PTs due to risk of orthostatic hypotension |
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Guanethidine
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Disrupts fxn of SNS nerve by inhibited AP-induced release of NT and inhibiting entry of DA into secretory vesicles
Side effects: orthostatic hypotension, impotence |
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Methyldopa
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Anti-HTN drug; acts centrally to decr. sympathetic outflow to the heart and BVs
-Result in decr. BP These are also a2 agonists but can fxn as b-antagonists by decr. SNS outflow Used to tx of HTN during pregnancy Risk of hemolytic anemia |
