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Pharmacology MT3
Flashcards for BIOL4404 MT3
| Question | Answer |
|---|---|
| CNS Drugs | Drugs with CNS effects that act on specific receptors that modulate synaptic transmission |
| Neurotransmitters | Chemical messengers that enable neuron to neuron communication and are released from presynaptic terminals |
| Ionotrophic Receptor | Receptor that is directly coupled with ion channels |
| Metabotrophic receptor | Receptor that is coupled to G proteins and 2nd messengers |
| What are the steps of synaptic transmission? | 1) AP to synpatic terminal -> activates Ca channels 2) Ca enters axon, interacts with binding proteins -> vesicles fuse with terminal mem 3) NTs released in synapse & diffuse 4) NTs bind R on postsynaptic mem 5) This opens ion channels & propagates si |
| What happens to neurons during transmission? | Neuron receives signal that causes excitatory post-synaptic potential (EPSP) in cell causing influx of ions; larger signal = bigger influx = cell more + = propagation of AP along axon |
| Excitation | Stimulating excitatory PW generates transient depolarization; Increasing stimulus strength increases size of depolarization so that the threshold for spike generation is reached |
| Inhibition | Flow of ions that keeps cell from becoming + enough to produce AP; Suprathreshold stimulus given shortly after stimulating an inhibitory PW prevents excitatory potential from reaching threshold |
| What are the mechanisms of CNS drug action? | 1) NT synthesis, storage, release (stop signal, decrease amount) 2) NT reuptake and degradation (influence amt in synapse) 3) Receptor activation or blockade (change response) |
| How is neural information organized? | Via hierarchical neuronal systems and diffuse neuronal systems |
| Hierarchical neuronal systems | Includes pathways for sensory perception & motor control; consists of large, myelinated fibers conduct APs quickly over long distances and release glutamate (excitatory NT) and local short circuit axons that release GABA (inhibitory NT) |
| Diffuse neuronal systems | Contain monoamine and peptide transmitters; unmyelinated, very branched for slower transmission; can innervate different regions of CNS and is involved in global functioning (sleep, waking, attention, appetite, emotion, etc.) |
| What are the major CNS Neurotransmitters? | 1) Amino acids, 2) Acetylcholine, 3) Monoamines, 4) Peptides, 5) NO, 6) Endocannabinoids, |
| Amino acids | Type of CNS NT; excitatory and inhibitory |
| Glutamate | Excitatory NT made from glutamine in pre-synaptic terminals and pkgd into vesicles; Released into synaptic cleft by Ca-dependent exocytosis; Acts on post-synaptic receptors on most neurons; Glia takes up & recycles glutamate to glutamine |
| GABA | Inhibitory NT (amino acids)released by interneurons in brain and spinal cord; ionotrophic (GABA-A) and metabotrophic (GABA-B) |
| Glycine | Inhibitory NT (amino acid) released by interneurons in the spinal cord; both ionotrophic and metabotrophic receptors |
| Acetylcholine | CNS NT that functions in different brain systems; CNS responses are mediated by muscarinic (G Protein coupled) and nicotinic (ligand-gated ion channels) receptors |
| Monoamines | CNS NTs such as DA, NA, 5-HT that affect coordinated movement, behaviour, mood, perception, learning, reward, sleep, and pain |
| Dopamine (DA) | Affected by several drugs that act at the 5 DA receptors which are ALL metabotrophic |
| Noradrenaline (NA) | Produced by FEW neurons that innervate MANY regions of the brain and act at A1, A2, and B receptors |
| Serotonin (5-HT) | Produced by FEW neurons that project to MANY regions of the brain and act at 12 diff. receptors (all metabotrophic EXCEPT 5-HT3) |
| Neuropeptides | Produced via translation and processing of preproproteins; can be co-localized and released with other NTs |
| Nitric Oxide | Not Classical NT; produced by enzyme NO synthase which is activated by calcium-calmodulin; role in synaptic transmission = controversial` |
| Endocannabinoids | Drugs and endogenous brain lipids that activate CB1 receptors to affect memory, cognition, and pain perception |
| Blood-Brain Barrier | Physical barrier of the CNS consisting of endothelial cells with tight junctions, astrocytes, and glial cells; prevent entry of many substances into brain except those that are highly lipophilic |
| When would the Blood-Brain Barrier be compromised? | Early in development, after injury, or during infection |
| What are the clinical uses of sedative-hypnotic drugs? | 1) Anxiety, 2) Sleep Disorders, 3) Anesthesia, 4) Management of seizure disorders, 5) Management of withdrawal states in physiologically dependent patients |
| Anxiety | Changes in mood, physiological arousal, and increased perceptual acuity; Associated symptoms include tachycardia, sweating, trembling, palpitations, tension, apprehension, uneasiness |
| What are the subgroups of Sedative-hypnotic drugs? | Benzodiazepines, Barbiturates, and Misc. (buspirone, chloral hydrage, meprobamate, zolpidem, zaleplon) |
| What is the mechanism of action of Benzodiazepines? | Benzodiazepines bind to part of the GABA-A receptor-Cl- ion channel so binding facilitates inhibitory action of GABA and increases how often the Cl- channel is open |
| What is the major isoform of the GABA-Cl- channel? | 2 A1, 2B2, gamma2 subunit |
| What are the adverse reactions to benzodiazepines? | Drowsiness, confusion, ataxia, cognitive impairment, withdrawal symptoms, increased risk for congenital malformations in 1st trimester, cross placental barrier |
| What happens to baby if benzodiazepines are given near term? | Hypoactivity, hypotonia, apnea, feeding problems |
| How do barbiturates act? | Barbiturates bind unique site on GABA-A receptor to increase duration Cl- channel is open and can directly activate the channel at high doses |
| What are the pharmacokinetics of barbiturates? | Well absorbed orally, distributed widely throughout body, metabolized in liver to INACTIVE metabolites excreted in urine |
| Why are benzodiazepines used more than barbiturates? | Safer - they have a higher TI & do not directly activate GABA-Cl channel; Barbiturates have risk to develop tolerance, induce drug metabolizing enzymes, physical dependence, severe withdrawal, risk of coma and respiratory depression in toxic doses |
| What are the pharmacodynamics of barbiturates? | 1) Sedation, 2) Hypnosis, 3) Anticonvulsant actions, 4)Muscle relaxation, 5) Medullary depression |
| What are the interactions of barbiturates with other drugs? | Barbiturates can reduce effect of 1) amphetamines, 2) birth control, 3) anti-epileptics, 4) TCAs and can enhance action of 1) alcohol, 2) CNS depressants, 3) opioid analgesics (dangerous in combos) |
| How does Zolpidem act? | Sedative-hypnotic drug that binds A1 GABA subunit to induce and maintain sleep |
| How does Zaleplon act? | Sedative-hypnotic drug that binds A1 GABA subunit to induce and maintain sleep |
| How does Buspirone act? | Anxiolytic that is a partial agonist of 5-HT1A receptor and also binds D2 receptors thus decreasing anxiety WITHOUT sedation; may take week or more of treatment before decrease in anxiety |
| What is the toxicity of sedative-hypnotic drugs (benzodiazepines, barbiturates, zolpidem, zaleplon, buspirone, etc)? | Lead to psychomotor dysfunction, additive CNS depression, overdose, tolerance & dependence |
| How do seizures occur? | Seizures are caused by synchronous neuronal firing within a seizure focus |
| What are seizures? | Period when brain is malfunctioning |
| What triggers seizures? | Head trauma, stroke, fever, alcohol and other sedative withdrawal |
| Partial seizure | Seizure localized in one area of the brain |
| Generalized tonic-clonic seizure | Seizure spread throughout the brain where body is rigid and jerky and may go into coma |
| Generalized absence seizure | Seizure with 3 Hz or 3wave/s EKG where patient is briefly unconscious but does not have bodily seizure; caused by repetitive loop through thalamus |
| How do antiepileptic drugs act? | Antiepileptic drugs either suppress formation or suppress spread of abnormal electrical discharge in the brain by decreasing activity of glutamate or increasing activity of GABA |
| Voltage-gated Sodium Channels | Sodium channels that rapidly open when neuronal membrane potential reaches threshold; causes rapid depolarization, conduction of action potential along axon and NT release; inactivated by closure of inactivation gate |
| Sodium Channel Blockers | Drugs that block sodium channels by binding the inactivated state to increase refractory period and prolong period of abnormal repetitive firing |
| What antiepileptic drugs are sodium channel blockers? | Phenytoin, Carbamazepine, and Valproic acid are sodium channel blockers |
| When are phenytoin, carbamazepine, and valproic acid used? | In all types EXCEPT absence seizures; given for chronic periods to prevent seizure |
| How does phenytoin work? | Decreases high frequency neuronal firing by binding inactivated sodium channels, effecting calcium channels, inhibiting NT release, decreasing glutamate & increasing GABA (BLOCKS ABNORMAL ACTIVITY ALONG AXON) |
| What are the side effects of phenytoin? | Gingival hyperplasia, acne, hirsutism, nystagmus, diploid, ataxia, vertigo |
| How does carbamazepine work? | Like phenytoin, reduces high frequency neuronal firing; closely related to TCAs |
| Which sodium channel blocker is the most commonly used? | Carbamazepine |
| How do you treat absence seizures? | Block T-type (LVA) Calcium channels in thalamic neurons to block rhythmic cortical discharge |
| Which antiepileptics are calcium channel blockers | Ethosuximide and valproic acid are calcium channel blockers |
| How does valproic acid work? | Blocks both sodium and calcium channels, inhibits metabolism of some substrates metabolized by CYP3A4 |
| What are the side effects of valproic acid? | Liver toxicity, pancreatitis, possible drug interactions |
| How do benzodiazepines and barbiturates (sedative-hypnotic drugs) treat seizures? | They enhance GABA activation of GABA-Cl- channel to treat statis epilepticus (uncontrollable seizures) - make inside of neuron more negative by letting Cl- in so neuron cannot fire (counteracts glutamate's depolarizing effect_ |
| How does phenobarbital treat seizures? | Phenobarbital acts at GABA-A receptors producing many effects such as blocking postsynaptic AMPA receptors; NOT used for absence seizures |
| What are the side effects of phenobarbital? | Sedation, drug interactions because induces P450 enzymes |
| How does Vigabatrin treat seizures? | Vigabatrin inhibits GABA transaminase to stop it from terminating action of GABA to increase GABA levels (counteracts glutamate) |
| How does Gabapentin treat seizures? | Gabapentin blocks GABA transporters to increase GABA in synapse |
| What are examples of adjunct drugs given in addition to antiepileptics? | Vigabatrin and Gabapentin are adjunct drugs |
| What treats tonic-clonic seizures? | Tonic-clonic seizures are treated by Carbamazepine, Phenytoin, Valproic acid, Phenobarbital |
| What treats absence seizures? | Absence seizures are treated by Ethosuximide, Valproic acid, Clonazepam |
| What are the effects of Phenytoin on microsomal enzymes? | Phenytoin induces some and inhibits other microsomal enzymes |
| What are the effects of Carbamazepine and phenobarbital on microsomal enzymes? | Carbamazepine and Phenobarbital induce microsomal enzymes |
| What are the effects of Valproic acid on microsomal enzymes? | Valproic acid inhibits microsomal enzymes |
| What are the teratogenic effects of Valproic acid? | Valproic acid is associated with neural tube deficits |
| What are the teratogenic effects of Carbamazepine? | Carbamazepine is associated with camiofacial anomalies and spina bifida |
| What are the teratogenic effects of Phenytoin? | Phenytoin is associated with fetal hydantoin syndrome |
| Affective Disorders | Group of mental conditions that includes depression and manic-depression |
| Major Depressive Disorder | Lowering of mood for 2 or more weeks and/or anhedonia; sleep and eating disturbances, feelings of worthlessness are common |
| What is the monoamine hypothesis of MDD? | Altered levels of NA, 5-HT, DA (the monoamines) cause depression |
| What is the Neurotrophic hypothesis of MDD? | Lack of dendrites in depressed cause delay in response due to synaptic remodeling and cause depression |
| What is the Neuroendocrine hypothesis of MDD? | Imbalanced hormone secretions cause depression |
| What are the groups of antidepressants? | 1)MAOIs, 2) Amine Reuptake Binding Drugs (Nonselective - TCAs, SNRIs; Selective - SSRIs), 3) A2 antagonists, 4)5-HT2 antagonists |
| Monoamine oxidase (MAO) | Enzyme in neural and other tissues that inactivates EXCESS NTs in the nerve ending |
| How do MAOIs work? | MAOIs irriversibly or reversibly inactivate MAO to increase vesicular stores of NA, DA, 5-HT in presynaptic nerve terminals so more is released when triggered |
| If you are using irreversible MAOIs, why must you wait before stopping the MAOI and starting another antidepressant? | If the MAOI is irreversible, you must allow time to regenerate MAO enzyme |
| What is the problem with MAOIS? | MAOIs inhibit MAO in brain AND periphery; Increase NA via tyramine from fermented foods can cause Hypertensive Crisis; avoiding oral route of administration can limit this problem |
| How long do you have to wait before starting to take MAOIs and alleviation of depression symptoms? | Several week delay between start of MAOI therapy and alleviations of symptoms of depression |
| Iproniazid | 1952 drug for tuberculosis that had positive effects on depressed because it slowed breakdown of monoamines (DA, NA, 5-HT) = basis for Monoamine hypothesis of MDD |
| What are the adverse effects of MAOIs? | CNS stimulation (agitation,convulsion), Risk of serotonin syndrome |
| How do TCAs and SNRIs work? | TCAs and SNRIs inhibit reuptake of NA and 5-HT to increase concentrations in synapse |
| What are the adverse effects of TCAs? | 1) Excessive sedation, 2)Antimuscarinic effects, 3) Sympathomimetic effects, 4) Orthostatic hypertension, 5)Tremor, 6) Weight gain |
| SSRI | Selective Serotonin Reuptake Inhibitor - group of heterogeneous 2nd generation antidepressants |
| How do SSRIs work? | SSRIs specifically block 5-HT reuptake to increase concentration in synapse |
| What do SSRIs treat? | SSRIs treat MDD, eating disorders, anxiety disorders, OCD |
| What are the adverse effects of SSRIs? | 1)Nausea, 2)Headache, 3)Anxiety, 4)Agitation, 5)Insomnia, 6) Sexual Dysfunction (Fewer anticholinergic effects & effects at different receptors than TCAs because of higher specificity) |
| How does Mirtazepine (antidepressant) work? | Mirtazepine blocks presynaptic A2 receptors, increases release of NA and 5-HT, blocks postsynaptic 5-HT2 receptors, and blocks histamine receptors; has antidepressant and antianxiety properties |
| How do Nefazadone and Trazodone (antidepressants) work? | Nefazadone and Trazodone are 5-HT2 antagonists with antianxiety, antipsychotic and antidepressant effects; rapid onset |
| How does Bupropion (antidepressant) work? | Bupropion weakly inhibits reuptake of DA, 5-HT and NA with few side effects; developed as adjunct for those quitting smoking |
| Why is there a 2 or more week delay before effects of antidepressants are seen? | In ST -ADs block reuptake -> increases NTs but triggers A2 R causing - feedback. If NT lvls stay high, A2 R downregulated & firing increases; Postsynaptic R are downregulated -> cell changes -> >> Neurotrophic factors -> Remodeling -> alleviates symptoms |
| Schizophrenia | Psychotic disorder that develops late in adolescence and is characterized by brief psychotic episodes and positive and negative symptoms |
| Examples of positive symptoms of Schizophrenia | 1)Visual & auditory hallucinations, 2)Delusions, 3)Disorganized thinking, speech, 4)Memory disorders, 5)Agitation |
| Examples of negative symptoms of Schizophrenia | 1)Social isolation, 2)Apathy, 3)Blunted emotions, 4)Personal neglect, 5)Poor attention span, 6)Lack of motivation, 7)Poverty of speech |
| Mesolimbic Pathway | Cell bodies in tegmentum project to limbic areas (nucleus accumbens); Increasing DA output here causes + symptoms of Schizophrenia |
| Mesocortical Pathway | Cell bodies in tegmentum project to prefrontal cortex; Decreased activity here causes - symptoms of Schizophrenia |
| Nigostriatal Pathway | Cell bodies in substantia nigra project to striatum; Blocking DA here causes abnormal movement; Often the site where antipsychotics produce adverse effects |
| Tuberoinfundibular Pathway | Cell bodies in hypothalamus project to the pituitary inhibiting PRL release; Blocking DA R here causes hormonal imbalances and increases serum PRL levels |
| What causes + symptoms of Schizophrenia? | Excessive neuronal activity in the mesolimbic pathway may cause + symptoms of Schizophrenia |
| What causes - symptoms of Schizophrenia? | Insufficient activity in mesocortical pathway may cause - symptoms of Schizophrenia |
| What type of drugs are antipsychotics for treatment of Schizophrenia? | All antipsychotics to treat Schizophrenia are Dopamine D2 receptor antagonists |
| D1-like Dopamine Receptors | D1, D5 |
| D2-like Dopamine Receptors | D2, D3, D4; antipsychotics act here |
| How do Typical Antipsychotics treat Schizophrenia? | Block D2 receptors in mesolimbic pathway to decrease positive symptoms but also block D2 receptors in nigrostriatal pathway causing extrapyramidal side effects |
| How do Atypical Antipsychotics treat Schizophrenia? | Block 5-HT2 receptors more often than D2 receptors to increase DA release in mesocortical pathway to decrease - symptoms while decreasing DA in mesolimbic pathway by binding D2 receptors to decrease + symptoms |
| What causes therapeutic effects of antipsychotics? | Therapeutic effects are due to blocking DA and 5-HT receptors |
| What causes adverse effects of antipsychotics? | Adverse effects occur because of blocking DA and other receptors |
| What are the SHORT TERM adverse effects of Typical Antipsychotics? | In ST - 1)Akathisia, 2)Pseudoparkinsonism, 3)Dystonia |
| How do you treat SHORT TERM adverse effects of Typical Antipsychotics? | Treat ST adverse effects of Typical antipsychotics by 1)Decreasing dose, 2)Switching to atypical antipsychotic, 3) Antimuscarinic drug for Pseudoparkinsonism |
| What are the LONG TERM adverse effects of Typical Antipsychotics? | In LT - Tardive Dyskinesia |
| How do you prevent Tardive dyskinesia when taking typical antipsychotics? | Give lowest possible dose for shortest time; Eliminate drugs with anticholinergic effects (antimuscarinics, TCAs, etc.) |
| What are the adverse effects of Atypical antipsychotics? | 1)Increase serum PRL levels in M and F, 2)Sedation, 3)Autonomic Side effects (cardiac, respiratory, GI, urinary effects), 4)Weight gain (20-25 KG!!), 5)Arrythmia, 6)Agranulocytosis |
| Tardive Dyskinesia | Long-term side effect of typical antipsychotics; Late occurring syndrome of permanent abnormal movement of the face and mouth that might be caused by cholinergic deficiency and DA receptor sensitization |
| Parkinson's Disease | Progressive disease characterized by resting tremor, rigidity, akinesia, bradykinesis due to loss of function in basal ganglia caused by degeneration of dopaminergic neurons in substantia nigra causing decreased DA in striatum |
| Akinesia | Difficulty initiating movement seen in Parkinson's disease |
| Bradykinesis | Slowing in execution of movement seen in Parkinson's disease |
| Akathisia | Inability to sit still; ST side effect of Typical antipsychotics |
| Dystonia | Freezing in abnormal postures; ST side effect of typical antipsychotics |
| How is Parkinson's Disease treated? | 1)Drugs that increase DA levels in surviving DA neurons, 2)DA receptor agonists, 3)ACh receptor antagonists |
| How is Levodopa (L-dopa) converted to dopamine? | Tyrosine from food is transported to brain across BBB and converted to L-dopa via tyrosine hydroxylase; L-dopa is taken up by dopaminergic neurons in substantia nigra and converted to DA by L-aminoacid decarboxylase (LADD) |
| Tyrosine hydroxylase | Enzyme that converts tyrosine to L-dopa and is rate-limited |
| L-amino acid decarboxylase (LAAD) | Enzyme that converts L-dopa to DA in the dopaminergic neurons of the substantia nigra |
| Levodopa | L-dopa; biosynthetic precursor of DA and drug that increases DA levels |
| How is L-dopa used pharmacologically? | L-dopa is taken orally and enters peripheral circulation -> some transported by pump through BBB -> taken up by substantia nigra which contains enzyme to convert it to DA -> DA released into striatum |
| What is the problem with using L-dopa as a means to increase DA levels? | L-dopa has a large first pass effect before it reaches the brain due to metabolism in peripheral tissues by LAAD (to DA) and COMT (to 3-O-methyldopa) |
| What are the adverse effects of L-dopa? | 1)Nausea, 2)Orthostatic hypertension, 3)Arrhythmia; Occur because of increase in DA and NA in peripheral tissues; These limit effectiveness of L-dopa because they occur in periphery before L-dopa can get to the brain |
| Carbidopa | Analog of L-dopa given WITH L-dopa |
| How does Carbidopa work? | Carbidopa inhibits coversion of L-dopa to DA by LAAD in PERIPHERAL TISSUES without interfering with conversion of L-dopa to DA in brain (can't cross BBB because highly ionized) |
| How do Tolcapone and Entacapone (Parkinson's disease drugs) work? | Tolcapone and Entacapone block COMT to increase bioavailability and half-life of L-dopa by decreasing conversion to 3-O-MD |
| What is the major difference between Tolcapone and Entacapone? | Tolcapone CAN cross BBB; Entacapone CANNOT cross BBB |
| What are the adverse effects of L-dopa? | LT use can cause involuntary movement or dyskinesia |
| What are the drug interactions with L-dopa? | 1)MAOIs slow metabolism of DA and NA and can cause hypertensive crisis if also taking L-dopa, 2)Antipsychotics block DA receptors and exacerbate motor dysfunction |
| How do Dopamine Receptor Agonists treat Parkinson's Disease? | Directly activate DA receptors |
| What are the advantages of using a Dopamine Receptor Agonist? | 1)Don't need functional dopaminergic neurons, 2)Can be used at different stages and in combo with L-dopa, 3)Activate specific DA receptor may limit adverse effects of L-dopa |
| What are the side effects of DA receptor agonists? | 1)Nausea, 2)Vomiting due to stimulation of DA receptors in vomiting center of medulla |
| What are the dose related CNS effects of a DA receptor agonist? | 1)Confusion, 2)Dyskinesia, 3)Sedation, 4)Vivid dreams, 5)Hallucinations |
| Selegiline | Drug for Parkinson's Disease that inhibits MAO-B which breaks down DA and inhibits oxidation of DA to dihydroxyphenylactic acid (DOPAC) to increase DA and supposedly decrease free radicals |
| How do acetylcholine receptor antagonists treat Parkinson's Disease? | ACh Receptor Antagonists block ACh receptors to correct imbalance of ACh caused by decrease in DA neurons |
| What are the adverse effects of Antimuscarinic drugs (i.e. ACh Receptor Antagonists)? | 1)In CNS - block ACh and cause drowsiness, inattention, confusion, delusions, hallucinations, 2)In periphery - resembles atropine and causes dry mouth, mydriasis, urinary retention, arrhythmia |
| Ethanol | Sedative-hypnotic drug with dose response |
| What are the pharmacokinetics of Ethanol? | Ethanol is 1)Rapidly and completely absorbed (delayed by food), 2)Distributed to most tissues, 3)Reach peak levels within 30mins |
| How is ethanol metabolized at LOW TO MODERATE doses? | At low to moderate doses, alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) using NAD+. Acetaldehyde is metabolized by aldehyde dehydrogenase to acetate which is also metabolized |
| Alcohol Dehydrogenase (ADH) | Enzyme in cytosol of cells in liver and gut that metabolizes low-moderate doses of alcohol to acetaldehyde when NAD+ is available |
| NADH | Reduced product of NAD+ that builds up in liver and is generated by alcohol oxidation; Contributes to 1)Metabolic disorders in chronic alcoholics, 2)Increased lactic acid and hypoglycemia in acute Alcohol poisoning |
| What happens when NAD+ is limited? | When NAD+ is limited, alcohol metabolism has zero-order kinetics where there is a linear relationship |
| How is alcohol metabolized at moderate-high doses? | At moderate-high doses, microsomal enzyme oxidizing systems (MEOS) oxidize ethanol to acetaldehyde using NADPH and O2 and can do so even when ADH system is saturated because of limited NAD+ |
| What happens with MEOS in chronic alcoholics? | In chronic alcoholics, the MEOS is always induced causing 1)Escalation of dose (increased alcohol metabolism), 2)Increased metabolism of other drugs affected by MEOS, 3)Increased toxic metabolites |
| What influences blood levels of alcohol? | 1)Body size and build, 2)Gender, 3)Liver metabolism and function, 4)Food consumption |
| Blood Alcohol Concentration (BAC) | Legal limit = <80mg/dL; has linear relationship with clinical effects |
| Standard drink | 3/4 can beer = 100mL 12% wine = 30mL 40% spirits |
| Why does ethanol have negative effects on the body? | Ethanol is a low potency drug consumed in large quantities so there are direct effects and metabolic consequences |
| How is alcoholism treated? | 1)Withdrawal symptoms must be managed - can substitute alcohol with long-acting sedative hypnotic drugs, 2)Behavioral modification, 3)Drug treatment with dilsulfiram, naltrexone, acamprosate, and others |
| What drugs treat alcoholism? | Dilsulfiram, Naltrexone, Acamprosate, and antiepileptics can be used to treat alcoholism |
| How does Dilsulfiram treat alcoholism? | Dilsulfiram blocks ADH to increase acetaldehyde to cause those who continue drinking to have extreme discomfort |
| How is methanol metabolized? | Via ADH but produces formaldehyde which is further broken down into formate and CO2 which causes blindness in a few hours when these compounds build up in body |
| How is ethylene glycol metabolized? | Via ADH but is metabolized into oxalate |
| How is methanol and ethylene glycol poisoning treated? | Ethanol and fomepizole treat methanol and ethylene glycol poisoning |
| How does ethanol treat methanol & ethylene glycol poisoning? | Ethanol has higher affinity for ADH and competes to block breakdown of ethylene glycol and methanol which can both be removed via dialysis |
| How does Fomepizole treat methanol and ethylene glycol poisoning? | Fomepizole blocks ADH to stop methanol and ethylene glycol breakdown |
| Selective Toxicity | Drug that kills what is attacking you but not own cells; toxic drug can be used as long as they are more toxic to target than normal tissues |
| Antibiotics | Agents produced by 1 organism that have toxic or inhibitory effect on another organism or cell; Kill bacteria, fungi, and cancer cells |
| Therapeutic Index | Measure of how effective drug will be at killing target and NOT being toxic; Large TI and wide therapeutic window = safer drug |
| What are the adverse effects of antibiotics? | 1)Allergic reactions at high doses, 2)Disturbances of normal microbial flora |
| Antimicrobials | Agents that kill microbes; Antibacterial + Antifungal agents |
| Antiinfectives | Antimicrobials + Antivirals |
| Bactericidal Antibiotics | Drug that causes death of bacteria by permanently disfiguring and inactivating proteins; Required in immunocompromised patients |
| Bacteriostatic Antibiotics | Drugs that inhibit growth of bacteria by temporarily inactivating and disconfiguring proteins to give time for immune cells to recruit and kill the bacteria; Growth resumes when removed; NOT given to immunocompromised - success depends on immune response |
| What features of the bacterial cell wall can we attack? | We can attack: 1)Completely unique structures, 2)Pathways absent in mammalian cells, 3)Structures that differ between us and bacteria, 4)Enzymes that differ between us and bacteria, 5)Unique cellular constituents, 6)Enriched cellular constituents |
| How do we kill bacteria by attacking cell wall? | Interfere with ability to construct cell wall so bacteria has no support |
| Gram Positive Bacterial Cell Wall | Contains 1)beta lactamase enzymes, 2)peptidoglycan strands, 3)Penicillin-binding proteins |
| Gram Negative Bacterial Cell Wall | Contains 1)Outer membrane with lipopolysaccharides, 2)Beta lactamase enzymes, 3)Porins, 4)Penicillin-binding proteins, 5)Peptidoglycan |
| Peptidoglycan | Fibrous scaffold in bacterial cell wall; cross-linked network of polysaccharides and polypeptides (catalyzed by PBPs) |
| Penicillin-Binding Proteins | Enzyme in bacteria that helps make scaffold (peptidoglycan) |
| Beta lactamase | Enzyme in bacteria that causes resistance to antibiotics; can kill antibiotics |
| Porins | Protein pores in Gram negative bacteria that pierce the membrane |
| Transpeptidation Inhibitors (aka Beta lactamase drugs) | 1)Penicillins, 2)Cephalosporins, 3)Carbapenems |
| Agents that attack the bacterial cell wall | 1)Penicillins, 2)Cephalosporins, 3)Carbapenems, 4)Vancomycin, 5)Bacitracin |
| Penicillins | Penicillin V and Amoxicillin |
| How does Penicillin disrupt the bacterial cell wall? | 1)Crosses cell wall into bacterium, 2)Binds to penicillin-binding protein, 3)Stops PBP enzyme, 4)Peptidoglycan is not made, 5)Cell loses rigidity without its scaffolding, 6)Fluid inside exerts outward pressure, 7)Bacterium bursts (lysis!) |
| What are the potential problems with attacking bacterial cell walls? | 1)Getting across outer lipid membrane in Gram negative bacteria (overcome via porins), 2)Interference by beta lactamases which creates resistance if drug has a beta lactam group in structure |
| Penicillin V | Penicillin with narrow spectrum; mostly for Gram Positive bacteria; doesn't breakdown in acid like Penicillin G |
| Amoxicillin | Penicillin with extended spectrum, is better absorbed, and has longer half-life |
| How do we get past beta lactamases? | 1) Use beta lactamase-resistant antibiotics, or 2)Combine antibiotic with a beta lactamase inhibitor |
| Beta lactamase inhibitors | Drugs with similar structure to beta lactam drug and competes with antibiotics to fool beta lactamase enzymes so that the antibiotic can sneak past and do its job |
| Cephalosporin | Penicillin-like drug with more side chains than Penicillin so it is more resistant to beta lactamase, better activity against Gram negative bacteria, and better ability to cross into tissue spaces |
| Carbapenem | Penicillin-like antibiotic with altered spectrum and is resistant to beta lactamase |
| Vancomycin | Antibiotic that binds to alanines in growing peptide chains in cell wall and prevents ability of peptides to cross-link |
| Bacitracin | Phosphorylase inhibitor - works inside the cell to block cell wall synthesis |
| Protein Synthesis Inhibitors | 1)Chloramphenicol, 2)Macrolides (Erythromycin), 3)Aminoglycosides (Gentamicin), 4)Tetracyclines |
| Chloramphenicol | Broad spectrum bacteriostatic active against many bacteria that inhibits protein synthesis |
| What are the problems with chloramphenicol? | 1)Bone marrow disturbances, 2)Common interactions with other drugs, 3)Gray baby syndrome |
| Macrolides | Bacteriostatic that inhibits protein synthesis best in Gram positive bacteria |
| Erythromycin | Macrolide bacteriostatic that inhibits protein synthesis well in Gram positive bacteria, is useful in penicillin-resistant infections, and absorption is reduced by food |
| Clarithromycin | Macrolide bacteriostatic with improved acid stability and oral absoprtion that is most active against Gram positive anaerobes |
| Azithromycin | Macrolide bacteriostatic with longer half-life, less likelihood for drug interactions, excellent tissue penetration and slow release from tissues that is best against Gram NEGATIVE anaerobes and spirochetes |
| Aminoglycosides | Antibiotic that inhibits protein synthesis in Gram negative enteric bacteria but is poorly absorbed orally and ALL are ototoxic and nephrotoxic |
| How do aminoglycodises inhibit bacterial protein synthesis? | Aminoglycosides can cause 1)Block formation of initiation complex, 2)Miscoding in polypeptide chain, 3)Block of translocation |
| Tetracyclines | Broad spectrum bacteriostatic against bacteria, mycoplasma, and some protozoa that differ in their pharmacokinetics |
| What are the pharmacokinetics of tetracyclines? | Tetracycline absorption is affected by milk and antacids, accumulates in developing bone and teeth, shouldn't be used in second 1/2 of pregnancy or in young children |
| What are the adverse effects of tetracyclines? | Gastrointestinal irritation |
| If macrolides, tetracylines, and aminoglycosides ALL block protein synthesis in bacteria, why are they different in use? | 1)They differ chemically so they differ in stability and absorption, 2)They interfere at different sites on the bacterial ribosome so they have different therapeutic actions |
| Dihydropteroate syntahse (DHPS) | Enzyme in the folic acid synthesis pathway that converts para-aminobenzoic acid (PABA) to folic acid |
| Dihydrofolate reductase (DHFR) | Enzyme in the folic acid synthesis pathway that reduces folate to tetrahydrofolic acid (THF) |
| Sulfonamides | Antibiotics that target the DHPS step (PABA to folate) of the folic acid synthesis pathway by competing with PABA because of its similar structure |
| Trimethoprim | Antibiotic that targets the DHFR step (folate to THF) of folic acid synthesis in bacteria |
| Sulfonamides + Trimethoprim | Synergistic Bactericidal |
| DNA gyrase | Protein that temporarily cuts DNA strands to untangle them for transcription and replication; aka Topoisomease enzymes |
| DNA gyrase inhibitors | Type of antibiotic that stops DNA gyrase from cleaving DNA for replication & transcription and causes replication arrest |
| Fluoroquinolone | DNA Gyrase inhibitor that blocks enzyme to prevent DNA transcription and replication; Overuse has led to widespread resistance esp. in respiratory pathogens |
| Polymyxins | Antibiotic with detergent-like properties that binds to phosphatidlethanolamine (PE) to disrupt bacterial cell membrane |
| What are the advantages of using Polymyxins? | Resistance rarely develops, allergy is rare |
| What are the disadvantages of using Polymyxins? | Human cells contain PE too, so polymyxins are toxic if given systemically; as such, use is restricted to Polymyxin B, used topically |
| Drugs that attack bacterial cell wall | 1)Penicillins, 2)Cephalosporins, 3)Vancomycin, 4)Bacitracin |
| Drugs that block bacterial protein synthesis | 1)Macrolides, 2)Tetracyclines, 3)Aminoglycosides |
| Drugs that interfere with DNA processes | 1)Fluoroquinolones, 2)Sulfonamides, 3)Trimethoprim |
| What are the advantages of using antimicrobials in combination? | 1)Wider spectrum for mixed infections, 2)Reduced dose for individual agents, 3)Synergism between antibiotics |
| What are the disadvantages of using antimicrobials in combination? | 1)Increased possibility of adverse reactions, 2)Antagonism between antibiotics, 3)Greater risk of antibiotic resistance |
| Synergism | Combines 2 poorly effective drugs that together produce better response than either alone |
| What are examples of synergistic combinations? | 1)Cell wall synthesis inhibitors + aminoglycosides, 2)B-lactam drugs + B-lactam inhibitors, 3)B-lactams that act on different PBPs, 4)Sulfonamides + Trimethoprim |
| What is an example of antagonistic combination? | Chloramphenicol + aminoglycosides |
| Septra (bactericidal) | Sulfamethoxazole (Bacteriostatic) + Trimethoprim (Bacteriostatic); does not need immune system to kick in |
| Antibiotic resistance | Occurs because bacteria are agile and an adapt to survive a toxin such as an antibiotic |
| What are the mechanisms of antibiotic resistance? | Bacteria adapt via 1)Reduced entry of antibiotic into bacteria, 2)Increased amount of target protein, 3)Lower binding of drug to an altered target protein, 4)Enzymatic breakdown of the drug |
| Sulfonamide resistance | May be due to 1)Decreased permeability of cell membrane, 2)Bacteria produce form of DHPS that binds sulfonamide poorly, 3)Increased production of PABA by bacteria |
| Trimethoprim resistance | May be due to 1)Decreased permeability of cell membrane, 2)Bacteria produce form of DHFR that binds trimethoprim poorly, 3)Bacteria produce MORE DHFR |
| Double antibiotic resistance | Way to eradicate resistant strain infections by coupling 2 antibiotics so that when 1 is inhibited by the resistant bacteria, the other antibiotic is released |
| Candidiasis | Most common type of oral fungal infection |
| Ergosterol | Lipid in fungal cell membrane that is equivalent to cholesterol in our membranes and is targeted by antifungals |
| How do antifungals work? | Target ergosterol and bind to form pores and leak out cell contents or inhibit enzymes that make ergosterol |
| Amphotericin B | Polyene macrolide antibiotic that is lipophilic on 1 side and hydrophobic on the other; aggregates, binds ergosterol and forms pores in lipid membranes; nephrotoxic |
| Fluconazole | Azole antifungal that inhibits fungal cytochrome P450 enzymes so ergosterol is not made |
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