Pharmacology 1: Exam 2 Medications

Non-Selective Agonists (α and β)

-Dopamine

-Epinephrine

-Non-Epinephrine

Non-Selective α agonist

-Oxymetazoline

Non-Selective β agonist

Isoproterenol

Selective α1 agonist

-Phenylephrine

Selective α2 agonist

-Clonidine

Selective β1 agonist

-Dobutamine

Selective β2 agonist

-Albuterol

Sympathomimetics (Agonists)

Catecholamines and non-Catecholamines

Sympathomimetics: Catechol Nucleus Substitutions

-Decreased potency

-Increased bioavailability

-Increased CNS permeability

Sympathomimetics: Amine Substitutions

-Increased size

-Increased Beta-AR activity

Sympathomimetics: C-alpha Subatitutions

-Inhibits MAO metabolism leading to an increase in duration of effect

Phenylephrine

-Selective α1 agonist

-α1 AR mostly found in smooth muscle vascular beds

-Causes vasoconstriction

Clonidine

-Selective α2 agonist

-α2 AR mostly on pre-synaptic nerve terminals

-Causes an inhibition of NT release (NE)

Nonselective Beta-Antagonists

-Propranolol

Selective Beta-Antagonists

-Metoprolol

-Atenolol

Nonselective Alpha-Antagonists

-Phenoxybenzamine

-Phentolamine

Selective Alpha 1-Antagonists

-Prazosin

-Tamsulosin

-Doxazosin

Mixed Alpha and Beta Antagonists

-Carvedilol

-Labetalol

Synthesis of Catecholamine NT

Tyrosine -> Dopa -> Dopamine -> Norepinephrine -> Epinephrine

Cocaine

-Blocks the reuptake of NE and DA

-Causes an increase in NE and DA in the synaptic cleft (Increasing the effect of both)

Amphetamines

-Transported into neurons like NT (NE)

-Flood of "NT" in the neurons causes a back flow of NT into the synaptic cleft

-Causes and increase in the amount of NT released and maintained in the synaptic cleft

Levodopa

-Dopamine precursor replacement

-Issues: Insufficient dose reaches CNS, peripheral ADR

Carbidopa

-Inhibits peripheral metabolism of levodopa by blocking AADC

Entacapone

-Inhibits peripheral metabolism of levodopa by blocking COMT

Tolcapone

-Inhibits peripheral metabolism of levodopa by blocking COMT

-Inhibits metabolism of DA by blocking COMT in the brain

Selegiline and Rasagiline

-Inhibits metabolism of DA by blocking MAO-B in the brain

-Selegeline is metabolized into amphetamines and not used very often

Ropinirole and Pramipexole

-Direct receptor agonism in nigrostriatal neurons (Acts like DA)

-Ropinirole can also be used for restless leg syndrome

Benztropine

Muscarinic antagonist

Amantadine

NMDA glutamate antagonist

Istradefylline (Nourianz)

-First in class adenosine 2A antagonist to decrease "off" symptoms

-Benefit to decrease unwanted tremors (Indirect pathway) and facilitate DA replacement therapy effects

"First Generation"/Typical Antipsychotics

-D2 Antagonists

-Chlorpromazine (Low potency)

-Thioridazine (Medium potency)

-Fluphenazine (High potency)

-Haloperidol (FGA, but different structure)

Haloperidol

-Blocks D2 and some D1 dopamine receptors (Antagonist)

-Can bind to 5-HT receptors, histamine receptors, and adrenergic receptors producing adverse effects

-Way fewer side effects compared to other FGA

Ingrezza (Valbenazine) and Austedo (Deutetrabenazine)

-Treatments for Tardive Dyskinesia (Via DA depletion)

-VMAT2 inhibitors

Second Generation Antipsychotics (SGA)/"Atypical"

-Have more binding sites for many different receptors

-"Safer" but not completely without ADR (May increase risk of T2D)

Risperidone (Risperdal)

-Binds to D2 receptors to block DA transmission

-Side effects can arise from binding to 5-HT2 receptors and alpha-adrenergic receptors (Does not bind to histamine receptors)

Aripiprazole (Abilify)

-A partial D2 and 5-HT1A agonist

-Has partial D2 agonism (Increases D2 activity when DA concentrations are low and decreases D2 activity when DA concentrations are high)

-Has functional selectivity at D2 receptors (Does not activate Gby signaling and partially inhibits Ga signaling)

Clozapine (Clozaril)

-Use for treatment resistant schizophrenia

-Discovered in 1959

-No EPS (Atypical antipsychotic)

-Efficacy may be due to multiple receptor binding profile

Lithium

-Used for Bipolar Mania (Type 1 and 2)

-Lithium enters cell through Na+ channels (Many proposed mechanisms)

-Works as a "mood stabilizer"

Reserpine, Amphetamine, Modafinil

Storage inhibitors (for ADHD)

Phenelzine and selegeline

-Metabolism inhibitors (MAOi)

-Phenelzine irreversibly inhibits tyramine mechanism enzymes (Interacts with foods)

Fluoxetine

-Selective serotonin reuptake inhibitor

-Improved safety profile over TCA (More common)

Duloxetine

-Serotonin-norepinephrine reuptake inhibitor

-Combined blockade is dose-dependent

Atomoxetine

-Norepinephrine reuptake inhibitor

-Used for ADHD by blocking NE uptake

Amitriptyline

-Tricyclic antidepressant

-Risk for potential overdose; non-selective (5-HT, NE, mAChR)

Bupropion and Trazodone

-Atypical antidepressants

-Weak NAT and DAT inhibitor (Inhibits reuptake of NA and DA; can be called NDRI)

Phenytoin (Dilantin)

-Introduced in 1938 (Oldest non-sedating anti-seizure medication)

-Use-dependent inhibition of VGSC (Enhances inactivation time)

-Used for tonic-clonic seizures and status epilepticus

-Teratogenic and impairs oral contraceptive efficacy

-Extensively bound to plasma proteins (Potential for drug-drug interactions)

-First order clearance

Ethosuximide (Zarontin)

-Inhibits low-threshold T-type Ca2+ currents in the thalamus

-Used for absence seizure treatment

Pregabalin (Lyrica) and Gabapentin (Neurontin)

-Bind alpha-2-delta subunit of pre-synaptic high threshold Ca2+ channels

BDZ and Barbituates

-Activate GABA-A receptors

Vigabatrin (Sabril)

-Inhibits GABA-T enzyme

Valproate/Valproic Acid (Depakote)

-Inhibits GABA-T

Topiramate (Topamax)

-GABA-A and NMDA receptors

Levetiracetam (Keppra)

-Binds pre-synaptic SV2A protein to enhance inhibitory NT release/prevent excitatory NT release

-Enhance neurologic "sprouting"

Exogabine (Trobalt)

-First in class K+ channel opener

-Enhances duration of KCNQ channel action to resist depolarization

Opioids

-Bind to mu opiate receptors in the nucleus accumbens

-This inhibits the release of GABA which allows uncontrolled DA release (GABA normally blocks the release of GABA)

Morphine

-THE opiate analgesic

-Structure is stereospecific

-Can be administered via IM/IV injection; oral bioavailability is poor

-Metabolized via glucuronidation at the 3-OH or 6-OH; 6-glucuronide morphine is still active

Heroin

-Increased penetration through BBB

-Increased potency; decreased onset of action

-Pro-drug (Converted back to morphine)

Fentanyl (Sublimaze)

-Similar structure to meperidine

-Very short duration (~45 minutes)

-Lipophilic: Readily crosses membranes

-No toxic metabolite

-Administered via transdermal, epidural, or buccal

Codeine

-Prototype for partial agonists (3-methyl-morphine)

-Inactive at opioid receptors (Pro-drug: De-methylated by CYP2D6 to morphine)

-Decreased efficacy vs. morphine

-Advantages: Increased oral bioavailability

Oxycodone and Hydrocodone

-OH/-H-oxymorphone

-Derived from thebaine

-5 to 10 times more potent than codeine

Tramadol

-Weak MOR partial agonist

-5-HT reuptake inhibitor

-NE reuptake inhibitor

-Can cause 5-HT syndrome and SSRI withdrawal

Naloxone and Naltrexone

-Structural differences from morphine: Large N-substitution

-Ability to bind, but not activate opioid receptors

-NLX lasts ~2 hours

-NTX lasts ~10 hours

NSAIDs

-Primary MOA: Inhibition of cyclooxygenase (COX)

-Causes an anti-pyretic, anti-inflammatory, and analgesic effect

Triptans

-5-HT1B/1D agonists

-Present on trigeminal nerves and vascular endothelial cells

-ADR include hyperkalemia, hypertension, and tachycardia

-Have characteristic benzene ring attached to 5 membered ring with NH on a corner

CGRP Antagonists

-Calcitonin Gene Related Peptide

-Rimegepant (Nurtec): CGRP competitive antagonist

-Erenumab (Aimovig): CGRP-directed monoclonal antibody