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95 Cards in this Set
- Front
- Back
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Nicotine biotransformation |
metabolite is cotinine metabolized by Cytochrome P450 half life of about 16 hours |
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Which Factor would most likely lead to lower nicotine consumption? |
Slow metabolization of nicotine (smokers try to keep nicotine levels at some idea level–if you’re metabolizing it fast, you smoke more of it). |
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Individual Variability in Rates of Nicotine Metabolism |
• Fast metabolizers consume more and are less likely to quit • Caucasians>Asians=African Americans • Females>Males |
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Nicotine mechanisms |
• Nicotine binds to ionotropic nicotinic receptors (which are usually for acetylcholine), acting as antagonist • Pre and post-synaptic nicotinic receptors • Opens Na +channel causing depolarization and subsequent action potential at all ganglia and the adrenal medulla |
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Nicotine Effects at Nicotinic Receptors |
• Activation when nicotine is applied w/ or w/o acetylcholine to produce neuron activity • Desensitization: If smoking continues, stimulation goes away: lose the activity of the cells. Nicotine becomes an antagonist. • Resensitization when nicotine is removed |
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Where are the main systems of nicotine receptors? |
1) Lateral dorsal tegmental nucleus projecting to ventral tegmental area (LDT/VTA) --dopaminergic effects in nicotine action --NA also involved 2) Medial Septum and nucleus basalas projecting to the hippocampus |
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Nicotinic receptors are not found on which of the following? |
Sympathetically-innervated tissues (except for adrenal medulla) |
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Where are the nicotine receptors? |
Basically everywhere (Basal forebrain cholinergic system, Skeletal muscle, Enteric system, Cholinergic Brain Systems) |
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Nicotine saturates nicotine receptors in brain |
• After one puff of cigarette, nicotine is competing for nicotinic receptors–lots of coverage of receptor sites • By 3 cigarettes,have filled most nicotinic receptors in brain (about 90%) -takes over system • Competition experiment: • As nicotine from a cigarette attaches to the alpha4 beta2 ACh nicotinic receptors in the brain, it displaces a radiolabeled tracer. The nicotine from 3 puffs displaces 75 percent of the tracer from study participants’ receptors. Takes over the system. |
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Nicotine: biphasic effect |
• Binds to two binding sites (alpha4 and beta2) on nicotinic receptors (which is necessary to open the sodium channel) • Acts as an agonist and opens ion channel - Sodium moves into cell • Nicotine receptors eventually saturates receptors but stop acting --Prevents Ach from binding (acts as an antagonist), causing withdrawal • When nicotine clears system, receptors that have been desensitized kick back - system makes more nicotinic receptors • the next cigarette (due to hypersentization) may be the most pleasurable (such as the first cigarette of the morning) |
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Acute Cognitive and Physiological Effects of Nicotine |
• Arousal• Alertness• Attentiveness• Relaxation• (acts as ideal mood modulator: relaxes tense feelings and heightens drowsy feelings) • May be related to activating sympathetic or parasympathetic systems• Could be potentially activating both systems (sympathetic: arousal; PS: relaxation) |
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other effects of nicotine |
• Increased respiration• Increased heart rate• Increased blood pressure• Suppressed appetite• Decreased diuresis• Increased GI activity(PS) |
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Toxic Effects |
• Dizziness• Nausea• Vomiting (area postrema)• Tremor• Brain seizures • Respiratory Suppression at high doses o Inhibits medullary respiratory centers (desensitization of respiratory systems in brain) o Blocks contraction of skeletal muscles • Death o (could be overexposed when collecting nicotine in fields or exposed to nicotine insecticide) ---Lethal human dose is 60 mg ---Each cigarette contains 5-10 mg |
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Effects of Nicotine on Muscles |
Skeletal Muscles at high doses • Muscle tremors• Muscle twitches• Respiratory suppression that can lead to death o Blocks contraction of respiratory (skeletal) muscles -Turns off brain systems that cause respiration and also affecting diaphragm and muscles involved in respiration |
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Therapeutic uses of nicotine |
• Smoking cessation Potential for treatment of:• Depression, schizophrenia, Alzheimer’s (involves nicotinic receptors), Tourette Syndrome, ADHD, Anxiety• People with schizophrenia often smoke: may be self-medicating |
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Factors in Smoking Addiction |
Physical Dependence •Development of tolerance & withdrawal Psychological Dependence •Dopamine reward system (not as dramatic) Conditioning Cues (conditioned stimuli) • Sensory (smell, taste, touch) • Mood (arousal,relaxes) • Social (peer cues) Symptoms of physical withdrawal • Irritability• Anxiety• Distraction• Restlessness• Insomnia• Hunger• Weight gain |
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Effects of Smoking on the Cardiovascular System |
Increases Demand• Increases heart rate /contraction• Increases blood pressure Reduces Oxygen Supply to Heart (affecting lung function as well)• Atherosclerosis• Carbon monoxide reduces affinity of hemoglobin for oxygen (reduces ability to carry it)• Impairs pulmonary function (Chronic Obstructive Pulmonary Disease) |
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Effects of smoking on the lungs |
Chronic Obstructive Pulmonary Disease (COPD): • Emphysema: Changes structural properties of lungs; Walls of alveoli (air sacks at end of bronchi) are inflamed–elasticity is altered and they may become overstretched and rupture; Can be fatal • Chronic Bronchitis: Less dangerous than emphysema; larger tubes (bronchial tubes) become inflamed (narrows them) and induces coughing spell so Can lead to other complications and illnesses • Asthma |
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Pharmacotherapy for Smoking Addiction |
o Nicotine Replacement ---Occupies nicotinic receptors o Buproprion ---Antidepressant that blocks dopamine reuptake o Varenicline ---Partial Nicotinic Receptor Agonist ---Provides some help with withdrawal effects and may reduce rebound effects because receptors are occupied, so prevents ebbs and flows that may encourage nicotine usage |
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What are the natural opioid agonists? |
Opium, morphine, codeine, thebaine |
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what are the semisynthetic narcotics (opioids)? |
Heroine, hydromorphone, oxycodone, etorphine |
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What are the totally synthetic opioids? |
pentazocine, meperidine, fentanyl, methadone, LAAM, propoxyphene |
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What are the endogenous opioids? |
endorphins, enkephalins, endomorphins, dynorphins |
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Criteria for classification as an Opioid Agonist |
o Exerts effect similar to morphine o Acts at Opioid receptors o Effects blocked by antagonist, Naloxone |
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Opioid Antagonists |
o Naloxone (Narcan) --Reverses effects of Opioid Agonists --Precipitates withdrawal in heroine users (can give to people who are overdosing on heroine/morphine) --(Closest example of “perfect” antidote for drug) o Naltrexone (Trexan) --Long-acting form --Suitable for addiction treatment o Structure similar to the agonists |
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Therapeutic Opioid Administration |
o Synthetics,morphine,codeine (oral) o Synthetics,morphine (parenteral) o Fentanyl–powerful opioid (Transdermal patch) |
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Non-‐therapeutic Opioid administration |
o Heroine, morphine (Parenteral) o Heroine (intranasal) o Opium, Heroin (inhalation) |
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Heroine |
o More potent than morphine o More lipid soluble (lipophilic) o Crosses BBB more efficiently o Converted into morphine by brain enzymes o Aspirin: Bayer made Acetylsalicylic acid, put acetyl groups on morphine to get a non-addictive form --Made diacetylmorphine (heroine)–whoops!–more potent form, limited medical use, and addictive At one point,could buy heroine as a medication (ex:as a sedative for coughs) |
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Morphine Biotransformation |
(Phase II Conjugation by the liver)– conjugated with glucuronic acid and eliminated |
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Morphine Mechanisms |
•Inhibits brain activity at multiple levels •Metabotropic receptors 1.Inhibits adenylcyclase activity via inhibitory Gi - less cAMP forms 2.Postsynaptic Inhibition (IPSP) - Axosomal synapse–Mu receptors - Potassium efflux - hyperpolarization 3. Postsynaptic Inhibition (IPSP) Axoaxonal synapse - Kappa receptors - closes calcium channels - Reduced Nt release 4. Autoreceptor activation - calcium channels close - reduced transmitter release |
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Bioassay for Opioid Effect |
o Guinea pig intestinal strip or mouse vas deferens (both smooth muscle) have opioid receptors on them • Smooth Muscle Bioassay o Put strip of intestine/ vas deferines in and then stimulate the strip electrically, action potential coming in, transducer picks that up,should cause muscle to contract (get shorter) When Opioids added, inhibits the contraction: Reduces the strength of the contraction • If Naloxone added, will reverse Opioid’s effects i.e.muscle will contract |
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Who discovered opioid receptors? |
Pert and Synder discovered Opioid receptors (1973) (before this, didn’t know we had opioid receptors) |
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How were opioid receptors discovered? |
The first receptor binding assay was developed specifically to identify opioid receptors Used 3H Naloxone to label receptors in brain and smooth muscle |
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Describe the process of discovering the Kd of Naloxone. |
Fixed amount of brain homogenate varied concentrations of tritiated Naloxone discover Bmax by finding the concentration at which Naloxone binding does not increase kd = concentration of naloxone at which they bind to half of receptors |
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Describe how the affinity of a compound for opioid receptors predicts inhibitory potency at smooth muscles. |
The concentration of drug necessary to bind 50% of receptors = IC50 = affinity the concentration of drug necessary to inhibit 50% of smooth muscle contraction = ED50 = potency ---the ratio between these two concentrations (IC50 and ED50, i.e. affinity and potency) are nearly linear |
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Describe how to get IC50 and ED50 for opioids. |
• Competition experiment gives IC50 ---Compete drugs against each other to see the concentration ofagonist drug needed to displace 50% of the tritiated Naloxone • Bioassay experiment gives ED50 ---stimulate muscle contractions with electrical signal, add agonist drug– concentration until 50% of muscle contraction is inhibited • biological effect predicted by calculating affinity of drug to receptor • Almost perfectly linear relationship ----Suggests that opioid receptors are regulating this phenomenon in small intestine • Important for understanding which drug mechanisms cause certain effects |
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How were endogenous opioids discovered? |
Kosterlitz and Hughes Discover Endogenous (natural) Opioids (1974) • Stimulate Muscle Strip Electrically • Record Smooth Muscle Contractions • Apply Brain Extract to Preparation • Record Inhibition of Contractions • Restore Contractions with Naloxone ---Even brain extract was binding with mu receptors to affect contractions in small intestine But how could they isolate the actual molecule / chemical that was causing this?--brain extract from pigs and calves--were able to isolate enough compounds to find Met-Enkephalin |
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First Endogenous Opioid Peptide Identified |
Met-Enkephalin (in the head) (5 amino acids) |
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Synthesis of Opioid Peptides |
• DNA transcribes long sequence of mRNA for precursor • mRNA translated into large precursor peptide • within that peptide, Enzymes cleave amino acids sequences for each peptide • ex: beta endorphin – part of lipotropin molecule – if you chop in half, get lipotropin • making a large hormone, enzymes are taking out the sequence that responds to whatever endorphin or endomorphin you need • still don’t know where endomorphin is coming from |
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What are the endogenous opioids? |
Endomorphin, Enkophalin, Dynorphin, Endorphin |
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How many amino acids does endomorphin have? What is its peptide precursor? What receptors does it bind to? |
4 amino acids, unknown, Mu |
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How many amino acids does enkephalin have? what is its peptide precursor? what receptors does it bind to? |
5 a.a., proenkephalin, mu and delta |
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How many amino acids does dynorphin have? what is its peptide precursor? what receptors does it bind to? |
8-29, prodynorphin, kappa |
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How many amino acids does endorphin have? what is its peptide precursor? what receptors does it bind to? |
16-31, POMC, Mu and Delta |
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How were endomorphins discovered? |
by tulane university professor James Zadina |
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What did Tulane University professor James Zadina discover? |
4thclass of endogenous opioids(endomorphins • Endomorphin1Try-‐Pro-‐Trp-‐Phe-‐NH2 • Endomorphin2Try-‐Pro-‐Phe-‐Phe-‐NH2 |
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Which receptor does most of the heavy lifting for the Opioid system? |
Mu |
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Which of the acute effects of opioids occur in the cortex? |
sedation, drowsiness, relaxation |
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Which of the acute effects of opioids occur in the mesolimbic dopamine pathway? |
Euphoria |
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Which of the acute effects of opioids occur in the medulla? |
pupillary constriction, nausea, vomiting, cough suppression, respiratory suppression |
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Which of the acute effects of opioids occur in the hypothalamus? |
hypothermia and reduced sex drive |
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Where does analgesia occur as a result of opioids? |
many areas: cortex, hypothalamus, thalamus, spinal cord, brain stem, limbic system |
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What affect do opioids have on the intestinal system? |
constipation |
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How do opioids induce analgesia at multiple CNS sites? |
Spinal Analgesia--Inhibition of pain sensation Brain Stem Analgesia--Inhibition of pain sensation Limbic, Thalamic, and Corticol Analgesia--Inhibition of pain perception – emotional component of pain – “I can still feel the sensation but it doesn’tbother me" – perception becomes less aversive |
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What are the toxic effects of opioids? |
Respiratory Suppression• Don’t act on lungs or diaphragm–rather,they act on the medullary centers of respiration• Opioids tend to be inhibitory, so in this case we are inhibiting the respiratory centers (shut them down)–can be shut down so severely they lead to fatal overdose |
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What are the therapeutic uses of opioids? |
• Analgesia (pain center, control sensation and perception of pain) • Cough suppression (codeine) – affects medulla – cough center • Anesthesia (fentanyl) - very powerful opioid–strong enough to induce surgical anesthesia as well as analgesia • Substance Abuse Treatment for opioids and other drugs • Reduce Intestinal motility (treatment for diarrhea) (used for thousands of years for this) |
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Describe Cellular (Pharmacodynamic) Tolerance of opioids |
• Decrease in opioid receptors o When receptors overstimulated, may sink down into membrane (down‐regulation) --Receptor phosphorylated: sinks down into membrane, and then dephosphorylated: comes back up • Increase in adenylylcyclase o Morphine leads to decrease in cAMP o Over time,cAMP levels adapt to chronic exposure to Morphine o When morphine use withdrawn, cAMP goes up before returning to normal --Creates dependence |
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Contextual Tolerance to Opioids (Siegel, 1982) |
• Context in which drug is taken reduces tolerance • Experiment:tookrats.30ratsweregivenheroineovertime,15receivednoheroine.Then,15oftheheroineratsweregivenabiginjectioninthesameroomastheywerereceivingtheoriginalinjections,and30%died.15oftheheroineratsweregiventheinjectioninadifferentroom,and65%ofthemdied(werelesstolerant).Asacontrol,thenon-‐heroineratsdiedatarateof95%. • Oneoftheriskfactorsforheroineoverdoseis anewenvironment |
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Opioid Dependence |
• PhysicalDependence o Withdrawalsyndrome: Oppositeofacuteeffects -connectedtoincreaseincyclicAMP)onlylastsabout1-2weeks and Notlife-‐threatening • PsychologicalDependence o Powerfulreinforcero Intensecraving,“rush”o IncreasesreleaseofdopamineinAccumbens |
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What are the acute effects of opioids? |
hypothermia, decreased blood pressure, peripheral vasodilation, skin flushing, miosis (constriction), drying of secretions, constipation, resporatory suppression, antitussion, decreased libido, relaxation, analgesia, euphoria |
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What are the withdrawal effects of opioids? |
hyperthermia, increased blood pressure, piloerection, chills, mydrasis (dilation), eye and nasal secretions, diarrhea, yawning, panting, coughing, sneezing, spontaneous orgasms, agitation, restlessness, pain, dysphoria, depression |
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Which substances are used for drug therapies for opioid addiction? |
methadone, buprenorphine, naltrexone, clonidine, and mixed preparations |
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describe methadone |
used for drug therapy for opioid addiction full agonist for opioid receptors administered daily, oral mild opioid effects Blocks withdrawal |
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describe buprenorphine |
Partial agonist at mu receptors (milder than methadone) typical opioid effects but milder reduced risk of overdose reduced intensity of withdrawal |
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Describe Naltrexone. |
opioid antagonist blocks effects of opioids precipitates withdrawal in users blocks life-threatening effects longer acting version of naloxone |
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Describe Clonidine. |
Noradrenergic alpha 2 autoreceptor agonist suppresses physical withdrawal symptoms may reduce release of norepinephrine (which then reduces withdrawal) |
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What are the signs of an opioid overdose? |
• Deep, slow snoring or gurgling • Heavy nod, not responsive to stimulation – apply sternal rub (rub breastbone hard with knuckles) • Slowed breathing • Cyanotic – bluish lips and nail bed – not getting enough oxygen • Pinpoint pupils (affects optic nerve itself, causes pupil to become tiny) |
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Risks of Opioid Overdose |
• Loss of Tolerance: Increased risk after period of abstinence • Mixing Drugs: Mixing opioids with other drugs, especially depressants such as benzodiazepine oralcohol. • Using alone: When using drugs alone there is no one present to see signs of overdose. • Variation in strength of ‘street’ drugs: Street drugs may vary in strength and effect based on thepurity of the drug and the amount of other ingredients used to cut the drug. • Serious illnesses: AIDS, liver disease, diabetes and heart disease |
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Which law required the regulation of opioids and cocaine? |
1914 Harrison Act |
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What did the Harrison Act require? |
The regulation of distribution of opioids and cocaine |
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schedule I substances |
no accepted medical use high abuse potential heroine, LSD, mescaline, marijuana, THC, MDMA |
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Schedule 2 substances |
high abuse potential, severe psychic or physical dependence, some medical use Opium, morphine, cocaine, codeine, amphetamine, merepidine, methylphenidate (ritalin), pentobarbital, PCP |
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Schedule 3 substances |
abuse potential less than 1 and 2, limited quantities of narcotics and non-narcotic drugs Paregoric, barbituarates other than listed in other schedule |
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schedule 4 substances |
abuse potential less than schedule 3 phenobarbital, chloral hydrate, diazepam, alprazolam |
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schedule 5 |
abuse potential less than schedule 4, limited amounts of narcotic drugs generally for antitussive (cough suppressent) and anti-diarrheal |
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what is substance use disorder? |
pattern of use of intoxicating substance leading to clinically significant impairment or distress, manifested by at least 2 symptoms occurring within 12-month period: large amounts taken, can't stop, failure to fulfill obligations, physically/psychologically hazardous, tolerance/withdrawal developed |
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Physical Dependence (Wikler) |
• Physical withdrawal maintains dependence• Every time you abstain, it induces withdrawal, so you take more to eliminate withdrawal• Initial drug use – repeated drug use – physical dependence – attempts at abstinence – withdrawal symptomsrelapse – loops back around to attempts at abstinence |
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Positive Reinforcement (Koob) (Psychological Dependence) |
• Brain experiences reinforcing effect of the drug• Relapse is based on compulsive desire to experience drug-induced euphoria • Initial drug use – positive reinforcement – repeated drug use – attempts at abstinence – impulsive desire toexperience drug-induced euphoria – relapse – loops back to attempts at abstinence • Cocaine administration in mice: Rodents self-administer cocaine and amphetamine at very high rateso Rodent has catheter, presses bar to get injection, will press at high rates (sometimes till they die) |
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Conditioned Place Preference Test |
Determine Pre-drug Compartment Preference • Condition Non-preferred Side to Drug • Condition Preferred Side to Vehicle • Test Post-Conditioning Preference Without Drug |
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Reward Pathway |
• Drugs of Abuse increase dopamine levels in the nucleus accumbens (Mesolimbic Dopamine Pathway –Reward Pathway – VTA – > NA) o Cocaine Blocks DA Reuptake in NA o Amphetamine Stimulates DA Release in NA |
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Incentive - Sensitization (Robinson) model of addiction |
The chase is better than the catch. The pursuit of the drug becomes reinforcing (cat analogy). Conditioningphenomena. Salience of cues associated with the drug. • Initial drug use - Positive reinforcement - Repeated drug use - Sensitization of drug “wanting” but not drug “liking” - Attempts at abstinence - Compulsive desire for the drug due to sensitized incentive salience system - Relapse |
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Nestler’s Model of drug addiction |
• Transcription factor D-FosB accumulates in Nucleus Accumbens with repeated exposures to all drugs of abuse • D FosB, a stable protein persisting for 2 months or more • Stimulates gene expression leading to dendritic restructuring in NA (growth of more spines) *Increasessensitivity of dopamine reward pathway |
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How does Nicotine affect dopamine release? |
-Cholinergic system (LDT/PPT) neurons releaseacetylcholine onto nicotinic receptors on DA neuron cell bodiesin the VTA –Excites release of DA inthe NA (reward) and PFC (arousal) |
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How do Opioids affect dopamine release? |
Inhibits GABA neuron firing in VTA, which disinhibits DA neuron firing in the VTA, which increases DArelease in the NA Two ways: Post-synaptic inhibition: potassium channels open, potassium efflux –hyperpolarization – IPSP Pre-synaptic inhibition: calcium channels close and reduces transmitter release (drugs that work at Mu receptors all get these kinds of effects) |
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What are the methylxanthines? |
caffeine, theophylline, theobromine |
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What are the sources of methylxanthines? |
caffeine (coffee, tea, chocolate, soda) Theophylline (tea) Theobromine (chocolate) |
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What are the pharmacokinetics of caffeine? (administration, absorption, distribution, metabolization, half life) |
oral administration, weak base absorbed by GI tract, crosses BBB, metabolized to paraxanthine (84%), theobromine (12%), theophylline (4%), half-life of 4 hours |
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What are the mechanisms of action of caffeine? |
Blocks adenosine receptors (low doses) inhibits phosphodisterase (high doses) blocks GABAa receptors (high doses) Increases calcium release (very high doses) |
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Describe the blockade of adenosine receptors by methylxanthines. |
--adenosine is a minor inhibitory transmitter --A2a receptors blocked by methylxanthines causes mild disinhibition of the brain |
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What are the acute physiological effects of caffeine? |
decreased blood flow to brain increased or decreased migraines increased respiration dilated airways increased gastric secretions diuresis |
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What are the acute toxic effects of caffeine? |
500-1000 mg: anxiety, irritability, insomnia, fever, flushing over 1500 mg: paranoia, delusions, hallucinations, stereotypies |
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What are the therapeutic uses of methylxanthines? |
headache, asthma, narcolepsy, sleep apnea |
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Caffeine tolerance |
cellular - increase in adenosine receptors behavioral - functioning in presence of drugs contextual - context in which drug is taken induces tolerance |
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caffeine dependence |
physical: headache, fatigue, craving psychological: increases DA release in cortex |
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caffeine lowers risk of: |
diabetes (type 2) cardiovascular disease liver disease parkinson's low to moderate (less than 3 cups per day) |
