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520 Cards in this Set
- Front
- Back
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Pharmacokinetics
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-Rate of absorption, distribution, metabolism, and elimination
-Tells bioavailability of a drug within the body on a time-dependent manner -Measures the time course of drug concentration in the body -Provides the means to quantify absorption, distribution, metabolism, and elimination parameters -Can be used to design optimally beneficial drug doses for individual patients |
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Pharmacodynamics
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-Variability in various drug-metabolizing
-Variability in pharmacological potency of the drug at defined concentrations --due to genetic or other variations in targets -Defines absorption, distribution, metabolism, and elimination parameters of a specific drug -Based on the genetic and species-specific variability in drug targets |
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ADME parameters
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-Absorption
-Distribution -Metabolism -Elimination -Key physiological processes that govern the time course of drug fate and efficacy in the body -Want biggest effect with smallest dose without getting any toxicity |
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Routes of drug administration
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-Intravenous (IV)
-Intramuscular (IM) -Inhalation (I) -Subcutaneous (SC) -Oral (O or PO) -Topical (TP) -All are major role in ADME properties |
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Enterohepatic Circulation
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-Determines drug efficacy
-Determines toxicity of orally administered drugs -Intestine and liver tissues are major sites of metabolism for oral drugs -Recirculation through hepatic biliary system is major determinant of drug efficacy and toxicity -Drug goes from intestine ⇒ enterocyte (some is metabolized) ⇒ portal circulation ⇒ hepatocyte (some is metabolized) ⇒ Bile ⇒ enterohepatic recycling ⇒ intestinal lumen |
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1st pass effect
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-Drugs delivered orally go into enterohepatic circulation and are filtered by hepatocytes in the liver
-Drug is mostly absorbed in the small intestine --due to neutral pH of intestine -Drug enters epithelial cells through transporters --Some is metabolized by CYP3A --Some is transported into the portal vein -Drug is subject to metabolism by intestine, liver, enterhepatic recycling, and gut microorganisms -Have to carefully dose the drug to account for 1st pass effect |
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CYP3A
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-Cytochrome P450 enzyme
-Within enterocytes -Metabolizes drugs to a certain extent |
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Metbolism of Drugs within Hepatocytes
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-Absorbed from Portal vein
-Major metabolism within hepatocytes -Modified and unmodified drug is put into bile |
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Enterohepatic Recycling
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-Drug goes from intestinal lumen ⇒ enterocytes (some is metabolized) ⇒ gut wall ⇒ portal vein ⇒ hepatocyte (some is metabolized) ⇒ bile ⇒ enterohepatic recycling ⇒ intestinal lumen
-Drug can recirculate many times --number of times drug recycles determines its pharmacological potency --The longer a drug recycles, the more effective it is, long-lived --Goes through only once, have to take drug more often |
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Liver Sinusoids
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-Portal vein divides into portal capillaries and ends up in liver sinusoids
-Sinusoids line hepatocytes -Drugs are filtered from sinusoids into hepatocytes --some of drug is metabolized in hepatocytes -Remaining drug is put into bile canaliculi, goes into bile duct |
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Phase I Drug Metabolizing Enzyme Types
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-Cytochrome P450 enzymes
--mixed function oxidases -Flavin mono-oxygenases -Monoamine Oxidases ---alcohol dehydrogenase --aldehyde dehydrogenase |
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Phase II drug Metabolizing enzymes
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-Mostly involved in drug detoxification and excretion
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Drug Transporters
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-ABC family pumps (require ATP)
-SLC family (solute carriers) exchangers --in-built ATP hydrolysis domain --need in-built membrane potential, need Na/K pump -Required for drug absorption from intestine or blood by tissues -In some cases needed by protein carriers |
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Phase I enzymes
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-Metabolize drugs
-Change chemical property of the drug -Oxygen is added, or there is a change to the groups on the cpd -Once metabolized, cpds are pretty much inactive (99% of drugs are inactivated once metabolized) --a few exceptions exist (erythromycin, codine) |
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Phase I enzymes with active metabolites
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-Enzyme activity is needed to make drug active
-Erythromycin-succinate --succinate group has to be removed fro Erythromycin to be active -Codine has to be converted into morphine in the liver by CYP2D6 |
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Phase I drug with toxic metabolite
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-Acetaminophen
-Metabolite is carcinogenic |
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Secondary sites of drug metabolism
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-Gut
-Lungs -Skin -Kidneys -Brain -Heart -Intestine, liver, and kidney are the most important |
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Types of oxidation reactions
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1. Oxygen is incorporated into the molecule
--hydroxylation --epoxylation 2. Causes loss of part of drug molecule --oxidative deamination --dealkylation |
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Mixed function oxidases
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-Enzymes that carry out oxidation reactions
-Mostly present in the microsomes -Some in mitochondria --important role in determining drug toxicity -A few in the nucleus, function is not known |
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Flavoproteins
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-Heme-containing proteins
-Flavin is the active center -Cytochrome P450 reductase --donates e- to cytochrome P450 enzymes |
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Components needed for rug oxidation
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-Cytochrome P450
-Cytochrome P450 reductase -NADPH -O2 |
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Drug Oxidation Cycle
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1. Oxidation of Fe3+ group on heme
-Cytochrome P450 combines with drug substrate to form complex 2. NADPH donates 2 e- -1 used to oxidize CP450 complex -1 used to activate bound O2, forms "activated oxygen" 3. Activated oxygen-cytochrome P450 substrate complex is formed 4. Complex transfers activated O2 to drug substrate -forms oxidized product -Oxidizing properties allow oxidation of many substrates |
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Electron flow in microsomal drug oxidizing system
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-Cytochrome P450 heme ion is mostly present in oxidized form
--involved in oxidation -Cytochrome P450 reductase supplies the electrons -Phosphatidylcholine is important for heme activity 1. Drug binds to the enzyme on membrane, NADPH is oxidized to NADP+ --e- used to convert cytochrome P450 heme from ferric to ferrous --Reduced heme attracts O2 2. Forms complex with CYP450, O2, and drug 3. Electron comes in and knocks off one O, forms H2O --2nd O forms OH group on drug --Ferrous is converted to ferric 4. Drug with OH is kicked off --CYP450 is ready to accept another drug |
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Cytochrome P450 biotransformations
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-Biotransformations are diverse
-Generally converts small molecules to more polar cpds -Reactions: --aliphatic hydroxylation --aromatic hydroxylation --Dealkylation at N-, O-, S- --N-oxidation --S-oxidation --Deamination --Dehalogenation -200 different genes identified in different animals |
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CYP450 Gene families
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-Multiple gene families
-Categories based on protein sequence homology and regulation -Most drugs are metabolized by CYP 1,2,3 -CYP1 can convert carcinogens into inactive forms -CYP3A4/5 in GI tract -Overlapping substrate specificity, 2+ enzymes can catalyze the same type of oxdation --indicates redundant and broad substrate specificity --if one gene is lost, another gene can take over specific function |
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CYP3A4/5
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-Very important CYP family, one of most important
-Present in many tissues --specifically GI tract -Metabolizes 33-35% of all drugs on the market -Presence in GI tract is responsible for poor availability of many drugs that are administered orally |
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Liver content of CYP450
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-CYP3A45 represents 26%, 33% of drug metabolism
-CYP2D6 |
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CYP2D6
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-Constitutive enzyme
-2% of total tissue CYP tissue pool -Handles 23% of drugs |
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CYP1A1 drugs metabolized
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-Caffeine
-Testosterone -R-Warfarin |
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CYP1A2 drugs metabolized
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-Acetaminophen
-Caffeine -Phenacetin -R-Warfarin |
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CYP2A6 drugs metabolized
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-17b-Estradiol
-Testosterone |
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CYP2B6 Drugs Metabolized
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-Cyclophosphamide
-Erythromycin -Testosterone |
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CYP2C Family drugs metabolized
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-Acetaminophen
-Tolbutamide (2C9) -Hexobarbital -S-Warfarin -Phenytoin -Testosterone -R-Warfarin -Zidovudine |
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CYP2E1 drug metabolized
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-Acetaminophen
-Caffeine -Chlorzoxazone -Halothane |
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CYP2D6 drugs metabolized
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-Acetaminophen
-Codeine -Debrisoquine |
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CYP3A4 drugs metabolized
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-Acetaminophen
-Caffeine -Carbamazepine -Codeine -Cortisol -Erythromycin -Cyclophosphamide -S-Warfarin -R-Warfarin -Phenytoin -Testosterone -Halothane -Zidovudine |
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Factors influencing Activity and level of CYP enzymes
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-Nutrition
-Smoking -Alcohol -Drugs -Environment -Genetic polymorphism |
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Dietary/Nutritional factors affecting drug metabolism
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1. Grapefruit Juice (and orange juice): CYP 3A4 inhibitor
--anti-anxiety, anti-depressant, anti-histamine, anti-seizure, Ca blockers --Drug will not be metabolized and will lead to drug toxicity --highly variable effects --fucocoumarins 2. St. John's Wort and other herbal products: --Inhibit CYP 3A4 and CYP 2D6 3. Isosafrole, Safrole (Root beer and some spices) --CYP1A1 and CYP 1A2 inhibitor |
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Acetaminophen History
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-AKA paracetamol
-Became a drug by trial and error -Initial Antipyretic, also Excessively toxic, induces methemoglobinemia -Next form extensively used in analgesic mixtures --causes nephropathy -Acetaminophen marketed in US in 1955 (Brodie and Axelrod) |
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Acetaminophen Toxicity
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-Safer compound, still Highly toxic
-Overdose results in more calls than any other substance -35% of severe liver failure cases are caused by acetaminophen -N-acetyl cysteine is effective antidote |
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Acetaminophen Metabolism
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-Modified by alcohol, obesity
-60% is conjugated into glucaronic acid via glucaronate transferase (inactive pharmacologically) -35% is sulfonated (inactive pharmacologically) -5% available for pharmacological activity --With alcohol: CYP2E1 and CYP3 --Metabolized into highly active N-acetyl-p-benzoquinone imine -Active form induces liver toxicity -Only 1% ends up in toxic state and body usually has enough enzymes to neutralize/take care of toxic metabolites |
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Dogs and Acetaminophen
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-Lack sulfonating enzymes
-More than 5% of acetaminophen is toxic due to lack of other pathways |
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Ibuprophen
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-NSAID
-When metabolizes, does not yield toxic or reactive compounds -Target itself is very important for homeostasis --taking too little does not have an effect --taking too much can result in serious side effects -Inhibits COX-1 and COX-1 --prevents prostaglandin synthesis -Can result in heart problems, intestinal bleeding, and other side effects |
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Ibuprophen Metabolism
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-Metabolized by CYP2C9 family and CYP2C19
-All derivatives are excreted by conjugation with glucaronic acid |
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Ibuprophen breed-specific toxicities
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-German Shepherd: resistant
-Labrador retrievers: sensitive, results in intestinal bleeding -More exist |
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Monoamine Oxidase
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-Phase I enzyme
-A form and B form -Exists in gut, liver, brain, and other tissues -Regulate metabolic activity of different NT and hormones -Destroys NT quickly to ensure short action |
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Dopamine Metabolism
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-Converted by Monoamine oxidase to L-dopa and NH4
-Need just enough, but not too much --excessive amounts is not good -Rapidly metabolized to prevent erroneous neuronal activity |
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Important Neurotransmitters
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-Dopamine
-Norepi -Epi -Serotonin Released into the blood, bind to receptors on surface of cells |
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Monoamine Oxidase Inhibitors
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-Affects dopamine, serotonin, and catecholamines (Epi and norepi)
--all compounds will be in excess --deal with pathological problem but also introduce other issues -Antidepressants -Used to treat depression, eating disorders, and other neurological disorders -Keep serotonin levels high -Have mostly been replaced by serotonin reuptake inhibitors |
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Serotonin reuptake Inhibitors
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-Inhibit re-uptake of serotonin in synaptic cleft
-Block transporters -Concentration is increased selectively -Will not initiate signal, but will amplify signal that is already present -Also inhibit catecholamine and dopamine uptake |
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Tyramine
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-Formed from tyrosine
-Monoamine coming from the diet -If blood levels of Tyramine rise, will disrupt catecholamine metabolism --Can cause fatal hypertension -Monoamine oxidase metabolizes, keeps tyramine at a reasonable level --prevent from getting into brain across BBB |
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Foods containing high levels of tyramine
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-Somked, aged, or pickled meat/fish
-Sauerkraut -Aged cheeses -Yeast extracts Fava beans -Beef and chicken liver -Game meats -Red wines |
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CYP2D6 polymorphism
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-Small number of enzymes in the liver, but act on a large number of drugs
-102 different forms -Affects drug metabolism and toxicity -Enzyme activity can vary widely --poor, extensive, or ultra-rapid metabolizer -Number of inactive alleles can cause low metabolism -Homozygous carriers= poor metabolizers (18%) -Homozygous WT carriers= efficient (70%) -Heterozygous carriers= 10-22% of population -Different doses have different effects person-to-person |
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CYP2D6 affects on Pharmacological potency of drugs
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-Catalyzes primary metabolism of codeine, beta-blockers, tricyclic antidepressants, estrogen receptor modulators, anti-hypertensive drugs, etc.
-Metabolizes codeine to morphine --morphine is active form -Metabolizes tamoxifen into 4-OH tamoxifen -Metabolizes debrisoquin into 4-OH debrisoquen --potent anti-hypertensive drug -Poor metabolizers will have poor pharmacological effect at normal dose -Ultrametabolizers will have higher than normal level of active compound --high with the same dose that will not affect a poor metabolizer --potentially could cause drug toxicity --Higher tendency for drug addiction |
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CYP2D15
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-Canine homolog of human CYP2D6
-9 have been identified -Also shows polymorphisms of poor metabolizers and ultrametabolizers |
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Celecoxib and Beagles
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-Fast and slow metabolizers have been identified
-Different urinary clearance for the drug -Conservation of fast and slow metabolizer phenotypes |
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CYP 3A12
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-Canine homolog
-Inhibited by fucocumarins and St. John's wort |
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Drug Transporters
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-Targeted by drug companies for different drugs
-2 major types: --ABC family ATP-dependent pumps --Facilitated transporters/Solute transporters |
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ABC family ATP dependent pumps
P-glycoprotein pumps |
-Large family of ATP-dependent pumps
-59 genes in humans, 49 genes in dogs -Pump drugs outside cells, exclude the drug from the cell -Primary function is to eliminate drugs and metabolites from tissues -Regulate tissue distribution -Important role in tumor cell drug resistance -Found in gut, gonads, kidneys, biliary system, brain, and placenta - |
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ABC family ATP dependent pump Morphology
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-ATP domain in cytoplasm
-Glycosyl residue facing outside of cell membrane -ATP hydrolyzed to ADP --energy is used to pump compounds |
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SLC family transporters
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-Transmembrane transporters involved in solute transport
-Organic Anion Transporters (OAT) -Organic Cation Transporters (OCT) -Involved in drug absorption and transport -Do not require ATP, use ion gradients or built-in transmembrane potential as energy source -Most are symports or antiports, some are uniports -Main function is absorption of drugs from intestinal cavity via intestinal epithelium --also resorption of silutes and organic compounds from urine |
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Distribution of ABC and SLC family transporters in endothelial and epithelial cells
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-Regulates drug absorption and excretion
-Absorption in small intestine -Transport from portal vein into liver --some drugs are excreted via liver and bile system --ABC family transporters transport out of hepatocytes -Transport into Kidney (SLC transporters) --most drugs are excreted in kidney (SLC and ABC family) |
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Hepatic Drug Absorption and Secretion
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-Depends on distinct types of transporter
-Pumps play a crucial role -Different transporters bring in different compounds --based on size and shape of cpds -ABC family transporters transport into bile canaliculus |
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Blood Brain Barrier Transporters
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-Various cpds come into via SLC transporters
--let only certain cpds in --EXTREMELY selective, much more selective than liver hepatocytes -If something happens to get through, it is pumped back out via ABC family transporters -Selectivity of pumps makes Blood Brain Barrier |
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ABC and SLC transporters as targets of drugs and inhibitors
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-NT transporters are targets in neuropsychiatric disease
-Cholesterol transporters in cardiac disease -Nucleoside transporters in cancer -Glucose transporters in cancer and metabolic syndrome -Most are SLC family, some ABC family also |
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Species differences affecting drug metabolism
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-Spotty information available
-differences have been recognized for years, but no real research -Ex: phenylbutazone |
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Induction affecting Drug Metabolism
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-2 major categories of CYP inducers
--Phenobarnital --Polycyclic aromatic hydrocarbons -Induction is an environmental and physiological adaptive response of an organism -Orphan Nuclear Receptors are regulators of drug metabolizing gene expression |
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Phenobarbital
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-Enduces metabolism of a wide variety of substances
-Causes proliferation of SER and CYP in hepatocytes |
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Dexamethasone
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-Acts like corticosteroids
-Used to treat inflammation and immune suppression -Induce CYP450 different forms |
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Orphan Nuclear Receptors
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-Transcription Factors
-Respond to xenobiotics and physiological cpds -Regulate metabolism by modulating gene expression -Activated by xenobiotics and bind to promoter region of a gene to induce expression |
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Xenobiotic
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-Comes into cell and activates family of nuclear receptors
--CAR or PXR -Once activated, receptor binds to promoter region of the gene and initiates transcription and expression |
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CYP3A Regulation
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-Regulated by PXR and RXR
-PXR and RXR are activated by certain drugs -Once activated, form heterodimer and bind to promoter region --specific binding cassettes -Induce CYP3A, enhances metabolism of a different drug -Giving one drug can modulate the activity of a different drug -Nutritional or physiological state affects drug metabolism |
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Aryl Hydrocarbon Receptor Activation
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-Activated by polycyclic aromatic hydrocarbons and PCBs Present in pollutants and cigarette smoke
-Activate transcription of CYP1A1 and CYP 1B1 -Enzymes cannot metabolically inactivate hydrocarbons -Results in activation of toxic chemicals, inflammation, impaired immune response, cancer, osteoporosis, pancreatitis |
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Pharmacokinetics
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-Factors that contribute to controlling the concentration of a drug at the site of action
-Bioavailability: how much of drug enters circulation --how much of drug is metabolized by liver before it reaches circulation -Distribution of drug -Metabolism/clearance of drug |
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Routes of Administration
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-PO (oral)
-Sublingual -Rectal -IV parenteral -IM -Subcutaneous -Interosseous -Transdermal/topical -Intraocular -Epidural Choose route based on compliance |
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Oral route of Administration
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-Pros:
--high rate of compliance, convenient --economical --Reversible, safe, can induce vomiting or limit absorption with charcoal with overdose -Cons: --Vomiting will not get drug into system --affected by pH and presence of food, absorption can be irregular --Can be highly metabolized by liver before drug enters circulation (1st pass effect) --May cause intestinal irritation --May be metabolized by microbes in digestive system Slow rate of absorption |
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Sublingual Administration
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-Can be used to avoid 1st pass effect
-Drug is not metabolized before getting into circulation -Slow effect |
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Rectal Administration
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-Avoids issues of vomiting
-reduces 1st pass effect -Absorption is slower, but some formulations work quickly -Can be used when patient is vomiting or oral administration is not practical -Absorption can be variable |
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IV Administration
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-Absorption is instantaneous
-Instant and accurate control of the amount of drug that enters circulation --can also be dangerous, not easily reversible -Endothelium is tolerant of irritating solutions -Need to know how to do it -Can cause damage to veins of patient with repeated injections |
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Subcutaneous Administration
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-Slow, sustained release
-Can co-administer a vasoconstrictor to limit absorption or local bleeding -Irritating solutions can cause tissue necrosis |
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IM Administration
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-Slow, sustained release with oil-based drug formulations
--can be faster with aqueous-based formulations -Can result in pain that lasts longer -Good for vaccination injection |
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Inhalation/Nasal Administration
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-Instantaneous
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Topical/Transdermal Administration
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-Specialized route
-Has local effect, gives specificity for administration |
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Bioavailability
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-Fractional Percentage of the drug that enters circulation after 1st pass effect
-Unitless quantity -IV dose is 100% bioavailable -PO dose is 50% absorbed, 20% metabolized by 1st pass --40% is available -Drugs are not uniformly distributed in water, unevenly distributed throughout the body |
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Factors affecting Bioavailability
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-Route of administration
-Physiochemical properties of the drug --charge, acid/base, lipid solubility, size -Physiology of the Patient --gastric pH, presence of food, type of species being treated |
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Drugs as Acids or Bases
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-All drugs are either weak acids or weak bases
-Have to cross membranes to get into the body -Cross via passive transport and carrier-mediated transport |
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Passive Transportation
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-Movement across a membrane
-Does not work for charged molecules -Uncharged molecules can move across -Charged molecules are repelled by the membrane outer layer or inner layer |
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Properties of Diffusion
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-Depends on lipid solubulity
-Not saturable --particles move across membrane based on concentration gradients --always move DOWN gradient -If there is a gradient across a membrane, drugs can accumulate on either side of the membrane -Only very small, uncharged molecules -pH has a big effect on diffusion --pH varies across membranes |
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How Drugs Cross membranes
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-Passive Diffusion:
--lipid soluble drugs --rate is influenced by size, larger molecules move slower -Carrier-mediated transport --charged or polar molecules --sometimes requires energy to move material across membrane --can contribute to establishing membrane gradient |
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Movement of Drugs across a membrane and pH
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-pH can have profound effect
-Many drugs are weak acids or weak bases --can be charged or uncharged species in solution -Since charged molecules do not diffuse across membranes, pH of environment can dramatically change rate at which a drug crosses a membrane -Weak acids are better absorbed from acidic compartments --weak acids accumulate in basic compartments -Weak bases are better absorbed from alkaline compartments --weak bases accumulate in acidic compartments -pH can also cause a steady-state concentration gradient of drug across the membrane |
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Factors affecting Drug Absorption
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-Solubility of the Drug in Aqueous Solution
-Dissolution of a solid --solid pills do not dissolve in acidic environments -Timed-release formulations, slow rate of dissolution -Enteric coating prevents dissolution in the stomach -Surface area available for absorption -Circulation at the site of absorption (cardiac output) -Binding of drugs to proteins (albumin) |
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pH control on Drugs
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-Controls:
--how much --Rate of absorption --distribution of drug throughout body compartments |
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pH and pKa dynamics
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-if pH is less than pKa, protonated species predominates
--basic drugs accumulate -if pH is equal to pKa, species are equal |
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Distribution of Drugs
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-After absorption drugs are distributed to compartments in the body
-Rate depends on: --properties of the drug --Charge on the drug --pH --Amount of circulation to area --Surface area available for movement into compartment |
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Drugs accumulating in compartments
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-Accumulate in compartments unevenly
-Distribute into lipids -Bond to protein -Become charged -Uneven distribution means drugs appear to distribute into different volumes -Need to use "volume of distribution" to determine how much drug needs to be administered to achieve therapeutic concentration |
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Volume of Distribution
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-Hypothetical volume of plasma into which a drug distributes if the drug were only distributed into plasma
-Takes into account uneven distribution of drugs -Apparent volume of plasma into which a drug is distributed -Assumes the drug has been distributed and there has not been any metabolism =bioavailable dose/concentration of drug in plasma -Measured in L or L/kg -Gives feel for how drug is distributing -Gives idea for how much you need to give to reach bioavailable concentration |
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Volume of Distribution Equation
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-Vd= Bioavailable dose/ Concentration of drug in plasma
-Concentration of drug in plasma assumes drug has been distributed throughout various compartments prior to metabolism -Concentration is determined by monitoring the concentration of drug in plasma at different times |
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Volume of Distribution in a Human
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70kg primate has 3L of plasma
5.5L of blood volume 12L of extracellular fluids 42L of total body water 42L total body water/70kg= 0.6L/kg |
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Volume of Distribution in 70kg human
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-42L total body water/72kg= 0.6L water/kg body weight
-If Vd is larger than 0.6L/kg, drug is likely accumulating in non-aqueous environments --fat, organs, accumulating in acidic/basic compartment -If Vd is less than 0.6L/kg, drug is accumulating in blood compartments --binding to plasma proteins |
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Use of Volume of Distribution
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1. Gives idea as to where drug is going in body
-High Vd: drug is accumulating in a body compartment outside of the blood --fat, organs, muscle, bone -Low Vd: drug does not have access to non-plasma compartments --accumulating in blood by binding to proteins 2. Helps determine the amount of drug that should be administered to get therapeutic concentration 3. Used to calculate other pharmacokinetic parameters |
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Volume of Distribution in Different Species
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-Varies based on age, fat content, and disease
-Varies based on species --Acidic rumen provides for larger volume of distribution in ruminants |
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Drug metabolism
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-Most often occurs in liver
-Drug interacts with enzyme and is converted into a more water soluble form --oxidation -Ultimately the drug is more water soluble --water-solubility allows body to get rid of the drug -Metabolism follows 1st order kinetics -Enzyme system is NOT saturated, same % of drug is metabolized for any given unit of time -process for elimination is not saturated -Drug never reaches Vmax |
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Drug Oxidation
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-Converts drugs into a more water soluble form to help with excretion
-Couples drug with small molecules or combination of small molecules -Occurs in the liver |
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Major routes for excretion of a drug
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-Urine
-Bile fluid -Sweat -Saliva -Tears |
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Drug Half-life
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-Time needed to metabolize 50% of a drug
-Follows 1st order kinetics --Same percentage of drug is eliminated during a given time interval --Most of the drug is gone by the 4th half-life |
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Km values for drug-enzyme interactions
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-Usually higher than concentrations of the drug in the patient
-Means enzymes are never saturated -rate of metabolism is proportional to the concentration of the drug -Follows 1st order kinetics --same fraction or % of drug is metabolized for any given time interval -Plot of concentration vs. time will asymptotically approach the X-axis -Plot of log(concentration) vs. time gives straight line |
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Factors affecting Metabolism
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-Age of patient
-Hepatic diseases -Renal diseases -Cardiac failure -Presence of other drugs -Can vary widely between species |
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Clearance
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-Effects of metabolism/elimination by all routes
-Volume of plasma cleared of drug per unit time -Ability of the body to eliminate drug by all routes -Have to make adjustments based on kidney function or other disease states -measured in ml/min per kg |
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Clearance equation
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Cl= Ke X Vd
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Variability in Plasma Concentration of a Drug
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-Depends on:
--rate of absorption --Dose --Rate of elimination of plasma concentrations -Blunting absorption blunts peaks, do not have to give drug as often -Doubling dose does not change curve, changes peak |
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Goal of drug Treatment
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-Maintain therapeutic concentrations without causing toxic side effects
-Can treat an animal with side effects at concentrations near levels needed to cause therapeutic benefit --depends on clinical situation |
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Things to consider with rate of Absorption
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-If rate of absorption is fast, peak concentration occurs within a few minutes
--IV administration -If rates of absorption and elimination are equal, will achieve plateau of concentration that does not fluctuate much --transdermal patch, continuous IV drip -When dose is increased, time course does not change, peak gets bigger -When elimination is slower fall from the peak takes longer |
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Usual Drug Distributive Activity
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-Usually drug rapidly distributes to central compartment
--slowly redistributes to peripheral compartments -Concentration in central compartment is fast and high -Drug redistributes to less perfused fatty tissue -Body continually metabolizes drug over hours -Body has many compartments, usually only 1 or 2 are important for a given drug |
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Central Compartment
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-Blood and heavily perfused tissues
-Specifics depend on the nature of the drug -Usually a given drug rapidly distributes to the central compartment and slowly redistributes to peripheral compartments |
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Benefit of Repeated Doses of a Drug
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-Single dose is usually not enough to achieve therapeutic benefit
-repeated doses are needed to maintain therapeutic concentrations without causing side effects -Eventually get to plateau state -Want to be able to blunt peaks and troughs --minimize fluctuations |
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Zero order Kinetics
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-Occurs when an enzyme is saturated
-Increases in concentration does not increase rate of metabolism -Same amount of drug is metabolized at any given interval --Not same percentage, same overall amount -Ex: alcohol in humans -Phenylbutazone |
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Multiple Compartment Pharmacokinetic Model
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-Drug distributes to central compartment first
--wears off and loses efficacy quickly -Various tissues can be in central compartment, always includes blood -Drug is still distributed to peripheral compartments and can last for much longer --slower release over time -Change in concentration in the plasma is the sum of 2+ decay processes -With multiple compartments volume of distribution reflects the hypothetical volume of plasma after redistribution and before elimination |
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Plateau Concenration
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-Average of peaks and troughs of repeated doses
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Age-related changes in Pharmacokinetics
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-Drug metabolizing enzymes are developmentally regulated
--not expressed at same levels throughout an animal's life -Young animals can have a lower percentage of body fat --affects volume of distribution |
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Weight related changes in Pharmacokinetics
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-Very heavy animals have higher percentage of body fat
-Body fat affects volume of distribution |
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Disease states and pharmacokinetics
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-Disease states slow metabolism
-Can also change Vd for a drug |
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Enzyme polymorphisms and pharmacokinetics
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-Can slow or accelerate metabolism
-Polymorphism is observed in more than 1% of population |
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Ruminants and Pharmacokinetics
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-Have higher volume of distribution for weak bases
-Rumen is not developed at birth, provides for difference between young and mature ruminants |
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Carnivore Urine and Drugs
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-Carnivores have acidic urine compared to plasma
-Herbivores have basic urine -Drugs cleared as weak bases are cleared faster in carnivores -Drugs cleared as weak acids are cleared faster in herbivores |
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Structure of Skin and Pharmacokinetics
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-Skin structure is dramatically different in rabbits and pigs
-Results in over 30x differences in rate of absorption of organophosphate cholinesterase inhibitors |
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Ligands
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-Molecules that are bound by receptors
-Proteins cells use to interact and communicate with other cells in the body -Agonists and antagonists exist |
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Agonist
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-Ligand that causes a biological response when bound to proper receptor
-Can be a cellular, physiological, or behavioral response -Activates receptor to initiate cascade of response -Something happens |
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Antagonist
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-Ligand that binds to receptor without an effect
-Endogenous mediators are blocked -Cell is not activated -Action by an agonist is prevented |
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Criteria for a Receptor
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1. Saturability
2. Specificity 3. Reversibility 4. Bifunctional Role -Saturability, Specificity, and Reversibility describes how a ligand/drug binds to a receptor |
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Saturability of a Receptor
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-Finite number of receptors
-So much drug exists that all receptors are bound -Adding more drug will not have an effect --no place for more drug to bind |
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Specificity of a Receptor
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-Receptor is Highly specific for certain molecules
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Reversibility of a Receptor
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-Ligand can come off of the receptor and remain unchanged
-Ability to have equilibrium between receptor and ligand |
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Classes of Receptors
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1. Ion channel receptors
2. G-protein coupled receptors 3. Tyrosine Kinase Receptors 4. Transcription factor receptors -Differentiate classes based on overall protein structure, cell signaling mechanisms, and time scale of the response -Different architecture of receptors responds to different ligands |
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Ion Channel Receptors
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-Ligand-gated ion channel
-NT receptors --Acetylcholine receptor --GABA receptor --Aspartate --Glycine |
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Ion Channel receptor Function
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-Governed by ion channel conductances
-Very fast action, occurs in milliseconds |
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G-protein Coupled Receptors
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-"Super class" of receptors
-LOTS of genes encode for G-protein coupled receptors -60% of pharmaceuticals act on GPCRs --drugs act as agonists, antagonists, and everything inbetween -Biological response is mediated by G-protein inside of the cell -Receptor weaves through the cell membrane, crosses membrane 7 times -Time scale of cellular action is fast (seconds) -Each receptor has a specific choreographed response |
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G-protein Coupled Receptor Action
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1. External signal binds to receptor (1st messenger)
--hormone, NT 2. G-protein acts as a transducer, relays signal to amplifier 3. Adenylyl cyclase acts as amplifier and uses ATP to activate 2nd messenger (cAMP) 4. Changes in the amount of 2nd messenger is critical for biological effect -2nd messenger activates the internal effector proteins 5. Internal effector proteins stimulate cellular response from protein kinase A -Receptor can either bind positive or negative stimulus -type of stimulus either increases or decreases cAMP production to start cellular response |
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G-protein coupled Receptor and Phospholipase C
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1. Positive stimulus binds to GPCR
2. G-protein relays signal to phospholipase C 3. Phosphatidylinositol 4,5 Bisphosphate acts as phosphorylated precursor -membrane lipid 4. activates Inositol trisphosphate to increase Ca ions 5. Ca ions activate Protein Kinase C, Ca CaM protein kinase, or TnC -different combinations give different specific choreographed response from cell |
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AT1 receptor
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-GPCR
-Can be inhibited to inhibit cAMP production -Can be activated to activate G-protein, phospholipase C --in turn activated PIP2 into Diacylglycerol and IP3 -End result is activation of Protein Kinase C and release of Ca from storage by IP3 |
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G-protein Coupled Receptor Links
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-GPCR can be linked to more than 1 G-protein
-Can have more than 1 reaction initiated by activation of receptor -GPCR may be able to initiate cell signaling not traditionally associated with G-proteins --can do more than activate G-proteins -Can activate Jak/Stat pathway -Early response genes -MAP kinase pathway activation |
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Tyrosine Kinase Receptor
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-has extracellular domain and intracellular domain
-Activated when dimer is brought together -Sets of intracellular signal, series of enzymatic actions -Receptors for insulin and growth factors use this pathway -Much slower action, takes minutes for effect |
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Transcription factor Receptor
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-Intracellular receptors
-Ligand binds inside the cell -Receptors for steroids, thyroid hormone, Vitamin D, and retinoids -Changes protein levels and gene products -Very slow timescale for action, takes hours to days for effect --slow to activate, slow to resolve once activated |
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Receptor Subtypes
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-Different "flavors" within a general category
-Many receptor systems have sub-types -Sub-types often show differential distribution in the body -Can be exploited, results in drugs that show tissue-specificity for a particular receptor --specific tissue or location gives specific side of action in the body |
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Bio Assay
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-Way to quantify the biological activity of a drug
--Measure of Potency -responsiveness of a biological system to a particular drug -Making use of a characteristic and reproducible biological response of a tissue preparation to quantitate the biological activity of drugs/ligands |
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Elements for a BIoassay
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1. Reliable, reproducible biological response to activation of a specific receptor system
2. Use biological response to assess/quantify the biological "punch" of ligands acting on the system -Can use specific change in response to define activity units for the drug -Can use system to quantify the bioactive potency of other production batches of the drug -Use to identify how much of a drug is present |
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Importance of Bioassays
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-Some drugs are prescribed in "activity units" due to variability of drug bioactive potency
--variation due to production --Peptide drugs are especially variable batch-to-batch -Need to know what the biological activity will be -Bioactivity is VERY important |
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Radioligand Binding Assay
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1. Receptors of a tissue are incubated with radioactively marked ligands
2. Ligand-receptor complex is isolated from free ligand 3. Radioactivity of ligand-receptor complex is counted --gives idea of how many ligands bound to how many receptors --More radioactivity indicates more receptors on cell surface bound with ligand |
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Experimental Analysis of Receptors
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-Comparison between drugs and receptor affinity for drugs
--Relationship between the receptor and ligand -Receptor affinity for a ligand is based on rate (on) compared to rate (off) |
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Law Of Mass Action
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-The receptor affinity for a ligand is a reflection of the rate on (kon) compared to rate off (koff)
-KD = dissociation constant -Kd= (koff)/(kon) -EX: cocktail party and different people |
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Dissociation Constant
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-KD
-Relative affinity of a ligand for a receptor -KD= (Koff)/(Kon) |
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Radioligand Binding and measuring total binding
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1. Combine tissue and radio-labeled drug
2. Incubate 3. Wash off any unbound drug --bound radioligands stay on the filter 4. Count radioactivity associated with the tissue -Can show saturability of a receptor -As concentration of radioligand increases, amount bound increases less |
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Radioligand Binding and measuring Non-specific Binding
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1. Combine tissue and radiolabeled drug and excess of non-radioactive competing ligand
2. Incubate 3. Wash off unbound ligand --only get non-specific binding of radioligand 4. Count radioactivity associated with the tissue -Specific binding shows reduced amount of receptors interacting only with radioligands -Non-radiolabeled ligands also bind and take up some receptors |
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Saturation Isotherm
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-Shows how a ligand binds to a receptor
-Depends on how many receptors are on the tissue and affinity of radioligands for specific receptor -BMAX= maximal number of binding sites, density of receptors on a tissue -KD= concentration of radioligand where half of maximal binding is obtained --Lower KD, higher receptor affinity --more ligand is bound at a lower concentration |
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Competition Binding Analysis
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-Radio-labeled and non-radiolabeled ligands mixed with receptors
-Ligands are competing for the same binding sites -Concentration of ligands determines which ligand is bound more |
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IC50
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-Concentration of competitor which inhibits binding by 50%
-Concentration at which half of competing radiolabeled ligands cannot bind anymore -Lower IC50 means higher receptor affinity, more biologically potent -Takes a low concentration of competing compound to change how competitor binds -If competing ligand never binds (no competition), binding of radioligand does not change |
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Occupancy Theory
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1. Interaction of a drug with its receptor is governed by law of mass action
2. Effect of drug is proportional to the fraction of the receptors occupied by the drug --Response is proportional to receptor occupancy --Maximal effect is reached when all receptors are occupied (saturability) |
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EC50
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-Concentration of a ligand that produces half maximal response or effect
-Lower EC50 means a more potent agonist --takes less of ligand to produce half of the maximal response -Gives order of potency for Full agonists |
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Partial Agonist
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-Binds to receptor and causes biological response but never reaches maximal level of bioactivity
-Never fully saturates |
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Intrinsic Efficacy
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-Ability of ligands to activate receptors is a graded property
--not "all-or-none" property -Full agonists get maximal response --intrinsic efficacy=1 --optimal binding domains activated -Partial agonist gets less than maximal response --intrinsic efficacy between 0 and 1, reflects strength of partial agonist vs. full agonist --some activation, but not best interaction for maximal response -Antagonist gets no response --intrinsic efficacy = 0 --no domains are activated |
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Factors Determining Effect of a ligand
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1. Fractional occupancy
--reflection of binding --does it bind 2. Intrinsic efficacy --ligand's ability to activate the receptor --what does it do once bound |
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Effect of Antagonists on Dose-Response curve
Competitive Antagonist |
-Competitive antagonists will block binding of agonist
-Antagonist competes with agonist but does not elicit a biological response -Causes parallel shift of dose-response curve to right -Does not affect the maximal response -Takes more concentration of agonist to get same response -Increased concentration of agonist will at some point out-compete antagonist |
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Effect of Antagonist on Dose-Response curve
Non-competitive Antagonist |
-Non-competitive antagonist causes reduced efficacy of agonist
-Changes the receptor itself --covalent modification of receptor or interacting regulatory site -May involve destruction of receptors -Shifts dose-response curve to the right AND decreases the maximum |
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Inverse Agonist
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-Induces a biological response when it binds to receptor
-Response is in the opposite direction from an agonist response -Changes function of receptor to illicit a biological response just like an agonist --response is opposite from agonist -Acts on SAME receptor as agonist, just has opposite action |
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Effect of a Surplus of receptors
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-Can get a greater level of response with the same concentration of agonist
-System is hyper-responsive -Can also get the same level of response with a lower concentration of agonist |
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Receptor Desensitization
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-With prolonged exposure to agonist system starts to tune out response
-"Desensitized receptor" -Takes a break in exposure to re-sensitize receptors --after break can get another response with agonist -B-arrestin covalently binds to intracellular domain of receptor within chronic agonist exposure -Need to take a "drug vacation" |
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Receptor Down-regulation
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-When ligand binds, receptor is sequestered into cell
--pulled out of membrane and into the cell -Intracellular processing removes the agonist from the receptor -Receptor is re-sensitized and placed back onto the membrane --can interact with another ligand and produce response -Take a "drug vacation" |
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Drug Vacation
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-Receptor desensitization and down-regulation necessitates taking patient off of a drug for a certain amount of time
-Need to resensitize patient to the drug -Must continue to treat condition with an alternate treatment --something that works on a different receptor and different mechanism |
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Terbutaline and B2-adrenergic receptors
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-B2 relaxes smooth muscles
-B1 increases heart rate -initially one concentration of terbutaline will stop contractions without getting into increasing heart rate zone -As receptors are sensitized, have to give more and more concentration of terbutaline --dose-response curve shifts to right and down --start to give dose that could cause cardiac issues -Eventually terbutaline will not work at all --Need a Drug vacation |
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Causes of Response Variability
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-Genetic factors
--Species differences can compound genetic differences -Age -Drug-induced loss of response -Effects of disease or altered physical states -Drug interactions -Pharmacodynamic interactions -Pharmacokinetic interactions -Adverse reactions |
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Pharmacokinetic response variability
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-How drug gets to where it needs to get to
-Differing concentrations at the site of action -Bioavaiabilty -Differences in absorption, distribution, metabolism, excretion |
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Pharmacodynamic response variability
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-different responses to the same concentration of drug
-Responsivity of site of action to the drug -Depends on receptor types present and how many receptors are present -Physiological and biochemical responses |
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Genetic Factors in Pharmacokinetic Response variability
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-GI tract differences contribute to absorption
--type of stomach, pH -Protein binding between species varies, alters distribution -Biotransformations of enzymes varies by individual, species, and sex --changes metabolism -Excretion is different between birds and mammals |
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Age and Response variability
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-Absorption changes, acid secretion is decreased and splanchnic blood flow is decreased
-Kidney function is also decreased -Changes in fat and muscle mass alter body composition and distribution -Lipophilic drugs have longer half-life in older animals -Plasma protein levels drop with age --drugs that bind to plasma proteins are more available in older animals |
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Drug sequestered into Body fat
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-Fat stores can take up drug and prevent drug from getting to receptors
-Fat can also store drug for later/slower release -More drug is available with less water in the body --amount of water decreases with age |
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Age and Metabolism of Drugs
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-Metabolism is decreased in neonates and geriatric patients
-Hepatic enzyme activity, liver weight are lower in young and old -Hepatic blood flow in decreased in older animals -1st pass effect is more profound in younger animals |
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Age and Excretion of Drugs
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-Renal excretion changes based on age
-Kidneys do not work as well in neonates or geriatrics --Low renal blood flow and glomerular filtration -Geriatric patients have 50% of renal filtration as young adults -Neonates have 20% of renal filtration as young adults -Drug clearance is higher with better kidney function --older and younger animals will have a harder time clearing drugs |
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Pharmacodynamic Changes associated with Age
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1. Neonates:
-Low numbers of receptors -Different receptor types -Altered receptor affinity 2. Geriatric: -may have altered receptor affinity -Altered coupling to receptors -Altered receptor numbers |
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Drug-Induced Loss of Response causing Drug response Variability
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-Will have gradual decrease in response to a drug
-Change in drug receptor conformation --drug will bind to receptor but have no effect -Loss of receptors due to down-regulation or endocytosis -Exhaustion of response mediators (2nd messengers etc.) -Increased metabolic degradation induces enzymes to remove the drug -Physiological adaptation --reflex or biochemical compensations to interacting organ systems |
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Effects of Disease or altered physiological states on Response Variability
Pharmacokinetics |
-Absorption can be altered with gastric stasis, malabsorption, and mucosal edema
-Distribution changes as pH changes --alterations in plasma protein levels and impaired blood brain barrier can also have effects -Metabolism is altered with liver disease and hypothermia -Excretion changes with renal failure and presence of proteins in tubular fluid that bind drugs |
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Effects of Disease or altered physiological states on response variability
Pharmacodynamic |
-Receptor numbers vary with disease states
-Can cause neurological disorders -Signal transduction pathways are also altered by disease states |
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Effects of Drug Interactions on response variability
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-Adding another drug can drastically alter how one drug is Absorbed, distributed, metabolized, or eliminated
-Can be beneficial --reduces toxicity while enhancing therapeutic effect --Can also delay onset of resistance -Can be adverse and cause problems --make drug toxic without intending |
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Sites of Action for Drug interactions
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1. External site of Action: in vitro
--Can be found with precipitation or chemical combination 2. internal sites of action --GI tract --Site of drug action (receptor) --RNA-DNA --Metabolic pathways |
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Mechanisms of Drug interactions
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1. Physiological mechanism:
-two drugs act at different sites to alter function -may augment or offset each other 2. Pharmacokinetic mechanism: -One drug changes the concentration of the other drug 3. Pharmacodynamic mechanism: -One drug changes the effect of another |
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Pharmacodynamic Drug Interactions
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-One drug changes the effect of another drug
-May or may not be predictable change -Drug can act indirectly on another drug by changing the intracellular or extracellular environment --pH, ion concentration -Additive effect for drugs with similar sites of action -Synergistic effect, effect is more potent than sum of drugs --drugs have different cellular mechanisms -Antagonistic effect: effect of A and B together is less than sum of A and B --specific receptor antagonists with same target sites -Large effects are seen when therapeutic range of affected drug is narrow --small change in effect leads to a greater loss of efficacy or toxicity |
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Factors Affecting Intestinal Drug Absorption
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-Disintegration time
-Gastric emptying -Dissolution rate -Intestinal transit time -pH of lumen fluid -Lumen surface area -Absorption in intestine -Transport across columnar cells -Hepatic blood flow |
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Physiochemical factors contributing to pharmacokinetic drug interactions
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-Chelation
-Change in luminal pH affecting drug ionization -Adsorption -Dissolution |
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Changes in GI motility and Drug Absorption
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-Early gastric emptying leads to increased absorption from small intestine
-Delayed gastric emptying decreases absorption -Increased intestinal motility leads to decreased absorption |
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Changes in Bacterial flora and drug absorption
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-Antibiotics affect the ability of bacteria to deconjugate drugs excreted into bile
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Drugs and GI Mucosal damage
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-Drugs can damage GI mucosa and affect drug metabolism
-Block active transport or carrier systems |
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Drugs and Altered blood flow
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-Affects distribution of drugs
-Decrease in cardiac output affects hepatic blood flow -Decreased hepatic blood flow changes clearance and 1st pass effect |
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Drug interactions that can change pharmacokinetic Distribution
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-Alter blood flow
-Alter tissue uptake or tissue protein binding (pH) --can interfere with hepatic uptake and alter 1st pass effect -Alter active transport at the site of action -Alter plasma protein binding |
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Drug Interactions and Plasma Protein binding
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-Highly bound proteins can be displaced by drugs that bind tighter
--leads to more free drug in the plasma, can cause acute toxicity -Limited effect --drug redistributes throughout the VD --Drug is excreted more readily -Concentration of free drug eventually returns to near what it was |
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Phenobarbital and Warfarin
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-Phenobarbital enhances biotransformation of warfarin
-Warfarin dose needs to be adjusted --if not readjusted, dosage may result in bleeding when phenobarbital is removed |
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Excretion and Drug Interactions
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-Glomerular filtration can be increased by displacement of drug from plasma proteins
-Tubular reabsorption is decreased by diuretics, alkaline pH for weak acid drugs, and acidic pH for weak base drugs -Tubular secretion is also decreased by competitors for active transport systems -Urine flow is increased by diuretics --decreases reabsorption of drugs, increases excretion --reduces drug concentration --reduces renal toxicity |
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Dose-related adverse drug reactions
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-Dose needs to be adjusted before continuing treatment
-Renal disease -Liver disease -Altered receptors -Altered pharmacogenetics |
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Non-dose related adverse drug reactions
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-Discontinue use of the drug
-Pharmacogenetic variants -Drug allergy -Unknown mechanisms |
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Adverse Drug Reaction predisposing conditions
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-Older animals
-newborns -Females -Multiple drug interactions |
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Autonomic Nervous System
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-Efferent division of the peripheral nervous system
-Involuntary action -Smooth muscle, cardiac muscle, exocrine glands -Divided into sympathetic and parasympathetic divisions -Sympathetic: thoracic and lumbar spinal segments -Parasympathetic: cervical and sacral spinal segments -Maintains homeostasis |
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Physiological actions of the Sympathetic Nervous System
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-"Catabolic" reactions, breakdown reactions
-"fight or flight" -Increases alertness -Pupillary dilation -Bronchial dilation -Increased perspiration -Increased HR and force, increased BP -Increased gluconeogenesis and glucose release from liver -Decreased GI motility, decreased blood flow to GI system --increased sphincter tone -Lipolysis and release of fat stores -Increased bladder tone and decreased urination -Increased blood flow to skeletal muscle and increased gluconeogenesis in skeletal muscle |
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Physiological actions of the Parasympathetic Nervous System
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-Anabolic, "build up"
-"rest and digest" -Eyes accommodate for near vision, pupils constrict -Decreased bronchial constriction and increased secretion -Increased saliva production, liquid saliva -Decreased HR and blood pressure -Increased GI secretion, motility --decreased GI sphincter tone -Decreased bladder sphincter tone |
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Eye reaction to ANS stimulation
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-Effector organs:
--Iris --Ciliary muscle -Sympathetic system: Mydriasis --increases pupil size -Parasympathetic system: Miosis --decreases pupil size |
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Heart reaction to ANS stimulation
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-Sympathetic:
--increased HR --Increased contractility --increased conduction -Parasympathetic: --decreased HR --decreased contractility --decreased conduction |
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Blood Vessel reaction to ANS
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-Sympathetic: constriction
-Parasympathetic: dilation |
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Lung reaction to ANS stimulation
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-Sympathetic:
--Airway smooth muscle relaxation and dilation --No change in airway glands -Parasympathetic: --Constriction of airway smooth muscles --Secretion from airway glands |
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GI tract reaction to ANS Stimulation
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-Sympathetic:
--GI smooth muscle relaxation --Some inhibition of secretion --Contraction of sphincters -Parasympathetic: --GI smooth muscle constricts --Secretion is stimulated --Sphincters relax |
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Salivary gland reaction to ANS stimulation
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-Sympathetic: Thick saliva and mucus
-Parasympathetic: watery, thin saliva |
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Anatomy of the Autonomic Nervous System
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1. Somatic innervation:
--one neuron system 2. Sympathetic innervation: --2 neuron system --short pre-ganglionic fiber and long post-ganglionic fiber --Ganglion is in sympathetic trunk --Postganglionic fiber goes to multiple target organs, causes multiple actions 3. Parasympathetic innervation: --long pre-ganglionic fiber and short post-ganglionic fiber --Ganglion is right on the target organ |
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Pre-ganglionic fiber NT in ANS
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-All pre-ganglionic synapses release ACh
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Post-ganglionic fiber NT in ANS
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-Release Norepi or ACh
-Sympathetic system releases Norepi --except for sweat glands, releases ACh |
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Catecholamine Structure
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-Catechol and Amine
-Forms ring with 2 carbons side chain and terminal amino group -NOT found at cholinergic synapses -Dopamine, norepi, epi --all are structurally similar |
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Biochemistry of Catecholamine Synthesis
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1. L-tyrosine is converted into Dopa via Tyrosine Hydroxylase
2. Dopa is converted into Dopamine via dopa decarboxylase 3. Dopamine converted into norepi via dopamine b-hydroxylase -Norepi negatively inhibits tyrosine hydroxylase in reaction of L-tyrosine to dopa --Negative feedback from product of reaction 4. In adrenal gland Norepi is converted into Epi via phenylethanolamine-N-methyltransferase |
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Catecholamine Synthesis Important Points
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-Adrenergic nerve terminal
-Rate limiting step is conversion of L-tyrosine into Dopa via tyrosine hydroxylase --reaction is limited by amount and availability of tyrosine hydroxylase -NorEpi acts as negative feedback, end-product inhibition of Tyrosine hydroxylase -Synthesis is regulated by increased nerve activity |
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NorEpi synthesis in Nerve Terminal
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1. Tyrosine in blood moves into nerve terminal
2. Tyrosine is converted into dopa via tyrosine hydroxylase in cytoplasm 3. Dopa converted into dopamine via dopa decarboxylase in cytoplasm 4. Dopamine brought into vesicles 5. D-beta-H is in vesicles, converts dopamine into Norepi |
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Epinephrine Synthesis in Adrenal Gland
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-Occurs in Adrenal Medulla, in chromaffin cells
-Norepi diffuses into cytoplasm of chromaffin cells and is converted into Epi via PNMT --occurs in cytoplasm -Epi is re-packaged into vesicles for release -Adrenal granules contain about 80% epi and 20% norepi -Exocytosis of vesicles is mediated by ACh and depends on Ca -No active re-uptake of Epi into adrenal gland --once epi is dumped into the blood, it is carried away |
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PMNT
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-Enzyme in adrenal medulla that converts Norepi into Epi
-Not found in nerve terminals -Epi synthesis occurs in adrenal medulla, NOT nerve terminal |
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Release of Catecholamines from Adrenal Gland
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-Adrenal gland acts as modified sympathetic ganglion
-Stimulation of pre-ganglionic fibers releases ACh directly onto chromaffin cells |
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Mechanism of Synaptic Transmitter Release
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1. Nerve depolarization triggers opening of voltage-gated Na and Ca channels
2. Ca-dependent vesicle fusion and exocytosis --Ca mediated process, vesicle will not fuse without Ca 3. Vesicle diffuses into synaptic cleft, releases NT into cleft 4. NT binds to receptors on post-synaptic cell, activates post-synaptic cells 5. Transmitter is metabolized |
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Targets for changing NT release from nerve terminal
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-LOTS of areas for possible therapeutic targets
-Can stop nerve depolarization -Na and Ca channels -Ca dependent vesicle fusion -Prevent diffusion of NT into synaptic cleft -Receptor binding and activation -Transmitter metabolism |
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Puffer Fish
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-Has compound that blocks Na channels
-Prevents nerve impulse transmission |
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Fate of Catecholamines Released into Synapse
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1. NorEpi binds to receptor on post-synaptic neuron directly
--Small synaptic cleft keeps concentration local and increased 2. Some norEpi binds to pre-synpatic autoreceptor --negative feedback, inhibits NorEpi vesicular release --keeps impulse in check 3. Reuptake into terminal --most is taken back into pre-synaptic terminal 4. Reuptake into synaptic vesicles 5. Some Transmitter is metabolized by monoamine-oxidase --makes subtle changes to structure |
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Monoamine Oxidase
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-Exists within nerve terminal
--on outer membrane of mitochondria -Competition between vesicle uptake and degradation -Enzyme -Metabolizes NorEpi NT once re-uptake happens |
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Catecholamine Metabolism
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-Monoamine Oxidase
-Catechol-o-methyl transferase (COMT) -Molecule is changed to be non-hydrophobic -Once non-hydrophobic, can be excreted -Changes metabolic Stability -NorEpi, Epi are broken down -End product is 3-methyl-4-hydroxy-phenylglycol |
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7-transmembrane Receptor Structure
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-G-protein coupled receptors
-Cross membrane 7 times -300-400 AA in each receptor -Catecholamines bind to and activate specific cell surface membrane receptors |
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Non-Secretory GPCRs in Human Genome
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-Family A/Class I: most common
--has lots of kinks -Family B/Class II -Family C/Class III: least common --Has large extracellular and intracellular domains |
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G-Protein Coupled Receptors
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-Can bind to a HUGE range of molecules
--Chemokines, small molecules, Ca, photons -Changes in AA sequence changes receptor and response from binding -Ligands make specific contacts with receptor --binding causes conformational change in receptor --receptor activates down-stream proteins |
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Biochemical classes of current drug targets
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-GPCRs are most prevalent and lucrative drug targets
-45% of drugs work via cell-surface receptors |
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Responses to receptor binding
|
-NorEpi binds to specific receptors to initiate physiological response
-Binding of NorEpi to different receptor sub-types with different affinities or different 2nd messenger pathways results in different responses -Different cell types can have different responses to the same receptor |
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G-protein Cycle
|
-G-protein is activated by receptor
--can activate receptor or inhibit receptor by binding different ligands -Activated G-protein inds GTP, alpha and beta sub-units not have decreased affinity for each other --conformational change -Sub-units go in different directions to initiate down-stream effects -At the end of reaction, Alpha/Beta subunit complex is regenerated |
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Gs-Mediated activation or Protein Kinase A
|
1. Ligand binds to receptor
2. receptor allows G-protein to bind GTP 3. A and B subunits separate --A subunit initiates binding of ATP into Adenylyl cyclase 4. Adenylyl cyclase is activated and produces cAMP 5. cAMP activates protein kinase A |
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Signal Amplification
|
-1 transmitter can initiate a very large response
-Amplification occurs at all steps in the process -Receptor can activate many G-proteins -G-proteins can activate may adenylyl cyclases -Adenylyl cyclase can pump out a lot of cAMP -Protein Kinase A phosphorylates many K channels for effect |
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Adrenergic receptors
|
-Receptors that bind catecholamines
-alpha and beta receptors exist -Receptors are defined operationally by rank order of molecule potency -Receptors are defined y genetic structure |
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Agonist Descriptors
|
-Agonists described by Potency and Efficacy
-Create semi-logarithmic plot of activity -EC50= point where agonist has 50% of maximum efficacy --if EC50 concentration is lower, it takes less drug to get the same level of activation -Drug that has less than 100% efficacy is a partial agonist -Want drug to work at highest potency possible --reduces side-effects and decreases toxicity |
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Agonst
Antagonist |
Agonist: activates receptors
Antagonist: blocks the activation of receptors --block action of agonist --binds to the same site as the agonist but does not activate receptors --Takes up space and blocks agonist binding action |
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Antagonist Potency
|
-Describes how antagonist effects agonist
-increasing concentrations of antagonist push agonist dose-response curve to right --more concentration is needed to reach same EC50 and same maximum effect -More potent anatagonist requires more concentration of agonist to cause same effects --causes more of a shift in dose-response curve to right |
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Rank Order of Adrenergic Receptors
|
-Receptors are defined operationally by Rank Order of agonist potency
-Alpha receptors: --Epi is most effective, then NorEpi, then Dopamine, then ISO -Beta receptors: --ISO is most effective, then Epi, then NorEpi, then dopamine |
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Distribution of Alpha Adrenergic Receptors
|
-Blood vessels: cause constriction
-Constrict skeletal muscle -relax smooth muscle of the GI tract -Contract urinary bladder sphincter |
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Distribution of Beta Adrenergic Receptors
|
-B1: Heart
--cause increased HR, increased conduction velocity and decreased refractory period --Increases contractility in the ventricles --Increases lipolysis B2: Dilates skeletal muscle --Relaxes smooth muscle in the GI tract --Relaxes the ciliary muscle in the eye --Increases O2 consumption and glyconeogenesis |
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Factors Determining Actions of Sympathetic Amines
|
-Relative potency of amine in activation of alpha or beta receptors
-Proportion and density of receptor type and subtype organ -Autonomic tone of an organ -Reflex that the organism makes in response to amine |
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Autonomic Tone of Blood Vessels
|
-Predominantly sympathetic tone
-Always a little sympathetic tone present, always a little constricted -Adding Alpha1 receptor antagonist will cause vasodilation |
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Ways to Modulate Adrenergic Transmission
|
1. Endogenous catecholamines
2. Synthetic "Directly Acting" sympathomimetics 3. Indirectly acting sympathomimetcs 4. Mixed acting sympathomimetics 5. Neuron blocking agents 6. Catecholamine metabolism blocking agents 7. Direct receptor blocking agents |
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Rank Order of Alpha Adrenergic receptors
|
1. Epinephrine is most powerful
2. Norepi is just a little less than epi 3. Dopamine is less strong 4. Isoproterenol is least effective on Alpha adrenergic receptors |
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Rank Order of Beta Adrenergic Receptors
|
1. Isoproterenol is most effective
2. Epinephrine is next effective 3. NorEpi is just a little less effective 4. Dopamine is least effective on beta sdrenergic receptors -For B1 receptors, Epi and NorEpi are equal potency -For B2 receptors, Epi is MUCH MUCH stronger than norEpi -For B3 receptors, NorEpi is MUCH MUCH stronger than Epi -Subtle changes in AA sequence allows for different receptor binding affinities |
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Cardiovascular effects of Catecholamine Agonists
|
1. NorEpi:
-decreases HR slightly -Increases BP -Increases peripheral resistance dramatically 2. Epi: -Increases HR -Maintains same BP -Decreases peripheral resistance slightly 3. Isoproterenol: -Increases HR -Decreases BP slightly -Decreases peripheral resistance a lot |
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Isoproterenol as a B-agonist
|
-GREAT b agonist!
-Need MUCH MUCH MUCH less Isoproterenol to activate B receptors |
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Low doses of Epi
|
-B-adrenergic receptor effects predominate
-Alpha receptors are affected before other NTs, but B-receptors are affected before A-receptors --due to lower EC50 -AEC50= 10 -BEC50= 0.1 --need a lower dose to activate B-adrenergic receptors |
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NorEpi and B2 adrenergic receptors
|
-NorEpi does not activate B2 adrenergic receptors well
-B2 receptors are in bronchioles and vascular tissue in skeletal muscle |
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Terminology for Cardiac Function
|
-Stroke Volume: ml/beat
--controlled by end diastolic volume, TPR, and ventricular contractility -HR: beats per minute --heart beats according to the rhythm of he SA node -CO: liters per minute --heart rate x stroke volume -Systolic pressure: pressure at peak ventricular contraction --pressure against blood vessels -Diastolic Pressure: pressure at peak of ventricular relaxation -Total Peripheral Resistance: frictional resistance to blood flow in the arteries --important for alpha-1 adrenergic receptors -Mean Blood Pressure: approximate average of systolic and diastolic blood pressure |
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ANS effect on the Heart Rate
|
-Heart beats according to rhythm of the SA node
--Autonomous beat -HR is regulated by the ANS -Sympathetic innervation causes faster depolarization -Parasympathetic Innervation causes slower depolarization and HR |
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Vagal reflex
|
-Based on baroreceptors (stretch receptors)
--located in aortic arch --sense increase in Mean Arterial Pressure -Send info to coordination center in medulla -Efferent pathways act on heart and blood vessels --slow heart and cause vasodilation --Counteract the increased mean arterial pressure |
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Adrenergic Receptors in the Heart
|
-Mostly B1 receptors
-Cause: --increased HR --Increased conduction velocity --Decreased refractory period --Increased contractility |
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Effects of Low Dose IV Epi
|
-Low Dose IV will activate B1 receptors in heart
--increases HR, increases contractility, increases CO -Activates B2 skeletal muscle vasculature --causes vasodilation and decreases peripheral resistance -Increases systolic pressure -Decreases diastolic pressure -Decreases peripheral resistance -No major change in man BP |
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Effects of High Dose IV Epi
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-Increases BP, leads to activation of baroreceptors in aorta and carotid sinus
--vagal reflec -Activates Alpha-1 adrenergic receptors in vasculature --leads to increased vasoconstriction and increased peripheral resistance -Vagus nerve increases parasympathetic tone in the heart, decreases HR |
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Effects of NorEpi IV
|
-Activates B1 adrenergic receptors in the hear
--increases contractility and tries to increase HR -Low doses of NorEpi do not affect B2 receptors in the vasculature --Epi has a MUCH MUCH MUCH greater effect on B2 receptors -A1-adrenergic effects predominate --vasoconstriction, increased peripheral resistance --results in increased systolic pressure, increased diastolic pressure -Increases BP -Vagal reflex results in bradycardia |
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NorEpi on B and A receptors
|
-B1 in the heart
-A in the rest of the body -Decreases HR -Increases contractility -Decreases CO -Increases systolic and diastolic pressure -Decreases blood pressure |
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Effects of Isoproterenol IV
|
-Activates B1 receptors in the heart
--increases HR, contractility, and CO -Activates B2 in skeletal muscle vasculature --vasodilation, decreases peripheral resistance -No increase in BP -Increases systolic pressure -Decreases diastolic pressure -Decreases peripheral resistance -No vagal reflex or significant change in mean BP |
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Effects of Low Dose Dopamine
|
-Most effects are on the brain
-Acts on A and B1 receptors --low affinity for B2 receptors -Small activation of B1 in the heart -Low dose does not activate A1 receptors, no significant vasoconstriction occurs -No real change in skeletal muscle vasculature, no change in peripheral resistance -No change in peripheral resistance, no change in diastolic pressure, no change in BP |
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Effects of High Dose Dopamine
|
-Activates B1 receptors in heart
--increases HR, contractility, CO, and systolic pressure -Also activates A1 receptors, causes significant vasoconstriction in skeletal muscle vasculature -Increases diastolic pressure and peripheral resistance -Leads to significant increase in mean BP -Eventually vagal reflex is initiated to decrease HR --will also decrease BP |
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Epi Low Dose vs. High Dose
|
-Increased HR vs. increased, then decreased HR
-Increased contractility vs. no change -Increased CO vs. initial increase, then decrease -Decreased diastolic pressure vs. increased diastolic pressure -No change in BP vs. increased, then decreased BP |
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NorEpi effects vs. Isoproterenol effects
|
-Increased then decreased HR vs. Increased HR
-Both have increased contractility -Increased then decreased CO vs. increased CO -Increased BP vs. no change in BP |
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Low dose Dopamine vs. High dose dopamine
|
-Increased HR vs. increased then decresed HR
-Both increased contractility -Increased CO vs. increased then decreased CO -No change in diastolic pressure vs. increased diastolic pressire -No change in BP vs. increased BP |
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Synthetic A1-Adrenergic Receptor Agonists
|
-Synthetic amines specific to A1 receptors
--little to no effect on B receptors -Vasoconstriction with increase in peripheral resistance -Increased systolic and diastolic pressures -No direct effect on the heart, no A1 receptors in the heart --no change in HR -Initially increase BP, then vagal reflex takes over to decrease BP |
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Synthetic A1-Adrenergic Receptor types
|
-Phenylephrine (works in the eye)
-Methoxamine -Oxymetazoline -Tetrahydrozoline -nasal decongestants |
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Effects of Synthetic Agonists
|
-A1 adrenergic agonists
-Act as nasal decongestants -Decrease tissue swelling by constricting blood vessels -A1 mediated vasoconstriction in the eye -Can give as a local anesthetic to constrict blood vessels |
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Effects of A2-adrenergic Agonists
|
-Stimulate presynaptic A2 receptors in CNS
--decrease sympathetic outflow to periphery -Pre-symaptic A2 receptors in periphery --decrease sympathetic tone -Post-synaptic A2 receptors in periphery --causes vasoconstriction -Originally used as nasal decongestant, but caused hypotension -Fast drug withdrawl can cause rebound hypertension |
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A2-adrenergic agonist fast withdrawl
|
-Can cause rebound hypertension
-Body senses it is being shutdown, pushes back |
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Xylazine
|
-A2-adrenergic agonist
-Decreases sympathetic tone -Used for analgesia and sedation -Entirely CNS mediated A2 effects |
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Clonidine
|
-A2-adrenergic agonist
-Causes hypotension, used as anti-hypertensive -Has biphasic response --A2-activation on vascular smooth muscle causes initial transient hypertensive phase --A2 activation in brainstem causes decreased sympathetic tone, decreases BP and HR |
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Dobutamine
|
-B-1 Adrenergic Agonist
-Synthetic derivative of dopamine -Exists and D and L isomers -Causes cardiovascular response in heart --Increases force of contraction without affecting chronotropic activity of heart -Does not increase O2 demand on the heart -increases force of contraction more than rate of contraction -Used for short-term treatment of heart failure |
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Isoproterenol
|
-Non-selective B-adrenergic agonist
--Acts on B1 and B2 receptors -Highly selective for B receptors -Used for treatment of Congestive Heart Failure --has cardiac stimulatory effects -Used for asthma due to bronchodilatory effects |
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B2-Adrenergic Agonists
|
-Terbutaline
-Albuterol -Metaproterenol -B2-specific at low doses, has dose-dependent selectivity --As dose increases, B1 activity increases --If dose is low, it goes to the right tissues -B2 stimulation increases bronchodilation and other smooth muscle relaxation -Little cardiac action due to no B1 activity with low doses -Used as asthma treatment, bronchodilator -Also used to prevent premature labor |
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B3-Adrenergic Agonists
|
-B3 receptors are found on adipose tissue
-Play role in fat metabolism -B3 receptor stimulation increases lipolysis --decreases fat stores -Selective agonists may be treatment for obesity |
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Effects of Indirectly Acting Sympathomimetics
|
-Are transported int the nerve terminals and increase release of endogenous catecholamines
-Ex: Tyramine, Amphetamine -Get into nerve terminal via transporters -Do not increase release of Epi from adrenal gland |
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Tyramine
|
-Indirectly Acting Sympathomimetics
-DEcarboxylated tyrosine -Physiological effects are similar to NorEpi release -Found in cheese and wine |
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Amphetamines
|
-Indirectly acting Sympathomimetics
-Physiological effect is similar to NorEpi release -Powerful CNS stimulant --causes euphoria, arousal, and psychosis -Very similar structure to methamphetamine |
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Catecholamine Reuptake Blockade
|
1. Presynaptic transporter: blocks reuptake of catecholamine
2. Vesicular transporter: blocks transport of catecholamine in nerve terminal 3. Post-synaptic transporter |
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NorEpi reputake Blockade
|
-Cocaine, Imipramine, Amitryptyline
-Block reuptake of NorEpi from synaptic cleft -Leads to increased NorEpi in synaptic cleft -Has mood altering properties due to CNS action --modulate serotonin and NorEpi levels in CNS -Different parts of the brain have different NT in action --which catecholamine is blocked depends on location in brain -Rapidly absorbed from mucus membranes --increases potential for systemic toxicity |
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Cocaine
|
-NorEpinephrine Re-uptake blocker
-Causes more NorEpi in synaptic cleft -Has been used topically as anesthetic --has vasoconstrictive properties -Can block Na channels |
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Indirectly Acting Sympathomimetics and Adrenal Gland
|
-No effect, no release of Epi
-Adrenal gland does not have an outer membrane catecholamine uptake transporter --does not pull Epi back into cells once released |
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Effects of Mixed Acting Sympathomimetics
|
-Cause release of endogenous catecholamines and directly bind to adrenergic receptors
--can cause increased NorEpi release -Active after oral administration -not degraded by MAO or COMT, has long duration of action -Increases BP and bladder sphincter tone -Causes bronchodilation -Some access to CNS and causes mile amphetamine-lie effects -Used to increase BP, decrease bladder incompetence, decrease asthma -May cause hypertension and cardiac arrhythmia |
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Ephedrine
|
-Mixed action Sympathomimetic
-Releases endogenous catecholamines and binds directly to adrenergic receptors -Increases BP -Causes bronchodilation -Increases bladder sphincter tone -Can also cause hypertension and cardiac arrhythmias -Not degraded by MAO or COMT --has long duration of action |
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Pseudoephedrine
|
-Mixed Acting sympathomimetic
-Causes endogenous release of catecholamines and directly binds to adrenergic receptors -Used as nasal decongestant -Has low cardiovascular and CNS effects -Acts as a vasoconstrictor |
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Adrenergic Neuron Blocking Agents
|
-Inhibit release of NorEpi from sympathetic postganglionic neurons
-Block transmitter release --guanethidine, bretylium, clonidine -Block vesicular storage --reserpine -Release false transmitters --a-methyl DOPA -Block NorEpi synthesis --a-CH3-p-tyrosine --NorEpi via negative feedback --Disulfiram |
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Guanethidine
|
-Blocks NT release
-Accumulates and replaces NorEpi in vesicles --causes NorEpi depletion -No NT activity itself -Stabilizes nerve membrane by decreasing nerve impulses that get into nerve terminals -Does not cross the BBB --no CNS effects, restricted to the periphery -Does not affect Epi release from adrenal medulla --enters cell via receptors that do not exist on adrenal medulla -High doses cause transient hypetension, drop in BP, and progressive drop in BP and CO -Used as anti-hypertensive |
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Bretylium
|
-Blocks NT release
-Blocks NorEpi NT vesicle fusion with the membrane -Does not cross BBB -Does not affect adrenal medulla |
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Clonidine
|
-Blocks NT release
-A2 agonist, stimulates autoinhibitory receptor -Decreases NorEpi vesicular release -Acts as anti-hypertensive |
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Vesicular Storage Blockade
|
-Prevents accumulation of NorEpi in vesicles
-Blocks NorEpi uptake into vesicles by MAO -Leads to decreased amount of NorEpi release per nerve impulse --never gets to 0, but decreases NorEpi overall -Can also get decrease Epi storage in adrenal gland to a lesser degree --does not need transporter to cross cell membrane |
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Reserpine
|
-Blocks vesicular storage of NorEpi
-Plant-based cpd -Blocks NorEpi uptake into vesicles -Extracytoplasmic NorEpi is degraded by MAO -Causes decrease amount of NorEpi released for each nerve impulse -Long-acting equine sedative |
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A-methyl-DOPA
|
-Causes false transmitter release
-Taken up into terminals and converted to A-methyl-NorEpi --A-methy-Norepi is stored in vesicles, acts as a "false transmitter" -Released upon normal neural stimulation -Has weak affinity for A1 receptors -May have A2 activity -Used as anti-hypertensive |
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NorEpi synthesis Inhibitors
|
1. A-Ch3-P-Tyrosine: depletes neuronal stores of NorEpi
--blocks tyrosine hydroxylase enzyme --Less tyrosine is converted into DOPA, less catecholamine synthesis 2. NorEpi: end product inhibition, negative feedback --Inhibits conversion of tyrosine to DOPA by competing for Tyrosine Hydroxylase co-factors 3. Disulfiram: blocks enzyme that converts Dopamine to NorEpi |
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MAO Inhibitor
|
-Blocks Catecholamine Metabolism
-Causes increased NorEpi in storage vesicles for release -Used as anti-depressant -Blocks degradation of dopamine and Serotonin in CNS -Pargyline, Moclobemide -Blocks MAO also prevents tyramine degradation --may cause hypertensive crisis --have to be careful |
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Wine and Antidepressants
|
-Do not mix!
-MAO inhibitors also inhibit tyramine breakdown -Consume yeast extract that contains tyramine can put tyramine concentration through the roof -Causes hypertensive crisis |
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|
DMT
|
-Ayahuasca Brew
-Metabolite of Serotonin -Entheogenic hallucinogenic indole -Quickly metabolized by MAO when ingested orally and does not have a hallucinogenic effect -Only hallucinogenically active when combined wit MAO inhibitor |
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Direct Adrenergic Receptor Blockade
|
-Blocks catecholamine action at adrenergic receptors
-Blocks binding, therefore stops action of endogenous receptor agonists -A-adrenergic receptor blockers -B-adrenergic receptor blockers -Direct receptor-mediated: bind to receptor and block agonist -Functional or Chemical antagonist: binds to ligand and prevents ligand/receptor interaction |
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Therapeutic Uses of A-Receptor blockers
|
1. Hypertension: decrease A1-mediated vasoconstriction, leads to decreased peripheral resistance
2. Congestive Heart Failure: Decrease arterial pressure --improves movement of blood out of the heart 3. Peripheral Vascular Disease: prevent peripheral ischemia due to sympathetic vasoconstriciton --raynaud's syndrome 4. Benign Prostatic Hyperplasia: decreases muscle tone in prostate, faciliates urination --decreases tone of urethral sphincter to help peeing 5. Shock: decreases vasoconstriction and facilitates perfusion and fluid replacement |
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A-Adrenergic Receptor Blockers
|
-Can be irreversible or reversible
-Irreversible: Dibenamine and Phenoxybenzamine -Reversible: Phentolamine |
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Irreversible A-Adrenergic receptor blockers
|
-Dibenamine and Phenoxybenzamine
-Haloalkylamines -Non-selective for A1 and A2 receptors -Covalently alkylate receptor at catecholamine binding site -Slow onset and Very long-lasting --last until modified receptors are recycled and new receptors are put onto the surface -Recovery required de-novo receptor synthesis -Causes a decrease in peripheral resistance --used to treat hypertension |
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Reversible A-Adrenergic Receptor Blockers
|
-Phentolamine
-Non-selective for A1 and A2 receptors -Short-acting blockers, only last for a few hours -Cause decreased peripheral resistance --used to treat hypertension -Can cause cardiac complications due to tachycardia and increased NorEpi release --B1 receptors -Goes onto and off of receptor at the same rate as the agonist |
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Effects of high Dose Epi
|
-Pulse rate initially increases then slows
-Increased BP leads to activation of baroreceptors in aortic arch and carotid sinus -Activates A1 receptors in vasculature, leading to vasoconstricion and increased peripheral resistance -Vagus nerve is activated, increases parasympathetic tone on the heart, leads to decreased HR --vagal reflex leads to bradycardia -Activates A1 in vasculature --increases B2 mediated vasodilation in skeletal muscle vasculature |
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Selective A1-Adrenergic Blocker
Prazosin |
-Reversible specific post-synaptic A1 receptor blocker
-Decreases A-1 receptor mediated vascular tone -Does not increase NorEpi release --No block of presynaptic A2 -Decrease BP with little or no reflex cardiac tachycardia -Useful for hypertension therapy -Autoreceptor is active, dec |
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Selective A1-Adrenergic Blocker
Tamsulosin |
-Reversible specific post-synaptic A1 receptor blocker
-Not used for anti-hypertensive therapy, does not block A-receptor responsible for vasoconstriction -3 sub-types of receptors (A1a, A1b, A1c) -Selectively blocks A1a in prostatic musculature and bladder neck --eases urination -Used to improve urination in men with benign prostatic hyperplasia |
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Selective A2-Adrenergic Blocker
Yohimbine |
-Reversible specific presynaptic A2-receptor blocker
-Derived from bark of west African trees -Blocks pre-synaptic A2 receptors -Increases NorEpi release from nerve terminals --blocks ihibitory A2 receptors -No direct effect on smooth muscle -No clinical uses in humans -Can be used to reverse xylazine |
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Side Effects of A-receptor Blockers
|
1. Postural hypotension
--blocks A1-mediated reflex vasoconstriction --when go from sitting to standing can't vasoconstrict 2. Reflexive Tachycardia: --A2 selective blocker --May increase NorEpi release and lead to tachycardia 3. Nasal congestion: --blocks sympathetic tone, keep mucosal blood flow low, leads to increased nasal mucus 4. Increased GI motility --Tone on gut is parasympathetic, A-receptors block sympathetic system and increases parasympathetic effects --Causes diarrhea due to increased motility |
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Therapeutic Uses of B-receptor Blockers
|
1. Cardiac Arrhythmias due to block of AV node receptors
2. Hypertension, decreases BP from high CO 3. Prophylactic: prevents myocardial stress 4. Anxiolytic: decreases sympathetic-mediated tremors and palpitations associated with Epi release due to emotional stress and anxiety 5. Glaucoma: decreases production of aqueous humor without affecting drainage |
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|
Non-selective B-Adrenergic Blockers
Propranolol |
-Non-selective for B1 and B2 receptor blockade
-Binds in the same place as the agonist but does not activate the receptor -Causes decrease in HR, contractility, and CO -At high doses will stabilize the membrane --can block impulse conduction in cardiac tissue -Will have significant withdrawl effect --hypersensitivity due to upregulation of receptors --have to taper off drug |
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Pindolol
|
-B-adrenergic receptor blocker
-Non-selective for B1 and B2 receptor blockade -Less membrane stabilization effects -Partial agonist, leads to less withdrawl syndrome --less reduction in heart rate than propranolol -High doses can increase HR, BP and cause bronchodilation |
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B-Adrenergic Receptor Blocker
Timolol |
-Non-selective for B1 and B2 receptor blockade
-Less membrane stabilization effects -Used for management of wide angle glaucoma (used as eyedrops) |
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|
Metoprolol
|
-Selective B1-Blocker
-Same effect as propranolol on B1 receptors -100x less potent than propranolol on B2 receptors -Has little effect on adrenergic B2-mediated effects -Cardioselective due to minimal B2 receptor activation |
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|
Butoxamine
|
-Selective B2-blocker
-Blocks smooth muscle relaxation and vasodilation -No pronounced cardiac effects, no B1 action |
|
|
Side Effects of B-adrenergic receptor blockers
|
1. Cardiac Failure: cannot be used in patients with congestive heart failure who need sympathetic drive
2. Bradycardia: blocks sympathetic drive and disrupts pulse conduction from atria to ventricles --no sympathetic drive to the heart 3. Bronchial Asthma: Can cause life-threatening bronchoconstriction in susceptible patients --not used in patients with asthma 4. Hypoglycemic shock in Diabetics --Epi release due to hypoglycemia stimulates B2-mediated hepatic glucose release --B2 blocked, no glucose release and will result in hypoglycemia |
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|
A-adrenergic Catecholamine Agents
|
1. Epi
2. NorEpi 3. Dopamine (A1 vascular) 4. Oxymetazoline (A1 vascular) 5. Clonidine (A2 presynaptic) |
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|
B-adrenergic Catecholamine Agents
|
1. Epi (B1 heart and B2 smooth muscle)
2. NorEpi (B1 heart and a little B3 fat) 3. Dopamine (B1 heart) 4. Isoproterenol (B1 heart B2 smooth muscle) 5. Dobutamine (B1 heart) 6. Albuterol (B2 smooth muscle) |
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|
A1 Adrenergic Agonists
|
-Phenylephrine
-Methoxamine -Oxymethazoline -Tetrahydrozoline |
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A2 Adrenergic Agonists
|
-Clonidine
-Xylazine |
|
|
Non-selective B1/B2 Adrenergic Agonists
|
-Isoproterenol
|
|
|
B1 Adrenergic Agonists
|
-Dobutamine
|
|
|
B2 Adrenergic Agonists
|
-Terbutaline
-Albuterol -Metaproterenol |
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|
B3 Adrenergic Agonists
|
-BRL 37344
|
|
|
Irreversible Nonselective A1/A2 Adrenergic Antagonists
|
-Dibenamine
-Phenoxybenzamine |
|
|
Reversible Nonselective A1/A2 Adrenergic Antagonists
|
-Phentolamine
|
|
|
Reversible Selective A1 Antagonist
|
-Prazosin
-Tamsulosin |
|
|
Reversible Selective A1 Antagonist
|
-Yohimbine
|
|
|
Reversible Nonselective B Adrenergic Antagonists
|
-Propranolol
-Pindolol -Timolol |
|
|
Selective B1 Adrenergic Antagonist
|
-Metoprolol
|
|
|
Selective B1 Adrenergic Antagonist
|
-Butoxamine
|
|
|
Indirectly Acting Sympathomimetics
|
-Tyramine
-Amphetamines |
|
|
Mixed Acting Sympathomimetics
|
-Ephedrine
-Pseudoephedrine |
|
|
NorEpi Reuptake Blockers
|
-Cocaine
-Imiprimine |
|
|
MAO inhibitors
|
-Pargyline
-Moclobemide |
|
|
COMT inhibitor
|
-Tolcopone
|
|
|
NT release blockers
|
-Guanethidine
-Bretylium -Clonidine |
|
|
NT Vesicular Storage Blockers
|
-Reserpine
|
|
|
NorEpi Synthesis Inhibitor
|
-Alpha-CH3-p-tyrosine
-NorEpi -Disulfiram |
|
|
False Transmitter Release
|
-Alpha-Methyl-DOPA
|
|
|
Anatomical Sites of Cholinergic Transmission
|
1. Pre-ganglionic fibers to all ANS ganglia
--sympathetic and parasympathetic pre-ganglionic fibers 2. Pre-ganglionic fibers to adrenal medulla 3. Parasympathetic Post-ganglionic fibers 4. Sympathetic post-ganglionic fibers innervating sweat glands --also some fibers to vessels in skeletal muscle 5. Neuromuscular Junction 6. CNS |
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|
Muscarine
|
-From mushroom (Amanita muscarina)
-Alkaloid -Same effects of nerve stimulation to organs innervated by craniosacral division of ANS --vagal stimulation to the heart -Parasympathomimetic |
|
|
Nicotine
|
-From tobacco plant
-Alkaloid -Causes primary transient stimulation at sympathetic and parasympathetic ganglia |
|
|
Acetylcholine
ACh |
-Acts at pre-ganglionic and post-ganglionic sites
-NT with dual actions --muscarinic --nicotinic |
|
|
Chemical Transmission of Neurons
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-Otto Loewi proved chemical-mediated basis for synaptic transmission
-Not electrical in nature, neurohormonal |
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Vagustoff
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-Substance that was responsible for neurohormonal transmission
-Turns out to be ACh |
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ACh Biosynthesis
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-Acetyl CoA and Choline joined by Choline Acetyltransferase
--forms ACh and CoA -Choline is synthesized from serine supplied by the diet and protein metabolism |
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Choline Acetyltransferase
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-Enzyme responsible for forming ACh
-Cytoplasmic enzyme |
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Steps in ACh biosynthesis
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1. Choline transported into the nerve terminal
--rate-limiting step 2. Choline and Acetyl CoA interact, Choline Acetyltransferaase does its magic 3. ACh and CoA produced 4. ACh is transported into vesicles --pre-formed, not synthesized in vesicles --Each vesicle can contain 10,000 ACh mol |
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Intracellular Metabolizing Enzymes for ACh
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-Do not exist
-No intracellular metabolizing enzymes, no mechanism for ACh degradation in cytoplasm |
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Hemicholinium
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-Synthetic compound
-Blocks uptake of Choline into nerve terminal -Decreased choline, decreased ACh synthesis -Limits amount of ACh in terminal and limits amount of ACh stored for release |
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Vesamicol
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-Blocks transport of ACh into vesicles once formed in cytoplasm
-Decreases amount of ACh stored in vesicles for use -Dereased amount of ACh released at each nerve impulse |
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Botulinus Toxin
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-Blocks the fusion of ACh vesicles with plasma membrane and release of ACh into synaptic cleft
-Blocks transmission of ACh -Toxins derived from Clostridium botulinum bacteria -Toxins bind to cell membrane and are internalized -Cleave Synaptobrevin, prevent vesicular fusion -One of most potent toxins known -Causes flaccid paralysis in muscles --death by paralysis of respiratory muscles, respiratory collapse |
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Mechanism of Synaptic ACh Release
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1. Nerve depolarization
2. Voltage gated Na and Ca channels opened 3. Ca-dependent ACh vesicle fusion and exocytosis 4. ACh diffuses into the synaptic cleft 5. ACh binds to receptors on post-synaptic neuron and activates membrane 6. ACh breakdown in synaptic cleft --Acetylcholinesterase |
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Ending ACh Action
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-One mechanism for termination of ACh response
-ACh is broken down, not taken back into the nerve terminal -Rapid enzymatic breakdown by Acetylcholinesterase |
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Cholinesterases
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-Enzymes that catalyze hydrolysis of choline esters
--breaks ester bonds -Acetylcholinesterase -Pseudocholinesterase |
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Acetylcholinesterase
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-Terminates ACh at nerve terminals
-Attached to collagen-like filaments on pre-synaptic and post-synaptic membrane -Very rapid degradation of ACh --one of most efficient enzymes known -Turnover rate of 150 microseconds -Ensures rapid termination of ACh action --helps prevent receptor desensitization |
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Pseudocholinesterase
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-Unknown function
-Synthesized in the liver -Found mostly in plasma -Not specific for ACh, will chop up any small molecule |
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Acetylcholinesterase Action
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-Preferentially hydrolyzes ACh
-Cleaves ester bond -Has very rapid action -Quaternary nitrogen on choline binds to Anionic site on enzyme --esterase site cleaves covalent bond between choline and acetate, frees choline --Acetate is released from protein, reactivates enzyme -Choline is generated, can be re-taken into nerve terminal for ACh synthesis --Choline re-uptake is rate limiting step in ACh synthesis |
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Anatomic location of Nicotinic vs. Muscarinic transmission
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Nicotonic:
--all autonomic ganglia (symp and parasym. ganglion) --adrenal medulla --NMJ --Spinal cord, optic tracts, other areas in the brain Muscarinic: --Parasympathetic effector cells (smooth muscle, cardiac muscle, exocrine glands --brain |
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Nicotinic Receptors
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-Located in all ANS ganglia
--sympathetic and parasympathetic ganglia -Adrenal medulla -NMJ -Spinal cord, optic tracts, other areas in brain -Divided into Nicotinic Neuronal and Nicotinic Muscle -Act as ligang-gated ion channel Ionitropic Receptors |
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Muscarinic Receptors
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-Parasympathetic system effector cells
--smooth muscle --cardiac muscle --exocrine glands -Brain -6 different forms of muscarinic receptors -G-protein coupled receptors, metabotropic receptors |
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Effects of activating Nicotinic ACh receptors
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-Receptors are ligang-gated, non-selective cation ion channels
-Stimulates ANS ganglia (sympathetic and parasympathetic) -Contracts skeletal muscle (NMJ) -Stimulates adrenal gland discharge of Epi and NorEpi -CNS effects --tremor, anxiety, sleep disturbances, respiratory and circulatory center effects |
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Nicotinic ACh receptor Structure
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-Located in ANS ganglia, NMJ, and in spinal cord, optic tracts, and other areas of the brain
-Has extracellular binding of ACh --different from catecholamines, ions move through the pore -Pentameric structure -4 sub-units with central cation channel -Binding of ACh causes opening of the central pore, ions flow through the pore according to concentration gradients --Na and K concentration gradients |
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Effects of Muscarinic ACh Receptor Activation
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-Receptors are 7tm GPCR
-Stimulates gland secretion from sweat, salivary, mucous, and lacrimal glands -Contracts smooth muscle in airway, GI tract, gall bladder, urinary bladder, and ureters -Pupillary constriction via contraction of iris muscles -Relaxation of sphincters in GI tract, urinary tract, and biliary tracts -Slows the HR |
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Muscarinic ACh overdose
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-S.L.U.D
-Salivation -Lacrimation -Urination -Defectation |
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Muscarinic ACh receptor sub-type distribution
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-M1: CNS, ANS ganglia, pre-synaptic and post-synaptic sites
--couples with Gq protein -M2: Heart, smooth msucle, ANS ganglia --couples with Gi or Go, inhibits production of cAMP -M3: Exocrine glands, smooth muscle, blood vessel endothelium --Couples with Gq -M4: CNS and autonomic ganglia --couples with Gi and Go -M5: CNS --couples with Gq |
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Effect of ACh on the Eye
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-Parasympathetic action predominates
-Sympathetic innervation causes Mydriases, pupillary dilation --accommodates distance vision -Parasympathetic innervation causes Miosis and constriction of the ciliary muscle --accomodates near vision |
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Effects of ACh on the Heart
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-Parasympathetic innervation predominates
-Sympathetic innervation: --affects SA node to increase HR --Increases contractility --Increases conduction velocity -Parasympathetic innervation: --affects SA node to decrease HR --decreases contractility --decreases conduction velocity |
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Effects of ACh on blood vessels
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-Sympathetic innervation predominates
-Sympathetic innervation constricts blood vessels -Parasympthetic innervation dilates blood vessels --not all vessels though, dilation is endothelial cell dependent |
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Effects of ACh on the Lungs
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-Sympathetic Innervation predominates
-Sympathetic innervation causes relaxation of airway smooth muscle -Parasympathetic innervation causes constriction of airway smooth muscle and secretion from the airway glands |
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Effects of ACh on the GI tract
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-Parasympathetic innervation predominates
-Sympathetic innervation: --relaxes GI smooth muscle --causes some inhibition of GI secretion --Contracts GI sphincters -Parasympathetic innervation: keeps things moving --constricts GI smooth muscle --stimulates GI secretion --Relaxes GI sphincters |
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Effects of ACh on Salivary Glands
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-Parasympathetic innervation predominates
-Sympathetic innervation causes increased mucous production -Parasympathetic system causes watery saliva -Both systems stimulate salivation but stimulate different TYPES of salivation -Sympathetic and parasympathetic systems are not in opposition |
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Muscarininc Receptor-Effector coupling in Cardiac Muscle
M2 receptors |
-Activation of M2 receptors are INHIBITORY in cardiac muscle
--inhibits cardiac contractility and rate -Inhibitory effects are due to inhibition of Adenylate Cyclase and activation of K channels -ACh binds to receptor, activates Gi and Go --Gi initiates release of K from the cell which decreases mV --Go decreases activity of Adenylate Cyclase, decreases cAMP production |
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Muscarinic Receptor-Effector coupling in Smooth Muscle
M3 receptors |
-Activation of M3 receptors is EXCITATORY in smooth muscle
-Excitatory effects due to opening of plasma membrane and intracellular Ca channels -M1, M3, and M5 are activated by ACh --interact with Gq --Modifies how Ca channels open on the extracellular and intracellular membranes -Results in MORE Ca in the cytoplasm --more Ca available for contraction |
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Cholinergic Pharmacology Tree
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1. Cholinergic Pharmacology
-Parasympathomimetics ---natural alkaloids ---synthetic ---ACh-esterase inhibitors -Anticholinergic Drugs ---anti-muscarinics --anti-narcotics |
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Therapeutic Uses for Parasympathomimetic drugs
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-Act as agonists
-Used to treat glaucoma in ophthalmology -Faciliate loosening of urinary tract sphincters --decrease tone on the urinary tract -Increase GI motility |
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Side effects of Parasympathomimetic drugs
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-S.L.U.D.
--salivation, lacrimation, urination, defecation -Miosis (pupil constriction) --important sign -Abdominal pain -Severe hypotension |
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Miosis vs. Mydriasis
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-Miosis: constricted pupil,
--accommodates near vision --Parasympathetic innervation -Mydriasis: dilated pupil --accommodates distance vision --sympathetic innervation |
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Affects of Drugs on the Lens and Eye
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-B-blockers decrease production of aqueous humor
-Muscarinic agonists contract circular fibers and constrict pupil --also relax lens for near vision --improve drainage in the eye -Muscarinic Antagonists dilate the pupil --occlude canal of Schlemm --increase intraocular pressure, can cause glaucoma |
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Parasympathomimetic Drugs
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-ACh
-Methacholine -Carbachol -Bethanecol |
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ACh as a Parasympathomimectic Drugs
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-No therapeutic applications
-Short duration of action --hydrolyzed in the GI tract --Metabolized by ACh-esterase and pseudo ACh-esterase -Does not cross the Blood-Brain barrier --has a + charge, cannot cross BBB -Works on cardiac muscle, GI, urinary bladder, and a little in the eye -Has some nicotinic activity |
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Methacholine as a Parasympathomimetic Drug
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-Synthetic ACh analog
-Is Methylated on beta carbon -Somewhat resistant to ACh-esterase -Selective Muscarinic activity compared to nicotinic activity -Used for GI and urinary stimulation -Cardiovascular effects: bradycardia and hypotension --limit clinical use -Has cardiac, GI, urinary bladder, and eye activity |
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Carbachol as a Parasympathomimetic Drug
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-Synthetic ACh analog
-Carbamylated ACh -Resistant to ACh-esterase -Muscarinic and Nicotinic activity -Selectively stimulates GI and urinary tracts -has limited clinical use due to ganglionic stimulation -Used to induce miosis/pupil constriction and treatment of glaucoma --increases aqueous humor outflow -Small effect on heart, larger effect on GI, urinary systems, some effect on the eye -Has nicotinic activity |
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Bethanecol as a Parsympathomimetic Drug
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-Synthetic ACh analog
-Carbamylated and methylated ACh -Resistant to ACh-esterase -Selective muscarinic activity -Used clinically to test pancreatic function --increases pancreatic secretions -Used to treat urinary retention, stimulates contraction of bladder -Minimal effect on the heart, lots of effect on the GI and urinary systems -No nicotinic activity |
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Pilocarpine
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-Parasympathomimetic drug
-Naturally occuring Cholinergic agent -100x more potent than ACh, need 100x less to get same effect as ACh -Mainly muscarinic agonist, also some nicotinic -Pronounced action on sweat and alivary glands --increases salivation and induces sweating --used to treat dry-mouth -Ophthalmology uses: --induces miosis, constricts pupil --induces opening of drainage canals for ocular fluid and leads to decreased intraocular pressure --Counteracts mydriasis action of atropine -Can cause increased BP and tachycardia via ganglionic stimulation |
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Arecoline
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-Parasympathomimetic Drug
-Naturally occurring Cholinergic agent -Acts at Nicotinic and muscarinic receptors -Derived from Betel nut -No current therapeutic uses -Causes marked peristalsis of GI tract, was used to induce expulsion of worms from horses once upon a time -Used in china as tapeworm treatment |
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Muscarine
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-Parasympathomimetic Drug
-Acts at Muscarinic Cholinergic Receptors -Derived from Amantia muscara mushroom -No current therapeutic uses -Antidote is muscarinic receptor agonist (Atropine) |
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Symptoms of Mycetisimus
Mushroom poisoning |
-Caused by Amantia mushroom ingestion, acts as muscarinic cholinergic receptors
--causes excess muscarinic activation! -Marked lacrimation, salivation, and sweating -Miosis, pupillary constriction -Severe abdominal pain -Frequent watery and painful bowel excretions -Cardiovascular collapse -Vertigo, weakness, confusion, coma, convulsions -Death in a few hours |
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Atropine
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-Anti-muscarinic agent
-Naturally occurring alkaloid --found in Deadly Nighshade -High affinity for muscarinic receptors --Competitive muscarinic receptor antagonist -Non-selective against most muscarinic receptor sub-types -Causes tachycardia, decreased intestinal contractility and motility -Dries airways and sinuses, causes bronchodilation -Pupillary dilation/mydriasis -Causes tremor, CNS delusion, excitement, and life-like dreams |
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Belladonna
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-Atropine
-Naturally occuring alkaloid in Deadly Nightshade -Put into eyes of women to dilate pupils --sign of "comeliness" -Used by professional poisoners in middle ages |
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Therapeutic uses of Atropine
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-Pre-anesthetic, decreases respiratory secretions associated with intubation and inhalation asesthetics
-Over the counter cold medications --decreases activity in lacrimal and nasal glands -Anti-asthmatic medications -Topical application in eye to allow long duration mydriasis |
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Homoatropine
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-Anti-muscarinic agent
-Analog of Atropine -More rapid onset and shorter duration of action vs. atropine -Less potent than atropine |
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Scopolamine
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-Anti-muscarinic agent
-Used as a pre-anesthetic to decrease respiratory secretions from intubation and inhalant anaesthetics -Used for motion sickness -Same peripheral actions as atropine to block muscarinic effects -Also has sedation effects -Used to be used to sedate mentally ill patients -Causes temporary amnesia |
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Propantheline
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-Synthetic Anti-muscarinic Agent
-Synthetic quaternary ammonium compound -Does not cross the BBB due to + charge --no CNS effects except in high doses -Used to mitigate GI spasm and secretions --decreases diarrhea --treatment for spasmotic colic in horses, decreases intestinal motility -Can be used to prepare rectal exams and reduce risk of rectal tearing -Used to reduce spasm and promote relaxation of esophagus |
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Tropicamide
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-Synthetic Anti-muscarinic Agents
-Synthetic quaternary amine compound -Has a much shorter duration of action than atropine -Used to dilate eyes, induces mydriases -Preferred over atropine due to recovery time -Given topically to keep systemic levels low |
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Recovery from Mydriases and Cycloplegia with Synthetic Antimuscarinic Agents
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Atropine: 7-12 days
Homoatropine: 1-3 days Cyclopentolate: 1 day Tropicamide: hours Medications applied topically and remain in the eye |
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Innervation of the Iris and Lens of the Eye
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-2 sets of muscles in the eye
--Circular fibers, contract to close iris (Miosis, parasympathetic innervation) --Radial muscle, contracts to open eye (mydriasis, sympathetic innervation) -Muscarinic agonists want to cause miosis, close the eye -Muscarinic antagonists want to cause mydriasis, open the eye |
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Muscarinic Angonists in the Eye
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-Cause Miosis, close the eye
-Contract circular fibers to constrict pupil -Relax the lens for near-vision -Improve drainage of the eye -Mushroom poisoning and S.L.U.D |
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Muscarinic Antagonists in the Eye
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-Cause mydriasis, open the eye
-Dilate the pupil -Occlude the canal of Schlemm and increase intraocular pressure |
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Control of the Iris
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-Radial dilator muscle:
--contraction causes pupil dilation (mydriasis) --Innervated only by sympathetic nervous system -Circular sphincter muscle: --contraction causes constriction of the pupil (miosis) --innervated by the parasympathetic system Parasympathetic done dominates the sphincter muscle |
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Control of the Lens
Ciliary Muscle |
-Muscular system that runs around the eye
-Contraction takes pressure off of zonular fibers --causes lens to bulge --accomodates for near vision -Relaxation puts tension on zonular fibers --pulls lens flat --accommodates for far vision -Innervated by parasympathetic system, provides constant contraction of the ciliary muscle |
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Cycloplegia
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-Paralysis of Accommodation in the eye
-Cannot change the ciliary muscle, cannot change focal length of the eye --no change in pressure on the zonular fibers, no change in lens width -Caused by muscarinic antagonists, block muscarinic receptors --no muscarinic receptors, no sympathetic innervation possibe -Muscarinic agonists can cause spasm of accommodation |
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Control of the Lens
Relaxation vs. Contraction |
-Relaxation causes the lens to flatten
--accommodates for far vision, focal point is far away form the eye -Contraction causes the lens to bulge --accommodates for near vision, focal point is closer to the eye |
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Glaucoma
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-Excess accumulation of aqueous humor in the eye
-Puts pressure on the eye, eye does not drain well -Puts pressure on the optic nerve and can cause damage -Can be due to narrow angle (acute congestive) -Can be due to Wide angle (chronic simple) |
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Narrow Angle Glaucoma
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-Acute Congestive glaucoma
-Iris obstructs the drainage through the Canal of Schlemm -Inducing miosis increases drainage --Pilocarpine and Physostigmine -Drugs are useful to reduce pressure until surgery -Muscarinic antagonists can cause by blocking parasympathetic tone |
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Wide Angle Glaucoma
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-Chronic Simple glaucoma
-Surgery is not useful -Drugs will increase outflow --Pilocarpine and Physostigmine --long-acting anti-ACh-esterases -Drugs are helpful but can lead to cataracts -B-receptor antagonists can decrease aqueous humor production in the eye --Timolol drops |
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Nicotinic Agents
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-Compounds that directly and indirectly modify nicotinic cholinergic receptor activity
-Ganglionic stimulants -Ganglionic Blockers -ACh-esterase inhibitors |
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Nicotene
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-Ganglionic stimulant
-Directly and indirectly modifies nicotinic receptor activity -Results in complex and unpredictable physiological responses --not therapeutically -Can stimulate, then inhibit receptor-mediated events --depends on dose -De-sensitization occurs -Modify both sympathetic and parasympathetic outflows --turns on BOTH systems! -CNS effects -Stimulates the adrenal medulla to release NorEpi and Epi into the blood --ACh stimualtes chromaffin cells -Can also act on nicotinic receptors in skeletal muscles --used in insecticides |
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Ganglionic Stimulants
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-DMPP
-TMA -Small molecules that modify activity -Cause stimulation, but do not desensitize receptors --initial stimulation is not followed by dominant blocking action -No flaccid paralysis |
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Ganglionic Blocker
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-Hexamethonium
-Trimethaphan -Specifically blocks ganglionic Nicotinic receptors Nn --not active against Nm -Therapeutic use is limited --blocks sympathetic and parasympathetic ganglia depending on tone of the organ |
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ACh-Esterase Inhibitors
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-Has muscarinic actions at autonomic effector organs
-Modifies Nicotinic ANS ganglia --results in desensitization -Will get flaccid paralysis at NMJ due to nicotinic stimulation -Has CNS effects |
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Classes of Anti-ACh-esterases
(ACh-esterase inhibitors) |
1. Reversible AChesterase inhibition
-quaternary nitrogen binds reveribly to anionic site on ACh-esterase 2. Carbamylation of ACh-esterase -Substrate for ACh-esterase -Occupy active site for an extended period of time 3. Phosphorylation of ACh-esterase -Covalently binds and irreversibly inactivates enzyme |
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Reversible ACh-Esterase inhibitors
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-Tensilon
-Simple competitive inhibitor -binds to anionic site of ACh-esterase -Competes with endogenous ACh for ACh-esterase --ACh cannot bind and cannot be cleaved -No covalent attachment -Rapid and reversible, short-acting (3-4 minutes) -Can be used to diagnose myasthenia gravis NMJ disease |
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Myasthenia Gravis
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-Antibodies bind ACh receptors and cause receptor to be removed from the surface of the muscle
-Decreased ACh receptor density, decreased muscle contraction in presence of same amount of ACh released -Can increase contraction by increasing the amount of ACh present --decreasing activity of ACh-esterase |
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Myasthenia Gravis vs. Patient in Cholinergic crisis
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-Give Tensilon to decrease ACh-esterase activity
-If myasthenia, patient will be transiently better -If cholinergic crisis, patient will be transiently worse --to much ACh-esterase inhibitor already present |
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Carbamylation of ACh-esterase
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-Slowly reversible
-Carbamyl ester interacts with esteric site of ACh-Esterase -Carbamylate enzyme persists and is slow to release --slow hydrolysis --30 minute release |
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Physostigmine
Eserine |
-Alkaloid
-Derived from West African plant Physostigma venenosum -Absorbed well from GI tract, crosses BBB -Originally used in therapy of Myasthenia gravis --increases ACh at NMJ -Used in treatment of glaucoma --Absorbed from eyedrops, increases ACh and leads to reduction in intraocular pressure --facilitates outflow of aqueous humor from the eye -Used in treatment of atropine poisoning --increase in ACh counteracts muscarinic blocking agent |
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Neostigmine
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-Prostigmin
-ACh-esterase Inhibitor -has quaternary nitrogen -Not well-absorbed orally, does not cross BBB -Only results in peripheral effects -Can be used for treatment of Myasthenia gravis |
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Pyridostigmine
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-Similar to Physostigmine and Neostigmine
-Shorter halflife -Used by soldiers prophylactically in anticipation of nerve gas exposure |
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Carbamylating Insecticides
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-Carbamylating compounds used commonly in garden insecticides
-All about dose -Comes in water dispersible powders, dusts, granules, oil, water-based liquid suspensions -Sprayable powders and dusts are most common formulas -Effective against a wide range of insect pests --forage crop pests, fruits and vegetables --ticks, fleas, lice |
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Phosphorylation of ACh-Esterase
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-Irreversible inhibition
-Organophosphates -Phosphate binds to 2nd site of ACh-esterase --if on long enough, will become covalent and inactivate ACh-esterase -THOUSANDS of compounds -Recovery of enzymatic activity requires new ACh-esterase protein, new synthesis --replenishment takes weeks -Need to block 80-90% of ACh-esterase before see effect -Exposure over time is cumulative, accumulate over weeks |
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Ach-Esterase Inhibitors
Nerve gasses |
-Originally developed by the germans, then british and US military
-Isopropyl methylphosphonofluoridate (Sarin) --disperses quickly, not very effective -VX-gas --more persistent, lasts longer --made into an oil that sticks onto things |
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Toxicology of Organophosphate Poisoning
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-Effects are due to Muscarinic and Nicotinic receptor stimulation and CNS effects
--S.L.U.D, miosis -Nicotinic actions at NMJ --excess involuntary twitching, fasiculations, and paralysis -Paralysis of diaphragm and thoracic muscles leads to respiratory failure -CNS effects |
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Pralidoxime
2-PAM |
-Antidote to Organophosphate poisoning
-Accepts phosphate and removes phosphate group from the proteins --regenerates native complex -Does not cross BBB -Does not work with Carbamylating ACh-Esterase inhibitors |
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Therapeutic uses of ACh-Esterase
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1. Glaucoma: reduces intraocular presure by facilitating outflow of aqueous humor from the eye
2. Anesthesia: reverses non-depolarizing neuromuscular blockers 3. Myasthenia Gravis: Increases ACh at NMJ --Neostigmine and Pyridostigmine are drugs of choice --drugs must be carefully titrated to prevent cholinergic crisis 4. Atropine poisoning --Physostigmine is drug of choice |
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Classes of Neuromuscular Blocking Agents
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1. Non-depolarizing competitive blockers
2. Depolarizing blockers |
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Therapeutic Uses of Neuromuscular Blocking Agents
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-Induce skeletal muscle relaxation
-Facilitates endotracheal intubation -Allows less anesthesia to be used during surgery -Orthopedic procedures for alignment of fractures -not therapeutic interventions alone, alone do not provide tranquilization, anesthesia, or analgesia -JUST relax muscle cells --have to make sure patient is ventilated |
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Overcoming competitive blockers
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-Competitive blockers can be overcome with increased concentration of agonist
-Add more with increased EC50 |
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Non-depolarizing competitive blockers
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-Competitive antagonists for Nm receptors
-Bind to Nm with high affinity but do not activate the receptor --Do not cause depolarization of the motor endplate -Can overcome by increasing ACh concentration --increase nerve stimulation --inhibit ACh-esterase to increase ACh |
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Curare
d-Tubocurarine |
-Non-depolarizing competitive Nm blocker
-South American arrow poison -Does not cross the BBB -Not orally bioavailable, cannot be eaten to have effects -Always administered IV and becomes widely distributed and concentrated at NMJ -Short onset time, 4-6 minutes -Long duration 80-120 minutes -Causes progressive paralysis --starts with fingers, small muscles of the orbit of the eye --moves on to limbs, trunk, neck, intercostals, and finally diaphragm -Recovery is in reverse order -Cardiac and smooth muscle are not affected --all muscarininc receptors -Large IV dose causes histamine release, causes transient hypotension |
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Pancuronium
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-Non-depolarizing NMJ blocker
-Long duration of action, 120-180 minutes -Metabolized by the liver -Kidney is major route of elimination -Does not generally cause release of histamine like Curare --no hypotension and circulatory complication |
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Atracurium
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-Non-depolarizing NMJ blocker
-Fast onset and intermediate duration of action -Hydrolyzed by plasma esterases, undergoes spontaneous degradation -Elimination does not involve the liver --can be used in animals with liver disease -No real histamine release, no hypotension |
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Depolarizing NMJ Blockers
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-Succinylcholine
-Hydrolyzed by pseudocholinesterase -Short duration, species-dependent -Cannot be reversed by ACh-esterase inhibitors |
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Succinylcholine Phases of Action
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1. Stimulation
--Activation of Nm receptors and muscle stimulation --Membrane repolarization prevented by persistent activation --Opens ion channels by binding to ACh site 2. Stays on receptor, so next time ACh comes it cannot bind --prevents ACh binding -Cannot reverse by ACh-esterase inhibitors --adding more ACh actually causes more problems, same paralysis |
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Ion Channels as targets
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-Targets for many drugs and toxins
-Local and General anesthetics -heart failure Tx -Anti-arrhythmia drugs -Anti-hypertensives -Anti-convulsants -Anti-diabetics -Insecticides -Plant and animal toxins |
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Cells excitable by ion channels
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-Neurons
-Muscle cells --smooth and skeletal -Secretory cells -Cells can be depolarized (excitatory) or hyperpolarized (inhibitory) |
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Excitatory ion channels
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-Contribute to depolarization
-Na (into cell) -Ca (into cell) |
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Inhibitory Ion channels
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-Contribute to hyperpolarization
-K (out of cell) -Cl (into cell) |
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Voltage Gated Ion channels Structure
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-Complex, multi-unit proteins
-Have ion selectivity -Large opening to small opening changes in voltage -Inactivated quickly -Many different types exist --different types are specific to tissue types --tissue specificity gives specificity for drugs |
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N-type voltage gated Ca Ion channel
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-On neurons
-Important for release of NT -Different distribution of subtypes can be exploited to develop drugs that preferentially target a specific organ |
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L-type voltage gated Ca ion channel
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-On cardiac cells
-Important for action potential in cardiac cells -Different distribution of subtypes can be exploited to develop drugs that preferentially target a specific organ |
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Characteristics of Ion currents
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-Depends on fraction of open channels
-Driving force for ion movement is important --Na or K --Electrochemical potential -Increased electrical potential leads to increased driving force across the membrane -Ion current is transient --stays open for a set period of time then closes --closes even if gradient still exists |
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Ion Channel Inactivation
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-Spontaneous closure of an ion channel
-Inactivation occurs even with sustained depolarization -Channel will stay open for a set period of time, then close --closes even if gradient still exists -intracellular domain of channel plugs the ion pore -Unplugs during depolarization |
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Inactivation particle
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-Intracellular domain of ion channel
-Moves into the ion channel to deactivate the channel -Plugs up pore and stops conductance |
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Modulated Receptor Hypothesis
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-Receptor= drug target
--not necessarily a protein involved in receiving endogenous extracellular signals -Channel proteins can exist in at least 3 functional states -Membrane potential favors different channel states |
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Use/State Dependence of Ion channels
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-Interactions of a drug as it relates to the "modulated receptor" (ion channel)
-Drugs impact how ion channel goes through different states -Effect of drug depends on channel's activity, depends on state -Drug enters channel more readily when it is open --Facilitates access to the binding site |
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Ion channel States
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1. Closed, non-conducting
--most stable at resting potential 2. Open, conducting --favored when cell is depolarized 3. Inactivated, non-conducting --Favored during prolonged depolarizations --Needs to be "reset" through closed/resting state, needs repolarization of membrane --plugged by inactivating particle even though membrane is still depolarized -Transition from Inactive to Closed is very unfavorable when the cell is depolarized --receptor will stay inactivated -Need repolarization for Inactivated receptor to go back to closed |
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Drugs preferentially biding to receptor conformation
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-Higher activity of nerve firing or HR leas to stronger binding
-Effects of the drug increase with time of use --Channel is increasingly blocked -Shows use-dependence |
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Ion Channel Drugs Blocking Channel
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-Acts by modifying channel function
-Physical block of pore -May prevent key intramolecular movement -Prevents switch to open state |
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Ion channel drugs changing gating behavior
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-Modified channel function
-Changes probability that a channel will open -Changes conductance properties of an ion channel |
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Voltage-gated Na channels and Local anesthetics
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-Act on nociceptors
-Local anesthetics block initiation and propagation of action potentials -Block Voltage-gated Na channels --Physically plug membrane channel pore from the inside --site of action is INSIDE the channel -Increasing concentrations of anesthetic cause: --increased threshold for excitation, harder for channels to open --slowing of impulse conduction --Decreased rate of rise of action potential --Decreased amplitude of action potential --Failure to generate action potential, deadens activity |
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Voltage-gated Na channels and local anesthetics
Effect on channel recovery rates |
-Recovery from Inactive to Closed from drug-induced block is much slower than a normal recovery
-Channel stays inactivated for longer --leads to prolonged refractory period --avoids conversion back to closed state -Increases recovery time |
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Voltage-Gated Na channels and Local Anesthetics
pH dependence |
-Effects permeability of the drug
-Local anesthetics are weak bases -Activity is strongly pH-dependent -Drugs must penetrate nerve sheath and membrane -Act from inside the membrane --non-ionized form penetrates the membrane --Ionized form binds to the channel -Unprotonated form goes into the channel, amine is protonated to become acidic --protonated form has more effect on the channel |
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pH and Voltage-Gated Na channels
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-Extracellular pH is more acidic in tissue that are infected
-Allows more protonated form of drug -Less drug is able to reach the target on the channel --decreased ability of the drug -Physiological state of the patient affects receptor's ability to do it's job |
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Local Anesthetics and Use-dependence
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-Local anesthetics show strong use-dependence
-Can enter membrane through open channels -Bind more strongly to Open and Inactivated states -Hydrophobic pathways does not show use-dependence -Hydrophilic pathway does show use-dependence |
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Voltage-Gated Na channels and Anti-arrhythmia drugs
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-Class I anti-arrhythmic drugs block voltage-gated Na channels
-Change contractility in the heart -Cardiac action potentials are much longer under drug than nerve action potentials -Cardiac firing rates are usually slower than nerve firing rates --long time between heart beats |
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Anti-arrhythmic drugs and use dependence
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-Many anti-arrhythmic drugs show use-dependence
-Bind more strongly to O or I states -Block high-frequency excitations, cannot open channel as quickly -Prevent tachycardia and premature beats -Block depolarized/injured tissue preferentially -Prevents rapid progression through action potential |
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Anti-arrhythmic Drug Classification
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-Based on how quickly drug dissociates/unbinds the Na channel
-Drug affinity increases during depolarization and decreases during repolarization --Allows less blockade between beats -If drug unbinds rapidly, it will have stronger activity during high rates of depolarization/tachycardia -If drug does not have enough time to unbind, will have accumulation of block |
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Lidocaine and Use-dependence
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-Binds to inactive state
-Unbinds rapidly -Only affects rapid activity -Blocks open phase |
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Quinidine and Use-dependence
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-Binds open state
-Unbinds slowly -Block remains on between beats, normal rates are affected -Can see the accumulation of the blockade |
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Anticonvulsants and Na channels
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-Most popular anti-convulsant drugs act by enhncing GABA's inhibitory actions
-Some anti-convulsants are Na channel blockers -Block is strongest when nerves fire at high frequencies |
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Voltage-gated Na channels and Toxins
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-DDT
-Pufferfish toxin -Azalea -Red tide -Scorpion toxin |
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Grayanotoxins
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-Stabilizes open conformation of voltage-gated Na channels
--increased Na into cell, increased depolarization -Present in rhododendrons and azaleas -Can be very toxic to grazing animals -not usually an issue for cats and dogs |
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Voltage Gated Ca channels
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-Ca is a very important intracellular signal
-Increased Ca aids in muscle cell contraction -Role in secretion/release -Modulates enzyme activity |
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Indirect Mechanism of Voltage-gated Ca channel opening
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-B-adrenergic receptors in cardiac muscle activate opening of Ca channels
-Activated by adenylyl cyclase, AC phosphorylates Ca channels -Also activated by alpha-unit of g-protein binding to Ca channel -Both activation routes increase the probability of Ca channel opening at ant given voltage --Will have more Ca influx |
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Classes of Voltage-Gated Ca channel Agonists
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1. Phenylalkylamines (verapamil)
-Binds to open state 2. Dihydropyridines (Nifedipine) -Binds to resting state 3. Benzodiazepines (Diltiazem) -Binds to inactivated state -All act from the inner side of the channel -All exhibit use dependence -All cause decreased inward Ca current and lower intracellular Ca concentrations |
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Cardiovascular implications of Voltage-gated Ca channel Agonists
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-Intracellular Ca is important for cell excitability and muscular contractions
-No Ca, less contraction -Decreased SA node pacemaker rate -Decreased AV node conduction velocity -Reduced cardiac muscle contractility -Vascular Smooth muscle relaxation -Decreasing the conduction rate decreases contractility |
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Pharmacological Effects of Ca channel antagonists
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-Mainly affects heart and vascular smooth muscle
-Cardiac action -Vascular and smooth muscle action -Other unwanted effects |
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Cardiac effects of Ca channel antagonists
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-Ca channel blockers
-Slows SA and AV node conduction velocity --Node conduction velocity depends on slow inward Ca current --Slows HR and stops supraventricular tachycardias by causing partial AV block -Reduces the force of contraction -No/Less Ca influx for contraction -Blocks Ca entry with channel blocker, leads to decreased contractile force |
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Vascular Smooth Muscle effects of Ca channel antagonists
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-Smooth muscle needs Ca influx for normal resting tone and contraction
-Blocking Ca entry leads to generalized arteriolar dilation --decreases arterial blood pressure -Nifedipine is most potent vasodilator --stronger affinity for Ca channel in vascular smooth muscle cells than for cardiac cells |
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Unwanted effects of Ca channel antagonists
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-Other types of smooth muscles are relaxed
-Can lead to hedaches and flushing -Constipation due to impact on GI muscles -AV block and negative inotropic effects |
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Ca channel Toxins
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-Dinflagellate
-Blister beetle -Ryania speciosa -Cobra |
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Cantharidin
"Blister beetle toxin" |
-Sometimes beetle is found in hay or alfalfa
-May be swallowed by livestock --horses are particularly susceptible, can die in 24-72 hours -Toxins target sites to increase Ca channel opening -Sheep and cattle are often exposed |
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Amino Acid NTs
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-Act directly or indirectly to modulate excitability
-Workhorses of the CNS, predominant NT in CNS --90% of synapses involve glutamate, GABA, or Glycine -Can be excitatory or inhibitory -Receptors mostly work through ionotropic receptors --ion channels -Some use metabotropic receptors (linked to 2nd messengers) |
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Glutamate
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-Major EXCITATORY NT
-Widely distributed through the CNS -Aspartate is also excitatory, but is more limited in distribution -Has metabotropic and ionotropic receptors |
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Glutamate in Post-synaptic neuron
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1. glucose is transformed into glutamate via glutaminase
2. Glutamate is transported into vesicles 3. Released at synaptic terminal 4. Binds to ionotropic and metabotropic receptors on post-synaptic membrane |
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3 major classes of Ionotropic Glutamate Receptors
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1. NMDA
2. Kainate 3. AMPA -All are heteromeric proteins with 5 sub-units -All are glutamate-activated cation channels -All are permeable to Na and K --overall conductance of Na overwhelms K in other direction -All are excitatory --cause or increase depolarization -Differentially responsive to other co-regulators |
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Glutamate and Neurotoxicity
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-Glutamate is toxic to neurons
-Excessive neuronal depolarization leads to cell death -Immediate effect occurs via necrosis --osmotic swelling leads to cell lysis --due to sustained influx of ions via AMPA, Kainate, or NMDA receptors -Delayed effect via apoptosis --sustained NMDA activation can initiate delayed apoptosis --Excessive activation leads to genetic changes, which lead to apoptosis |
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Glutamate Inactivation
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-rapid re-uptake mechanism
1. Re-uptake into presynaptic neuron and into neighboring glia 2. converted to more benign Gln in neighboring glial cell, then sent back to pre-synaptic neuron 3. Re-uptake by excitatory Amino Acid transporters --powered by electrochemical gradient of Na and K --active transport |
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Clinical Examples of Glutamate Neurotoxicity
Ischemia |
-Interruption of blood flow to brain results in massive release of glutamate and prolonged NMDA activation
-Decreased O2, decreased OxPhos, decreased ATP production --membrane potential cannot be maintained, membrane is inactivated --glutamate is released from membrane -results in neuronal cell death -Drug targets to PCP binding site reduce cell death but increase sensitivity to pain -New drug targets to glycine are in process |
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Clinical Example of Glutamate Neurotoxicity
Domoic Acid |
-Toxin in marine algae
--can accumulate in shellfish, crabs, and other marine animals -Agonist for NMDA receptors -Results in headache, confusion, muscle weakness, and coordination deficits -Poisoning in sea mammals and sea birds |
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GABA
Gamma-aminobutyric Acid |
-Major INHIBITORY NT in CNS
-Widely distributed throughout the CNS -Important in inhibitory control of interneurons -Has to be synthesized by cells from glutamate precursor --Glutamic acid decarboxylase enzyme does the job -Cannot have a neuron that releases Glutamate AND GABA |
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Glutamic Acid Decarboxylase
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-Enzyme that converts glutamate into GABA
-Cannot have Glutamate and GABA in the same neuron -If cell has Glutamic Acid Decarboxylase, will release GABA -If cell does not have Glutamic Acid Decarboxylase, will not form GABA and will only release glutamate |
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GABA inactivation
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-Very similar to glutamate removal and activation
-GABA does not cause toxicity -Prolonged presence in synapse decreases excitability only --no neurotoxicity -removed form synapse via ionotropic receptors, metabotropic receptors, neighboring glial cells, and other receptors on pre-synaptic neuron membrane -In neighboring glial cell is transformed into Glutamine, then transferred to pre-synaptic neuron |
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Families of GABA receptors
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1. GABA-A:
-Allows Cl ions into neuron -results in membrane hyper-polarization -Inhibitory, makes it harder for the post-synaptic cell to be depolarized 2. GABA-B receptors: -G-protein coupled receptors, several subtypes -Forms heteromeric complexes -Connected to K channels to cause membrane hyper-polarization |
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GABA-A receptors
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-Ligand-gated ion channels
-Allow Cl into the cell -Sensitive to certain CNS-depressant drugs --Benzodiazepines and Barbituates --Drugs increase Cl channel activity, further inhibit depolarization |
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Benzodiazepines and Barbituates on GABA-A Receptor
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-Enhance GABA-A currents
-Accentuate GABA's inhibitory actions --Makes cell more inhibitory -Increase probability of opening, more likely channel will open -Increase open time, prolongs open state |
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Barbituates
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-Sedative-hypnotic anxiolytic
-Na-amytal, pentobarbital, phenobarbital -Sedation, anesthesia, and seizure control -Use depends on duration of action by the drugs -Side effects: confusion, impaired judgement, slow reflexes -Lethal at high doses, causes respiratory depression --VERY inhibitory, suppresses all systems -High incidence of tolerance can lead to abuse -Pronounced withdrawl effects -Easily and commonly abused |
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Benzodiazepines
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-Sedative-hypnotic anxiolytics
-Diazepam (valium), alprazolam (xanax) -Low incidence of tolerance -Less severe withdrawl -Can target anxiety without excessive sedation -Short-acting benzodiazepines are used as anxiolytics -Long-lasting benzodiazepines are used as anxiolytics, muscle relaxants, anti-convulsants -Make neuron more inhibitory -Patients with panic disorders have fewer GABA-A receptors |
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Glycine
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-Important INHIBITORY NT
-more limited distribution and sphere of action --Mainly in medulla and spinal cord inhibitory neurons |
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Glycine action and inactivation
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-Ionotropic receptors on post-synaptic neuron
--More receptors, more inhibition -Glycine is removed from synaptic cleft into pre-synaptic neuron and into neighboring glial cells |
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Strychnine
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-Poisonous alkaloid
-Derived from apple seeds -Targets glycine receptor, acts as an antagonist -Competitive antagonist for glycine receptor -Need to have increased glycine to have same effect --can eventually increase concentration enough to get a response |
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Spinal cord integration of excitatory and inhibitory signals
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-Synaptic summation
-Modulation of nerve from both ends -Summation of systems determines if neuron fires or not --takes all excitatory and inhibitory stimuli into account |
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Peptide Transmitters
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-INsulin, growth hormone, ADH, etc.
-VERY important for homeostasis -Act in peripheral tissues and in CNS |
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Peptide Transmitter Synthesis and Breakdown
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1. Transcription
2. Translation 3. Prepropeptide 4. Signal peptidase cleaves prepropeptide to form propeptide 5. Converting enzyme cuts propeptide to form peptide neurotransmitter 6. Inactivating peptides cut into inactive peptide fragments |
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Neuroactive Peptide Modifications
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-post-translational modifications include:
--phosphorylation --acetylation --glycosylation -Carboxypeptidase cuts at C' end -Aminopeptidaase cuts at N' end -Endopeptidases cut in the center |
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Peptide transmitter vesicles
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-Generation of peptide NT is result of packaging of peptides into different class of vesicles
-Large, dense core vesicles -Small synaptic vesicles |
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Large Dense Core Vesicles
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-Vesicle for peptide transmitters
-Generally houses peptide transmitters -Peptide NT synthesis in cell body and then transporter to terminal |
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Small Synaptic Vesicles
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-Generally contain non-peptide transmitters
-Non-peptide NT capable of being made quickly and on-site -Made in the nerve terminal |
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Frequency Dependency of NT released when colocalized in the same neuron
|
-Method for modulating synaptic communication
-Depends on firing properties -Glutamate: released with low-frequency neuronal firing -Substance P (peptide transmitter): released with high frequency neuronal firing |
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Post-synaptic action of Peptide transmitters
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-Acts via G-protein coupled receptors
-Modulate ion channel activity indirectly via G-proteins -Often involved in slow transmission -response generally lasts longer -Peptidaases degrade bioactive peptides into inactive fragments |
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Pain Stimuli
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-Heat
-Cold -Mechanical --shearing, excessive stretching, ripping -Inflammation/chemical irritation |
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Nociceptors
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-Pain receptors
-Specialized neurons that respond to pain stimuli -free nerve endings in the epidermis -Connected to nerves that transmit into into certain areas in CNS that are responsible for processing pain signal info -Use glutamate and Substance P as a transmitter |
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Transmission of Pain Message
|
-2 types of nociceptors
-A-delta: --conduction velocity is very fast, myelinated fibers --Sharp, prickling, well-localized pain --brief pain --Use glutamate -C: --slow conduction velocity, unmyelinated fibers --Dull ache, diffuse pain --Long lasting perception of pain --Use glutamate and substance P |
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A-delta Fibers
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-Connect to nociceptors
-Sharp, prickling, pain -Short duration -Use Glutamate as activating NT |
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C-fibers
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-Diffuse, slow ache
-Uses glutmate and Substance P as NT --mild stimulation is glutamate? --strong stimulus releases Substance P? |
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Substance P
|
-Peptide
-First understood in 1930's -Potent hypotensive and smooth muscle contractile properties -Connected to pain in 1950's --found in dorsal root of he spinal cord -NT released from specific neurons -Central and peripheral release -Tachykinin family --Neurokinin A, Neurokinin B, Neuropeptide K, neuropeptide-gamma |
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Substance P Synthesis
|
-Synthesized from DNA to RNA to protein
-Bioactive peptides are separated away from inactive peptide precursor -All tachykinins come from the same protein precursor |
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Substance P Degradation
|
-Degraded by peptidases into inactive fragments
-Can be broad peptidases or specific peptidases -Neutral endopeptidase -Angiotensin converting enzyme (ACE) |
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Neurokinin/Tachykinin Receptors
|
-Respond to specific peptides
-All tachykinins can bind/activate all 3 NK receptors, but there are preferences -4 sub-types: NK1(Substance P), NK2(Neurokinin A), NK3(Neurokinin B), NK4 -All are G-protein coupled receptors -All linked to Phospholipase C --use IP3 and DAG and 2nd messengers |
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Peripheral Localization of Substance P
|
-Not only involved with pain transmission
-In skin: blood vessels, primary afferent neurons -Cardiovasculature: in arterioles -Respiratory Tract: Role in bronchoconstriction -GI tract: Contracts all parts of GI tract -Immune Response: mediates extravascular migration of inflammatory cells to inflamed tissues |
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Substance P as NT in brain
|
-Mood (depression)
-Anxiety -Control of respiration -Nausea -Emesis |
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Substance P and Pain in Naked Mole Rats
|
-No substance P in skin of Naked Mole Rats
--evolutionary adaptation to living in uncomfortable environments? -If substance P cDNA vector is injected into paw, animal feels pain when it didn't before --is now able to make substance P |
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Opiates and Pain
|
-Long association between opiates and pain
-Opium, morphine -Heroine -Lots of analogs of opiates that are useful for pain management |
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Endogenous Opioids
|
1. Endorphins
2. Enkephalins --small peptides, only 5 aa --can get many enkephalins released from pro-enkephalin 3. Dynorphins --much more potent than endorphins and enkephalins All are peptide based, synthesis from DNA to RNA to inactive precursors to cleavage to bioactive proteins |
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Opiate Receptors
|
1. Mu
--associated with analgesia 2. Kappa --Associated with analgesia 3. Delta --May be important for euphoric effects of opiates Many many different sub-types, 3 main sub-types responsible for most of physiological actions of opioids in body |
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Substance P, Opioids, and Pain
|
-Opiates Enkephalin act on the synapse, block communication of Substance P and glutamate for pain
-Inhibits release of Substance P and glutamate NT from afferent neuron (no NT release from nociceptor) -2nd neuron does not transmit pain anymore |
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Opioid Actions in the Brain
|
-Involved in coordinating brain's response to extremely pleasurable and extremely stressful and painful stimuli
-Activates dopamine release in the nucleus accumbens --produces sensation of great pleasure -Mediate adaptations to stress and extreme pain in the thalamus, hypothalamus, and brainstem --inhibits NorEpi release and increases serotonin and ACh release --inhibits pain sensation --alters arousal state |
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Nitric Oxide
|
-Gas
-Very small molecule -Created in the body -Permeates cell membranes easily -Radial, very reactive --reacts with O2 and other O2 species --products from reaction can also react strongly with proteins and other macromolecules in the cell -Short half-life -Very local effects -Binds very fast and acidly to heme (better than O2) |
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Nitric Oxide Synthesis
|
-Arginine precursor is converted into Citrulline and NO via Nitric Oxide Synthase
-Nitric Oxide Synthase is enzyme --only present in cells that make NO |
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Nitric Oxide Receptor
|
-Binds very fast and strongly to heme
--binds better than O2 -Heme is a central part of its signaling mechanism -cGMP acts as 2nd messenger --wide range of targets -Many different effector mechanisms --Stimulates Protein Kinase G --alters conductances in various ionotropic receptors --stimulates a phosphodiesterase that converts cAMP to AMP and reduces cAMP levels (acts as inhibitor for cAMP) |
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Mechanism of Action of cGMP
|
-Ion channel targets
-cGMP-dependent protein kinases -cGMP-stimulated phosphodiesterase II -cGMP-inhibited phosphodiesterase III Regulated by NO |
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Control of Constitutive NO synthesis by Ca-Calmodulin
|
-Allows for communication from post-synaptic neuron to pre-synaptic neuron
--opposite direction -When Ca and calmodulin are bound, activate NO Synthase --increases production of NO -No diffuses into pre-synaptic neuron, stimulates cGMP production and decreases cAMP production --modulates firing of pre-synaptic neuron |
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Endothelium Derived Relaxing Factor
|
-Found to be NO!
-In blood vessels -Released in cardiovascular area and acts as potent vasodilator - |
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Peripheral Actions of NO
|
-Acts on vascular smooth muscle cells as potent vasodilator
--epidermal derived relaxing factor -Regulation of intestinal function --relaxing function -Acts in skeletal muscle as retrograde messenger --regulates myotube innervation and glucose transport -used by macrophages to kill microbes -Penile erection |
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CNS actions of NO
|
-Possible role in long-term planning, learning, memory
-Neurotoxicity from ischemia -Possible role in neurodegenerative diseases --parkinson's disease, huntington's disease |
