Drugs/Pharmacology Flashcards
The Ideal Anesthetic Agent
Goal: unconsciousness, amnesia, analgesia, autonomic reflex inhibition, and skeletal muscle relaxation. Sadly, no single agent can do all of these so we have to use combinations of them together to achieve these affects.
The Four Anesthetic Stages
1.) Analgesia: the first stage of anesthesia in which there is loss of pain sensation but not consciousness or amnesia.2.) Excitement: the second stage of anesthesia in which inhibitory neurons are depressed and neuronal excitability may be evident the form of hypertension, tachypnea, irregular breathing, retching/vomiting, delirium, and/or violent behavior.3.) Surgical Anesthesia: the third stage of anesthesia in which eye movements cease, pupils are fixed, respiration is constant, and skeletal muscles are relaxed (idea state for general anesthetics)4.) Medullary Depression: the final stage of anesthesia in which death may occur if the patient falls to deeply into general anesthetic. The vasomotor and respiratory centers are depressed too much.
Minimal Alveolar Concentration (MAC)
The way in which we measure the immobility of an anesthetic. Defined as the concentration of inhaled anesthetic required to stop movement in 50% of patients given a standardized skin incision. In other words, this is an inverse measure of potency for inhaled anesthetics. Larger value is a less potent anesthetic.
Use of MAC and Blood:Gas Partition Coefficient
MAC is used to compare the potency of drugs (as discussed above) w/ a larger MAC meaning a less potent anesthetic. Solubility of a drug determines out potent the anesthetic will be and the blood:gas partition coefficient is used to measure this. This coefficient defines the likelihood that the drug will be found in the blood or in its gaseous form. The larger the ratio then the more soluble the drug is, but the more soluble the drug is then the longer it will take to induce anesthesia because more drug is bound to plasma proteins and thus can't bind its CNS target.
MAC-Blood:Gas Partition Coefficient relationship
Solubility in the blood, which is measured by the blood:gas partition coefficient, is the physical property of inhalation anesthetics that correlates best w/ its MAC. A high MAC means a drug is not very potent. Likewise, a high blood:gas partition coefficient means that a drug will take a long time to have an effect due to it being bound in the blood. Note that these two properties of anesthetic agents are inverse of each other. A high MAC (low potency) generally has a low blood-gas partition coefficient and vice versa.
Side Effects of General Anesthesia
Respiratory depression and hypotension. Inhaled anesthetics increase cerebral vascular flow and thus ICP. They also reduce blood pressure and may cause malignant hyperthermia.Some more specific side effects include:Etomidate: excitability and myoclonus along w/ adrenocortical suppressionKetamine: increased cerebral blood flow along w/ sympathetic stimulation leading to transient hypertension and increased heart rate.
IV Anesthetics
IV drugs are usually the go to for induction anesthesia (initially putting someone under). Propofol is the most common (Etomidate and Barbiturates are also used). All of these agents are thought to allosterically agonize GABAa receptors which results in chloride ion influx and hyperpolarization. Note that IV agents can be used to maintenance anesthesia as well (Ketamine which works through NMDA antagonism).
Inhaled Anesthetics
Mainly used for maintenance anesthesia. NO and the volatile halogenated gases (halothane, desflurane, isoflurane, enflurane, and sevoflurane) are the main maintenance anesthetics. These are through to work through K+ channels, NMDA channel antagonism, or GABA signaling. Potency of these drugs are measured through MAC, blood:gas partition coefficient, etc.
Ezogabine (a.k.a retigabine)
MOA: opens KCNQ potassium channels. Pharmaco: bioavailability ~60%; peaks in 30 minutes to 2 hours. Moderately binds plasm protein, metabolized in the liver, excreted in the urine, and has a half-life of 7-11 hours. Uses: focal seizureAEs: dizziness, somnolence, confusion, blurred vision.Minimal interactions.
Lacosamide
MOA: Na+ channel blocker. Pharmaco: 100% bioavailability; half-life ~13 hours; peaks in 1-2 hours. Uses: Focal seizuresAEs: dizziness, HA, nausea; small increase in PR interval.
Levetiracetam
MOA: SV2A ligandPharmaco: ~95% bioavailability; half-life 6-12 hours; peaks in 1-2 hours. Uses: Focal seizures, generalized tonic-clonic seizures, myoclonic seizures. AEs: nervousness, dizziness, depression, seizures
Gabapentin
MOA: alpha-2-delta ligand for Ca2+ channels. Pharmaco: bioavailability ~50% (decreases w/ increased dose); peaks in 2-3 hours; half-life is 5-9 hours; excreted in the urine. Uses: focal seizures; neuropathic pain; postherpetic neuralgia; anxiety. AEs: somnolence, dizziness, ataxia
Pregabalin
MOA: alpha-2-delta ligand for Ca2+ channels. Pharmaco: ~90% bioavailability; peaks in 1-2 hours; mostly secreted in urine; half life is 5-7 hours. Uses: focal seizures; neuropathic pain; postherpetic neuralgia; fibromyalgia; anxiety. AEs: somnolence, dizziness, ataxia.
Ethosuximide
MOA: inhibits low-threshold Calcium channels (T-type)Pharmaco: >90% bioavailability; peaks in 3-7 hours; metabolized in the liver; ~20% excreted in urine; half life of 20-60 hours. Uses: absence seizuresAEs: N, HA, dizziness, lethargy.Interactions: valproate, phenobarbital, phenytoin, carbamazepine, rifampicin.
Valproic Acid
MOA: unknownPharmaco: > 90% bioavailability; peaks depend on formulation; bound by plasma protein; metabolized in the liver; half life of 5-16 hours. Uses: generalized tonic-clonic seizures, partial seizures, absence seizures, myoclonic seizures, and migraines prophylaxis. AEs: N, tremor, weight gain, hair loss, teratogenic, hepatotoxic.Interactions: phenobarbital, phenytoin, carbamazepine, lamotrigine, felbamate, rifampicin, ethosuximide, primidone.
Phenobarbital (& Pentobarbital)
MOA: positive allosteric modulator of GABAa receptors; reduces excitatory synaptic responses. Pharmaco: > 90% bioavailability; peaks in 30 minutes to 4 hours; metabolized in the liver; somewhat excreted in the urine; half life of 75-140 hours. Uses: focal seizure, generalized seizure, myoclonic seizure, neonatal seizures, sedationAEs: sedation, cognitive issues, ataxia, hyperactivity. Interactions: valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others.
Vigabatrin
MOA: irreversible inhibitor of GABA transaminasePharmaco: complete absorption w/ peak concentration in 1 hour (half life of 5-8 hours)Uses: focal seizure; infantile spasmsAEs: Drowsiness, dizziness, psychosis, visual field loss.Note: minimal drug interactions.
Tiagabine
MOA: GAT-1 GABA transporter inhibitorPharmaco: nearly complete absorption (~90%). Peak concentration in 30 minutes to 2 hours. Highly bound to plasma proteins. Metabolized by the liver. Half-life of 2-9 hours.Uses: focal seizuresAEs: Nervousness, dizziness, depression, seizures.Interactions: phenobarbital, phenytoin, carbamazepine, primidone.
Clonazepam
MOA: Positive allosteric modulator of GABAa receptors. Pharmaco: bioavailability >80% and it peaks in 1-4 hours. Highly bound to plasma protein. Metabolized by liver. Half-life is 12-56 hours. Uses: Absence seizures, myoclonic seizures, infantile spasms. AEs: sedationInteractions: additive w/ sedative-hypnotics.
Diazepam (and Lorazepam)
MOA: Positive allosteric modulator of GABAa receptors.Pharmaco: Nearly complete oral and rectal absorption (>90%). Highly bound to plasma proteins. Metabolized to active metabolites. Half-life is up to 100 hours. Uses: Status epilepticus, seizure clusters; sedation, anxiety, muscle relaxation, acute alcohol withdrawal. AEs: SedationInteractions: additive w/ sedative-hypnotics.
Phenytoin
MOA: sodium channel blockerPharmaco: absorption is formulation dependent. Highly bound to plasma protein. Dose-dependent elimination. Half life of 12-36 ours. Note: fosphenytoin is for IV/IM routes. Uses: focal seizures, tonic-clonic seizures. AEs: diplopia, ataxia, gingival hyperplasia, hirsutism, neuropathy.Interactions: phenobarbital, carbamazepine, isoniazid, felbamate, oxcarbazepine, topiramate, fluoxetine, fluconazole, digoxin, quinidine, cyclosporine, steroids, oral contraceptives.
Carbamazepine
MOA: Sodium Channel blockerPharmaco: rapidly absorbed orally w/ ~80% bioavailability. Peaks in 4-5 hours. Plasma protein bound. Metabolized in the liver. Half-life is 25-65 hours. Uses: focal and focal-bilateral tonic clonic seizures; trigeminal neuralgiaAEs: Nausea, diplopia, ataxia, hyponatremia, HA. Interactions: phenytoin, valproate, fluoxetine, verapamil, macrolide antibiotics, isoniazid, propoxyphene, danazol, phenobarbital, primidone.
Topiramate
MOA: multiple MOAs. Pharmaco: bioavailability ~80% which peaks in 2-4 hours. Little protein binding. 20-70% excreted in the urine. Half-life of 20-30. Uses: focal seizures, primary generalized seizures, Lennox-Gastaut syndrome; migraine prophylaxis. AEs: somnolence, cognitive slowing, confusion, paresthesias.Interactions: phenytoin, carbamazepine, oral contraceptives, lamotrigine, lithium.
Lamotrigine
MOA: sodium channel blockerPharmaco: nearly complete absorption, peaks in 1-3 hours, moderate plasma protein binding, half life of 8-35 hours. Uses: focal seizures, generalized tonic-clonic seizures, absence seizures, other generalized seizures, bipolar depression. AEs: dizziness, HA, diplopia, rashInteractions: valproate, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, succinimides, sertraline, topiramate.
Zonisamide
MOA: unknownPharmaco: nearly complete absorption, peak concentration in 2-6 hours, modest plasma protein binding, metabolized in the liver, 30% excreted by the urine, half life of 50-70 hours. Uses: focal seizures, generalized tonic-clonic seizures, myoclonic seizures. AEs: drowsiness, cognitive impairment, confusion, skin rashMinimal interactions.
Pharmaco of Local Anesthetics
Extracellular anesthetic exists in equilibrium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane (hydrophobic pathway).
Sensitivity to Local Anesthetic
The sensitivity of a specific nerve fiber to a local anesthetic is dependent on axonal diameter, myelination, and some other factors. When comparing nerves of the same type: larger, faster conducting fibers are less sensitive than slower smaller fibers. When comparing nerves of the same size: myelinated nerves are blocked before myelinated nerves. Therefore, the general order of nerve inhibition by local anesthetic is: Pain> sensory (temp, touch, pressure) > motor.
MOA of Local Anesthetic
Local anesthetics work to block Na+ channels from the cytoplasmic side of the channel, thus the main MOA is to prevent Na+ influx and thus subsequent AP initiation and propagation.
Amide Local Anesthetics
These local anesthetics include Lidocaine, articaine, bupivacaine, prilocaine, mepivacaine, ropivacaine, and levobupivacaine. These local anesthetics undergo biotransformation in the liver and will have a longer duration than esters.Remember all of these local anesthetics have two "i's" in them.
Ester Local Anesthetics
these local anesthetics include benzocaine (topical only), procaine, cocaine, chloroprocaine, and tetracaine. These are metabolized by esterases in the plasma and the liver (this leads to a short duration of effect).
Routes of Local Anesthetic Administration
Topical, Parenteral, Peripheral Nerve block, Epidural, Spinal
Topical Local Anesthetics
Benzocaine, lidocaine, and cocaine are used in this manner. Typically used prior to injection of other anesthetics to reduce injection pain. Prior to eye surgery or endoscopy.
Parenteral Local Anesthetics
Subcutaneous or submucosal injection. Can be done w/ Lidocaine, bupivacaine, procaine, chloroprocaine, mepivacaine, ropivacaine, and cocaine. Note that cocaine also has vasoconstrictive properties so it is only used topically/parenterally when bleeding needs to be controlled. You can add Epi to local anesthetics to induce vasoconstriction. Note that this prolongs duration of action and reduces AEs of systemic administration.
Peripheral Nerve Block
this where local anesthetics are injected close to the nerve trunk near the intended area of anesthesia. Can be used when pain to a limb needs to be blocked for a resetting maneuver. Options for this include lidocaine, mepivacaine, ropivacaine, and bupivacaine.
Epidural
Admin of anesthetic via injection to the epidural space. Common in L&D. Bupivacaine, lidocaine, mepivacaine, prilocaine, and ropivacaine are used here. (Not Chloroprocaine).
Spinal
This occurs when anesthetic is injected into the subarachnoid space in cases of surgical anesthesia for chronic pain. Chloroprocaine is more frequently being used in lower doses as a spinal agent. Other options include procaine, tetracaine, bupivacaine, lidocaine, mepivacaine, and ropivacaine.
Anesthetics Contraindicated for Infiltration
Benzocaine cannot be used for infiltration. It can only be applied topically. It is highly lipophilic and not very soluble, making it impractical to administer in an infiltrative manner (IV injection etc.).
AEs of Local Anesthetics
In general local anesthetics may produce sedation, light headedness, and restlessness when given in high doses. Bupivacaine has some cardiotoxicity issues which limits its use, but IV infusion of lipid (lipid resuscitation) can be effective at reversing this toxicity.Benzocaine is an oxidizing agent that can lead to increased MetHb.Lidocaine is associated w/ transient neurologic syndrome (TNS) which is a syndrome of dysesthesia, burning pain, and aching in the lower extremities.
Restricting Local Anesthetics
Cocaine has good anesthetic effects, but it also has vasoconstrictive properties, so it is only used topically/parenterally when bleeding needs to be controlled. You can add Epi to local anesthetics to induce vasoconstriction. Note that this prolongs duration of action and reduces AEs of systemic administration. By having the blood vessels constrict you are limiting the spread to other areas of the body.
Pharmacodynamics of Opiates
A lot of this depends on which receptor the drug binds to. The receptor options include the Mu receptor (inhibition of respiration, sedation, analgesia, GI transit, euphoria, dependence), Kappa receptor (pupillary constriction, sedation, anesthesia, GI transit), and Delta receptor (feelings and behavior). Opioid receptors are found in both ascending and descending pathways. Mu agonists inhibit calcium channels in primary afferent neurons. Less calcium influx prevents release of glutamate which decreases activation of secondary afferent neurons. Mu agonists also prevent GABA release, resulting in indirect activation of inhibitory pain neurons (prevent the usual release of GABA which inhibits these inhibitory neurons).
Absorption of Opiates
IV, IM, oral, transdermal patches, buccal tablets, rectal suppositories, intrathecal and epidural mechanism of administration have all been used. First pass metabolism varies widely which is why some opiates are stronger than others.
Distribution of Opiates
Pretty standard, dictated by blood flow but may accumulate in skeletal muscle because of the mass or adipose tissue because opioids are highly lipophilic. It first goes to high blood flow organs. They do have the ability to cross the BBB and placenta (fetal withdrawal may be evident).
Excretion of Opiates
Mainly glucoronidated conjugates are eliminated in the urine, some unchanged drug may also appear in the urine.
Metabolism of Codeine, Oxycodone, Hydrocodone
CYP2D6; metabolites are more potent than parent compound. May be combined w/ acetaminophen. Codeine -> morphine -> M3G/M6G; Oxycodone -> oxymorphone -> oxymorphone-3 glucuronide; hydrocodone -> hydromorphone -> hydromorphone-3-glucuronide.
Metabolism of Morphine and Fentanyl
Morphine undergoes a phase II biotransformation producing metabolites M3G and M6G. M3G is not good (causes seizures) M6G is a very potent Mu agonist. Parental morphine is potent and active. Metabolites have limited ability to cross the BBB. Fentanyl has phase I biotransformation. Fentanyl is both potent and active and is metabolized by CYP3A4. Fentanyl has a quick onset but not a long peak duration. Morphine takes longer to peak onset, but lasts much longer.
AEs of Opiates
General note is that the risk of dependence and AEs increase w/ the degree of agonism. AEs are divided into acute and chronic use.· Acute: respiratory depression, N/V, pruritus, urticaria, constipation, urinary retention, delirium, sedation, myoclonus, seizures, hypotension.· Chronic: hypogonadism, immunosuppression, increased feeding, increased growth hormone secretion, withdrawal effects, tolerance, dependence, abuse, addiction, hyperalgesia, impairment while driving, decreased libido, dysmenorrhea.
Drug Interactions w/ Opiates
If you give a strong agonist in the presence of a partial agonist you will get withdrawal symptoms. Another one is sedative-hypnotics which can produce a CNS depression or respiratory depression when given together. Antipsychotics produce increased sedation and respiratory depression when given with opioids. Another drug interaction is w/ MAOIs which can cause hypertension, hyperpyrexic coma, and serotonin syndrome if administered together. Finally, serotonergic medications run the risk of serotonin syndrome.
Contraindications of Opiates
Includes pregnancy, patients w/ impaired pulmonary function, patients w/ impaired hepatic function, patients w/ impaired renal function, and patient's w/ endocrine disease may have prolonged/exaggerated responses.
Tolerance of opiates
Repeated dosing has diminished analgesic effect. Patient may require higher doses to achieve analgesia. Usually takes 2-3 weeks of frequent dosing.
Dependence of Opiates
Failure to administer the drug results in withdrawal. Onset of withdrawal as early as 6-10 hours for morphine and heroin. Peak symptoms at 2 days, symptoms generally gone by 5 days.
Addiction of Opiates
Chronic disease of reward, motivation, memory leads to pathologic pursuit of reward and relief through substance use.
Treating Heroin Addiction
Buprenorphine is used in opiate detox because it has a less severe and shorter duration of withdrawal symptoms compared to methadone (you can get a prescription for suboxone (aka buprenorphine). Methadone has the longest lasting withdrawal symptom, but the symptoms are much less severe than that of heroin (must be administered in the presence of a doctor).
Signs and Symptoms of Heroin Overdose
Opioid overdose presents w/ pupillary constriction, comatose state, and respiratory depression. They are treated w/ naloxone in the pre-hospital setting. In the hospital patients receive respiratory support. Sometimes whole bowel irrigation for heroin body packers is needed. If seizures occur then give benzodiazepines.
Indications for Opioids
· Analgesia: opioids can be used for analgesia peripherally, in the spinal cord, supraspinal levels, and systemically.· Acute Pulmonary Edema (morphine): left ventricular heart valve failure provides relief from dyspnea maybe through reduced anxiety or reducing preload and afterload by reducing venous tone and peripheral resistance respectively.· Cough: Mu receptors hyperpolarize cells in the cough center. This makes it difficult to fire. (Codeine)· Diarrhea: stimulating mu receptors in the GI tract slows movement.· Shivering (meperidine): Demerol· Anesthesia: sedative, anxiolytic, analgesic properties.
Opioid Antagonists
Includes naloxone, naltrexone, and nalmefene. These are competitive inhibitors of Mu receptors. Naltrexone and naloxone (Narcan) are for opioid overdose. Narcan is a reversible competitive inhibitor, so you need to keep administering it until they are done w/ their respiratory depression. There is no dependence w/ antagonists.
Glutamate Synthesis
Note that most of the glutamate we have (~85%) will cycle in the glutamate-glutamine cycle as follows: Glutamate is released from glutaminergic neurons and taken up by astrocytes; astrocytes convert it to glutamine by glutamine synthetase which is released and recycled back to glutaminergic neurons; glutaminase in glutaminergic neurons converts glutamine back to glutamate. While this is the case for the majority of glutamate a small portion (15%) is generated denovo from pyruvate. Pyruvate becomes OAA from pyruvate carboxylase (astrocytes only). OAA + AcCoA = aKG which when acted on by glutamate dehydrogenase becomes glutamate.
Glutamate Degradation
The 15% of glutamate that is generated denovo is to make up for the small amount of it that is oxidized. Note that for the most part the glutamate is just recycled to neurons via a symporter w/ Na+.
Release/Reuptake of Glutamate
Vesicles accumulate glutamate in an Mg+ and ATP dependent process for release. Ca2+ causes vesicles to fuse causing release into the synapse. After release it is taken back up by presynaptic neurons as a means to control synaptic glutamate concentrations. Glutamate is taken up by Na+ dependent transporters (it is coupled to the electrochemical gradients for Na+ to allow glutamate reuptake to occur against its concentration gradient. Clinically it is important to note that ischemia reduces ATP synthesis and thus Ca2+ transport out of the cell is limited. This causes excess release of glutamate and hyperactivation of their receptors.
NMDA Receptors
An Ionotropic Glutamate receptor. Mainly permits Ca2+ entry into the postsynaptic neuron/cell. These receptors are both ligand and voltage gated. At membrane potentials < -50 mV, extracellular Mg+ blocks ion flux through NMDA receptors. Some additional stimulus (i.e. AMPA activity) is required to depolarize the cell to > -50 mV in order for NMDA receptors to be activated. Once open, Ca2+ rushes in and both depolarizes the cell even further and helps stabilize receptors on the postsynaptic surface. These receptors are antagonized by Ketamine and PCP.
AMPA Receptors
An Ionotropic Glutamate Receptor. Mainly permits Na+ entry into the postsynaptic neuron/cell. These receptors are tetramers comprised of a combination of subunits (GluA1-A4); receptors lacking A2 are permeable to Ca2+ (linked to ALS). These receptors respond to small amounts of glutamate to increase the neuron to > -50 mV, at which point NMDA receptors become activated. Ca2+ from NMDA receptor activation increases AMPA receptors (this is the basic mechanism of plasticity).
Metabotropic Glutamate Receptors
Classified as either Presynaptic or Postsynaptic. Presynaptic mGluR: overall these receptors will decrease NT release by a variety of mechanisms including blocking VGCCs or blocking glutamatergic and GABAergic transmission. Due to these functions these are considered inhibitory autoreceptors.Postsynaptic mGluR: these receptors have a wide range of effects. All of them will inhibit L-type Ca2+ channels. Some will inhibit N-Type Ca2+ channels. All of them will close VG K+ channels (which results in slow depolarization and excitation). Note that in some cell types, Ca2+ dependent K+ channels (BK channels) are activated while in others Kir channels are activated.
Glycine Receptor
Glycine is an inhibitory stimulus primarily in the brainstem and spinal cord. Note that only a small fraction is used for neural transmission (since it is an AA after all). It is synthesized from glucose via serine (SHMT) which requires vitamin B6 (pyridoxal phosphate). Glycine receptors are similar to GABAa receptors and contain Cl- channels. Strychnine (convulsant toxin) selectively antagonizes glycine receptors. Other ligands for these receptors include serine, alanine, and taurine.
GABA Synthesis (GABA Shunt)
GABA is synthesized from glucose by a pathway termed the GABA shunt. This shunt is predicated on converting aKG to Glutamate via GABA transaminase (GABA-T). Glutamate is then converted to GABA by Glutamic Acid Decarboxylase (GAD).
GABA Fates
GABA is transported into vesicles by vesicular transporters termed VGAT/VIAAT. In the presence of an action potential this GABA is released into the synaptic cleft. Once in the cleft GABA can bind its receptor, be transported by GAT back to the presynaptic terminal to be repackaged for release, or it can be taken up by glial cells for degradation
GABA Degradation
GABA is degraded by GABA-T which uses aKG from the Krebs cycle to regenerate a molecule of glutamate. The byproduct of the GABA-T reaction is Succinyl Semialdehyde (SSA) which is converted to Succinate via SSADH. Succinate enters the Krebs cycle where aKG is formed.
GABAa Receptor
This is an ionotropic receptor w/ a GABA binding site and a Cl- channel. There are 5 or more subunits which can be arranged in different combinations. These combinations explain why GABA receptors exhibit molecular heterogeneity. Binding results in opening of the channel and hyperpolarization. Many drugs act via this receptor including benzodiazepines. Binding of benzodiazepines both facilitates the opening of chloride channels and increases the receptor affinity for GABA. Flumazenil is an antagonist to the benzodiazepine binding site and reverses their effects. Barbiturates also bind to these receptors. When bound they increase the duration of channel opening.
GABAb receptors
These receptors are metabotropic and as such are GPCRs. They are expressed on both the pre- and postsynaptic membranes. These receptors open K+ channels, decrease Ca2+ conductance, and inhibit adenylyl cyclase. These receptors produce a slower but longer-lasting inhibition compared to their counterpart. Pre-synaptically they prevent the release of GABA. The only drug that works through these receptors is Baclofen which is a muscle relaxant.