Drugs Flashcards
Bupropion
antidepressant drug that helps with nicotine addiction.
Blocks nAChR on DA neurons in VTA.
Varenicline
- Treat nicotine addiction
- Partia agonist of a4ß2. Less dopamine release.
Topiramate
- Treat nicotine addiction
- Decrease normal reward-related DA response to nicotine in lab. animals
Ethanol
-CNS Depressant
-Target glutamate, GABA and glycine. Also has an effect on 5HT and ACh.
-Acts on GABA A: main inhibitory transmitter in the CNS. Has 2 binding sites for Cl-.
-EtOH release GABA from presynaptic neuron to increase inhibition and can influence tonic inhibition.
-Releases glycine from presynaptic terminal
-Blocks Glutamate (N2B subtype specificity) transmission and NMDA receptors.
Overall increased inhibition and decreased excitation
-Blocks ACh release, blocks v-gated Ca channels
-Decreases reabsorption of water by kidneys.
-Highly lipid soluble, activates CTZ
- Able to metabolize half a drink per hour. Other wise, it is 0 order elimination
-Converted to acetaldehyde by alcohol dehydrogenase then into acetate by acetaldehyde dehydrogenase
- ADH found in liver and gastric mucosa. Dimer with 6 subunits
-10% of metabolism happens by the p450 system (can be induced with chronic drinking). 5% is exhaled unchanged.
-TI=4
-teratogenic toxicity. induces fetal alcohol syndrome (mental retardation).
-Alcoholic liver disease (first-pass effect impaired), cirrhosis, fluid-filled abdomen, hepatic encephalopathy, liver damage, testicular atrophy
-Chronic use: upregulation and withdrawal hyperexcitability
-Withdrawal can lead to delirium tremens (intensity proportional to amount consumed)
-Treatments: treat acute withdrawal with CNS depressant, NMDA receptor antagonist, opioid receptor antagonist (lowers EtOh effects)
Disulfiram
- Treat alcohol addiction
- Blocks breakdown of acetaldehyde by blocking the enzyme.
Cocaine
- CNS stimulant
- Acts on nerve impulses and reuptake of serotonin, dopamine and noradrenaline
- Blocks V-gated Na channels: CNS excitation (convulsions) followed by inhibition (respiratory arrest)
- Blocks the neurotransmitter/sodium symporter (NSS) present for dopamine (reward pathway, all dopaminergic receptors are GPCR with 7 subunits, high density in the cerebral cortex), noradrenaline (sypathetic autonomous nervous system) and serotonin. K exits the cells as Na enters with the transmitter.
-Administration:
orally (high first-pass, slow absorption,little euphoria)
Nose: Not well absorbed, intense vasoconstriction,
IV: infection risk, scars, highest BAC
Smoking: faster absorption, cheapier, easier to sell for kids.
- Cocaine is lipid soluble, crosses BBB very quickly and effect wears off vey quickly.
- Metabolism by human carboxylestarase 1 (high conc. in the liver)
- Cocaine + alcohol –> cocaethylene (toxic metabolite, replacement of methyl with ethyl)
- Metabolites can be found in urine after many days and detected in hair follicles.
- Toxicity leads to Cardiovascular problems, vasoconstriciton in heart and decreased blood flow to heart muscles, generalized hypertension, rupture if an aneurysm (caused by dilation of an artery in the brain), seizures, agitated delirium (does not reuire hgh does and is rapifdly fatal, extreme aggressiveness, variant in D2 reeptor linked in temperature control, hyperthermia, breakdown of skeletal muscles), neuronal injury, ‘crack babies’, fetal death
-Chronic usage: Dopamine depleted since reuptake is blocked –> increased amount of receptors.
- withdrawal: hyperactivity, new glutamate receptors (Ca and Na), longlasting changes in synapses, slower reaction time.
-Addiction: binge use for many hours/days. Combine with ethnol or heroin.
Tolerance -> dysphoria, despair, increase reuptake receptors,
- Chronic: psychiatric illnesses, 2 reactions phases when cocaine is ceased (crash (high cravings, agitation, fatigue..) and withdrawal (cravings in the location)), long term effects
-Treatment for addiction: behavioral therapy.
- Research for a drug that partially blocks DA receptors, and vaccine with antibody for cocaine.
Nicotine
- Weak base
- Excellent GI absorption: relevant in regards to poisoning (one cigarette could be lethal for children) –>triggers CTZ
- Metabolism: CYP2A6 (in some people defective)
- Half-life: 2 hrs
- CYP2A6: activates procarcinogen
- Agonist and antagonist of nicotinic cholinergic receptors (5 units crossing membrane 4 times). Most common receptor is å4ß2 (2å and 3ß , for sodium and calcium). Homomeric å7 allows passage of Ca. Nicotine binds between an å and ß. Both subunits are involved in addiction
- Longer inactivation of the receptor –> increase nAChR in prefrontal cortex .
- First stimulates then blocks receptors in the autonomic ganglia
- Cigarette contains monoamine oxidase inhibitors
- There is predominance of å4ß2 receptors in the VTA (on dopaminergic and gabaminergic neurons)
- Presynaptic å7 enhance glutamate release and duration which stimulate the DA cell (longer excitation and lower inhibition).
-Addiction is treated with patches and sprays. Decrease nicotine metabolism by CYP2A6. Nicotine vaccine that prevents nicotine from entering the BBB.
Amphetamines
- CNS stimulant
- increase dopamine and noradrenaline release. Act on their reuptake. Effects mainly due to NA synapses
- Blocks Monoamine Oxidase (MAO) –> even higher level of NTs
- No tolerance for motor abilities
- Some metabolites are biologically active and toxic
- ‘Designer amphetamines’: Derivatives of amphetamines like ice(smokable) and methamphetamine.
- Chronic use: neuronal loss, DA receptors decrease, DA neurons destroyed –> Parkinsons
Ecstacy (MDMA)
- CNS stimulant, hallucinogen
- derivative of amphetamine
- Prominent effect on dopaminergic and serotoninergic pathways.
- Mostly 5HT transporters.
- High levels of serotonin affects hypothalamus, hippocampus (memory), neocortex (reward)
- ACute effects -> elevated mood, stimulation, heightened perceptions and reduced appetite.
- Adverse effects: on spinal chord, jaw clenching, hyperthermia, heart arrhytmias, renal failure. Short term –> irritability followed by depression. Long-term –> changes in brain chemistry and brain structure (5HT and its metabolite and its transporter reduced), memory area damaged, loss of 5HT neurons
Caffeine
- mild CNS stimulant
- xanthine family
- Absorbed rapidly, peak conc. at 1/2-2hrs
- Distribution: rapid, to all tissues
- Metabolism: 4-5 hrs (enzyme induced by smokers)
- half-life depends on age: 65-102hrs in newborn vs. 3-7.5hrs in adults
- Pharmacodynamics: competitive antagonist of adenosine receptors (adenosine norally blocks the activity of cholinergic stimulatory networks)
- increases gastric acid secretion, individuals vulnerable with panic attacks should avoid.
- lethal dose : 100 cups
Benzodiazepines
- Anxiety treatment
- Abonormal anxiety: panic attack or as persisting state, panic disorder.
- Benzo: benzene ring, diaz: 2 N, epine: N-ring.
- Variation of benzodiazepime: diazepam, alprazolam.
- Major effects: antianxiety, induced sleep (sedative hypnotic), anticonvulsant, muscle relaxant, amnesia, treat acute stress-related anxiety
- TI= 500-1000
- Target GABA A (ligand-gated ion channel, 5 subunits crossing membrane 4 times), has an allosteric binding site, facilitate action of GABA. The most common GABA A is 2ß2,2å1,1gamma2. GABA binds between å1ß2
- Shift dose-response curve to the left -> positive allosteric modulator
- Barbiturates , in comparaison, open the channel on their own, alter duration of opening, not as selective.
- Benzodiazepines increase frequency of opening, no direct action, much safer and selective.
- Alcohol and general anesthetics can act on both extrasynaptic and synaptic receptors.
- Absorption: highly lipid soluble, peak in an hour.
- Distribution: wide in the body, variable in protein binding, rapidly reach brain
- Metabolism: long half-life, active intermediates. broken down by CYP3A. Diazepam and chlordiazepoxide are broken to nordiazepam, further broken down to oxazepam.
-can reach fetus easily
Withdrawal: anxiety attacks, wont’t be able to sleep, hyper, last a week, nightmares (more REM)
å1gabaA: sedation and sleep
å2 GABA A: antianxiety and analgesic
- GABA B receptors: not involved in anxiety or insomnia, GPCR for K+. Mainly a modulator, inhibits other neurotransmitters. GABA B agonist given as a muscle relaxant, treat multiple sclerosis.
- Musicians take beta-blockers instead of benzodiazepines
- Schizophrenia: psychosis, genetic factor involved, involved with dopaminergic pathways(D2 receptor is of interest). Symptoms reduced by blocking D2.
- Dopaminergic receptors: GPCRs that activate cAMP
- D2 receptors are located pre and post-synaptically. Act on glutminergic transmission as well.
Depression
- decreased levels of amine neurotransmitters in the synapses: dopamine, noradrenaline, serotonin
- 3 drug categories:
1. Selective serotonin reuptake inhibitors (SSRIs): inhibit reuptake of 5HT.
2. Monoamine oxidase inhibitors (MAOIs): increase [transmitters] acting postsynaptically
3. Tricyclic antidepressants (TCAs): interfere with reuptake of transmitters (NA,his, ACh) –> many side-effects like GI problems, blurred vision (muscarinic), sedation (his)ad vascular problems (adrenergic) - Over 10 different types of 5HT receptors, 7 major families, 5HT3 is ligand-gated ion channel and the rest are GPCRs, distribution in the brain varies, also found in GI tract, PNS, blood vessels, etc.
- Symptoms like constipation, dizziness, dry mouth and blurred vision are lower with SSRIs
-Seasonal affective disorder: triggered by day length and light cycle. Treated by a light box.
Fluoxetine
- Prozac
- treat depression
- SSRI: block 5HT reuptake receptors
Chlordiazepoxide
-first benzodiazepine
Diazepam
Benzodiazepine
-Anti-anxiety
Alprazolam
- Benzodiazepines
Panic Attacks
-Used for treating insomnia because of very short half-life
Flumazenil
Blocks the effect on benzodiazepines
-Treat overdose
Zolpidem
Acts on benzodiazepine site but is not a benzodiazepine
-Non-benzodiazepines binds to the alpha1 (Sedation) subunit of GABA –> more selective
desmethyldiazepam
important intermediate of benzodiazepines.
very biologically active, has half-life of days
broken down to oxazepam (also biologically active)
Corticosteroids
-Anti-inflammatory agents
-Hypothalamus releases corticotrophin releasing factor (CRF,CRH).
CRF: 41 aa, pro-hormone releases the active part which is CRF.
- CRF atcs on GPCR in the ant. pituitary to stimulate pre-prohormone –> pro-hormone –> POMC. POMC processed to release ACTH and ß-LPH
-ACTH: acts on the adrenal cortex (glucocorticoid synthesis in the zona fasciculate/reticularis). increases delivery of cholesterol to the inner mitochondria membrane (increases transcription of steroidogenic enzymes e.g CYP11A1) in the goal to increase the amount of cholesterol available to make the glucocorticoids, increase number of transporters for cholesterol. Transcription of the different enzymes involved in the pathway of cortisol production increased.
-Glucocorticoids: lipophilic, transported in the circulation with CBG (corticosteroid binding protein). Binds to GR in thecytoplasm and leaves its complexe to enter the nucleus. They interact in a dimer with glucocorticoid response elements on the DNA.
Increase transcription of specific glucocorticoid receptor responsive genes
Also represses gene expression (NFKB,AP-1) involved in inflammatory and stress response.
-Regulate 10-20% of all expressed genes
- Effects: increased glycogenolysis and gluconeogenesis, increased lipolysis, lipogenesis, protein catabolism (decrease osteoblast formation and activity)
- Anti-imflammatory: decreased production of prostaglandins, cytoines, and interleukins
- Phopholipids (phospholipase A2) –> arachidonic acid (COX-2) –> prostaglandins, leucotrienes.
- Cortisol: affects activity of PA2, repress transcription of COX2, repress synthesis of interleukins (IL-2, IL-3) and platelet activating factor (PAF), decreased proliferation and migration of WBC, transcriptional repression, inhibit immune signal, triggers apoptosis i inflammatory cells.
-Used as replacement therapy for adrenal insufficiencies, antiinflammatory and immunosuppressive action, myeoloproliferative dseases (cancer caused by excess division. induce apoptosis), prevention of respiratory distress syndrome in premature babies (induce surfactant)
Dexamethasone
- Glucocorticoid
- altered version of cortisol (fluorine and methyl group added). Fluorine enhances both mineralocorticoids and glucocorticoids activity and methyl represses mineralocorticoid activity)
-Too much cortisol –> Cushing’s syndrome. high level long-term exogenous steroids leads to shut down of HPA axis and adrenal atrophy. Best method is to slowly decrease consumption of drug.
Non-steroidal anti-inflammatory drugs (NSAIDS)
- can be taken chronically, not serious side-effect, steroids are more powerful
- Compounds taken from the white willow and meadowsweet plant. Salicilin isolated
- Arachidonic acid: 20C, polyinsaturated, found in membranes. liberated from the membrane by phospholipaseA2
- Prostaglandins: unsaturated carboxylic acids, 20C, cyclopentane ring, made by almost all cells, autocrine and paracrine functions, rapidy inactivated
- Cyclooxygenase: dimer, embedded in the ER
- COX-1: physiological roles, COX-2: more pathological
- Protaglnadins acts on GPC prostanoids receptors PGE2 acts on 4 types of receptors. Involved in cytoprotection of the stomach, vasodilatation body temperature control. Pathological roles such as pain, inflammation and fever
- NSAIDS block protaglandin synthesis. Used as anti-inflammatory, analgesics, antipyretics, prophylaxis of myocardial indarction and stroke, antithrombotic
- Injured cells release PGE2, other prostaglandins, bradykinin (involved in pain and vasodilatation), serotonin
- COX-2 is the major enzyme that produces PGE2
-ASpirin: the acetyl group sticks irreversiby in the enzyme. Blocks thromboxane A2 and blocks activation of platelets. Long-term use lowers colon cancer risk.
-Metabolism: Aspirin deacetylated to salicilin, then conjugated by glycine.
-Half-life: low dose= 3hrs, high dose=15 hours
-Changing the pH of the urine can alter the amount of salicylic acid excreted. Excreted more in alkaline urine (administer bicarbonate in overdose to alkalinize urine).
-toxicity (salicylism): tinnitus, headache
Reye’s syndrome: rare disorder affects the ell in the brain and in the liver (when aspirin is taken while having a viral infection)
- Traditional NSAIDS: ibuprofen, naproxen
- COX-2 involved in renal electrolyte homeostasis and renal blood flow maintenance, produces prostacyclin that causes vasodilatation
Celefecoxib
acts only on COX-2 (active site is bigger than COX-1)
Rofecoxib
One of the first COX-2 inhibitors
Acetaminophen
Analgesic, antipyretic, not anti-inflammatory
-Half-life : 2-3 hours.
75% conjugated and excreted, make a toxic intermediate leading to necrosis (there is more if you overdose, can lead to hepatotoxicity)
Ethanol induces the p450 that converts acetaminophen into the toxic metabolite and depletes glutathione stores for conjugation.
-Antidote: glutathione precursor, N acetylcysteine
N-acetylcysteine
glutathione precursor for acetaminophen poisoning
Opioids
- Analgesic
- targets CNS for pain relief
- naturally occuring alkaloids are morphine and codeine.
- many types of opioids synthesized by the body such as endorphin, enkephalins and dynorphins
- opiates: drugs derived from the opium poppy
- Opioids: drugs with morphine-like action synthesized in laboratory.
-Afferent transmission of pain is reduced
Pre-synaptic: release of calcium interfered
Post-synaptic: hypoerpolarization
-Activate a descending pain-inhibitory pathway
-can impact emotional reaction to pain
-opioids receptors are GPCR (either alter conc. of Ca or K+)
-kappa receptor drug targets are non addictive but unpleasant
-opioids receptors can form dimers, oligomers
-Effects: analgesia, GI inhibit motility, cough suppression, euphoria, respiratory depression, miosis
- Oral absorption : slow and incomplete. Intramuscular : BAC rises slowly,
- Half-life: 2-4 hours, 20% crosses BBB
- A few metabolites are biologically active.
- OH at 3’ is essential of morphine is essential for activity
- Large amount of morphine metabolized to normorphine (neurotoxic)
- Mu receptors present in GI. No tolerance for constipation. Activation of circular muscles more thanlongitudinal and rectal sphincter tone –> increased water absorption
- Morphine stimulates CTZ, Gastric mucosa acts on vomiting centers as well labirinthine apparatus.
- increase antidiuretic hormone.
-Codeine: synergistic with NSAIDS, methyl-morphine, metbaolized into morphine by CYP2D6
Hydromorphone
- opioid drug
- mu receptor agonist, absorbed orally, treat severe pain
Meperidine
Opioid
good analgesic, less depressive side-effects than morphine
Fentanyl
-Opioids Highy lipid soluble level peaks in few minutes very short time of action -can be administered as skin patches, lollipops
combined wiht antipsychotic drug (droperidol) –> neurolept analgesia (minimal disruption of cardiovascular and repiration system
Loperamide
acts only on neurons in the intestine.
-Treats diarrhea and chronic inflammatory bowel conditions.
Methadone
-opioid
Weak agonist
-absorbed orally, blocks withdrawal symptoms.
-used to treat addiction
