Med-Chem/Pharmacology: Autonomic Nervous System (Lecture 4)

ADME properties of Beta-blockers:

-Nadolol as the only renally eliminated beta-blocker -Esmolol has short half-life so it can be used perioperatively

1) Tolterodine is converted to active metabolite (5-hydroxy tolterodine) by? A. CYP2D6 B. CYP3A4 C. Both CYP2D6 & CYP3A4 2) The active metabolite (5-hydroxy tolterodine) is further converted into inactive metabolites by? A. CYP2D6 B. CYP3A4 C. Both CYP2D6 & CYP3A4

1) A 2) C

Question from class: Know the structure of atropine compared to benztropine? Group 1: R1= Phenyl R2= Hydroxyl R3 = OH Ester Group 2: R1= Phenyl R2= Phenyl R3 = H Ether *Word bank: atropine, benztropine*

1) Atropine 2) Benztropine - lack of hydroxyl group on the R3 position means no hydrogen bonding

Solifenacin/Vesicare is metabolized by? A. CYP2D6 B. CYP3A4 C. Both CYP2D6 & CYP3A4 Darifenacin/Enablex is metabolized by? A. CYP2D6 B. CYP3A4 C. Both CYP2D6 & CYP3A4

1) B 2) C

Match the following definitions and terms: 1) Act as agonists at adrenergic receptors 2) Don't bind to the receptor, displace NE & trigger release of NE (increase) from postganglionic neurons 3) Act as agonist at adrenergic receptors and don't bind to the receptor thus displace NE and trigger release of NE (increase) from postganglionic neurons

1) Direct sympathomimetics - mimic ACh & NE 2) Indirect sympathomimetics - increase the levels of NE within the synapse at the target organ 3) Mixed sympathomimetics

Match the following descriptions with the appropriate drug: 1) -Greater affinity for alpha-1 receptors -Useful as a decongestant -Also a CNS stimulant 2) -Greater affinity for Beta-2 receptors -Useful for bronchodilation (asthma) -Also a CNS stimulant *Word bank: Pseudoephedrine, Ephedrine*

1) Pseudoephedrine 2) Ephedrine

Parasympathetic is to ___1___ as Sympathetic is to____2____.

1. Acetylcholine 2. Norepinephrine

For ____1____, the separation between nitrogen and oxygen has to be with 2 carbons (this is very critical) but with ___2____, the separation can be longer (more than 2 carbons).

1. Agonists 2. Antagonists

Match the following adrenergic and antiadrenergic drug classes for hypertension with their correct indication: 1) Decrease Inotropy/Chronotropy (lower heart beat & HR) 2) Vasoconstriction 3) Inhibit sympathomimetic response/tone

1. Beta-1 blockers 2. Alpha-1 blockers 3. Alpha-2 agonists

1) Sympathetic system innervates iris______ 2) Parasympathetic system innervated iris _____

1. Dilator muscles 2. Constrictor muscles

Match the following Norepinephrine and Epinephrine statements: 1. Secondary amine 2. Adrenaline 3. Noradrenaline 4. Primary amine A. Epinephrine B. Norepinephrine

1. Epinephrine 2. Epinephrine 3. Norepinephrine 4. Norepinephrine

Know the SAR (Structure Activity Relationship) rules for Muscarinic antagonists: *3 rules*

1. Have to have a tertiary amine or could be a quaternary amine that's part of the ring system. 2. The "X" has to be separated from the Nitrogen by a number of carbons (is flexible). The "X" is normally an oxygen from an ether or ester BUT could also be a carbon. *(Oxygen adds potency)* 3. The carbon next to the "X" that is linked to 3 different groups MUST contain an aromatic ring (R1 position). R2 position can be another ring but its not a must. R3 can be anything (ex: -H, -OH, -CH2OH or -CONH2) -- could be involved in hydrogen bonding if R1 & R2 are not strong enough. *Many antihistamines & CNS drugs have similar structures -- reason why they have anticholinergic side effects like dry mouth, constipation*

Activating alpha 1 receptors results in a/an ____1____ in blood pressure while activating alpha 2 receptors results in a/an____2____ in blood pressure. *Word bank: Increase, decrease*

1. Increase BP 2. Decrease BP

Match the following Muscarinic receptor agonists with their indication: 1. Methacholine 2. Carbachol 3. Cevimeline 4. Pilocarpine 5. Bethanechol A. Miosis & cataract surgery B. Asthma diagnosis & bronchoconstriction C. Bladder contraction (treatment of urinary retention) D. Increase salivation E. Treatment of xerostomia/dry mouth *Muscarinic receptor antagonists are indicated for the opposite* *Agonists act directly on muscarinic receptors*

1. Methacholine - asthma diagnosis & bronchoconstriction 2. Carbachol - miosis & cataract surgery 3. Cevimeline - increases salivation 4. Pilocarpine - treatment of dry mouth/xerostomia 5. Bethanechol - bladder contraction (treatment of urinary retention)

1. ______ mimic the effects of ACh by binding specifically to the muscarinic receptors at various sites 2. _____ enhance ACh by preventing decomposition/breakdown of ACh. 3. _____ compete with ACh to bind to muscarinic receptors & also antagonize the effects of ACh. *Word bank: Muscarinic antagonists, Acetylcholinesterase inhibitors, Muscarinic agonists*

1. Muscarinic agonists (more parasympathetic) 2. Acetylcholinesterase inhibitors 3. Muscarinic antagonists (more sympathetic) *Agonists need to bind and act on the receptor while Antagonists need to bind and prevent the agonist from displacing them since they're competing*

The autonomic nervous system pathway is known as a two-neuron system. The fiber leaving the CNS and entering the ganglion is the ____1_____ and is usually _____2___. The fiber leaving the ganglion and going to a specific target organ is the ___3____ and is usually ___4____. *Word bank: myelinated, non-myelinated, preganglionic fiber, postganglionic fiber*

1. Pre-ganglionic fiber 2. Myelinated 3. Post-ganglionic fiber 4. Non-myelinated

What are the 3 types of acetylcholinesterase inhibitors?

1. Reversible carbamate inhibitors 2. Non-covalent inhibitors 3. Irreversible inhibitors

Acetylcholinesterase process:

1. Serine carries out a nucleophillic attack on the carbonyl carbon of acetylcholine resulting in serine in the active site being acetylated & choline leaving the active site. 2. Acetylcholinesterase is then regenerated by hydrolysis and is ready to hydrolyze another molecule of acetylcholine. *If the acetyl group is attached to the enzyme, the enzyme will not work*

CNS effects of atropine are complex & wide ranging and only depend on dose. 1) Therapeutic doses result in: 2) Higher doses result in:

1. Slight stimulation 2. Hallucinations, disorientation & restlessness

What are the 2 exceptions of the sympathetic system's release of ACh instead of NE?

1. Sweat glands 2. Innervation of the adrenal medulla

What are 2 ways to mimic the effects of ACh?

1. Through binding of muscarinic agonists 2. Inhibiting the acetylcholinesterase enzyme so ACh can last longer since its not broken down quickly

Name the enzymes involved in the synthesis of Norepinephrine & Epinephrine: 1) L-Tyrosine is converted to L-Dopa by? 2) L-Dopa is converted to Dopamine (a catecholamine) by? 3) Dopamine is converted to Norepinephrine by? Word bank: Dopamine-B-Hydoxylase, Tyrosine hydroxylase, Aromatic L-Amino Acid Decarboxylase

1. Tyrosine hydroxylase 2. Aromatic L-Amino Acid Decarboxylase 3. Dopamine-B-Hydoxylase *Norepinephrine is then stored in the vesicle until its released into the synaptic gap*

"TM3" contains a critical aspartate residue involved in ionic bonding/electrostatic interaction with the amine group of epinephrine. (At physiological pH, the amine is mostly ionized/protonated) A. True B. False

A

"TM6" contains 2 key interactions: 1) Phenylalanine and the catechol ring interact via Van der Waal's forces 2) Asparagine forms a hydrogen bond with the beta-hydroxyl group on epinephrine. A. True B. False

A

1) Its a depolarizing agent that binds and stays at the receptor preventing ACh from binding & to keep muscle in a depolarized state which eventually leads to muscle relaxation & inability to re-polarize (lack of ACh response to contract again) 2) Contains 2 quaternary amines that are separated by an aliphatic chain (long carbon chain) 3) Binds too strongly to the nicotinic receptors thus has no antidote *KEY* 4) Has a long duration of action in the body due to lack of ester group *KEY* Which of the following drugs fit the above description? A. Decamethonium B. Succinylcholine

A

Acetylcholine (ACh) is the neurotransmitter & nicotinic receptors are the target receptors of the somatic nervous system. A. True B. False

A

Acetylcholine is a flexible neurotransmitter and can bind to different receptors BUT Muscarine and Nicotine can only bind to Muscarinic M receptors and Nicotinic N receptors respectively. A. True B. False

A

Acetylcholinesterate inhibitors tend to have cholinergic effects. A. True B. False

A

Alfuzosin, Tamsulosin, and Silodosin are highly selective for smooth muscles in the prostate (α1A) & treat Benign Prostatic Hyperplasia (BPH). A. True B. False

A

Alpha-1 selective adrenergic receptor antagonists were found to block alpha-1 receptors in the prostate (BPH) and reduce blood pressure. A. True B. False

A

Aminoalcohols such as procyclidine (Kemadrin) and Trihexyphenidyl (Artane) are used to treat tremors and spasms associated with Parkinson's disease (oral drugs). A. True B. False

A

Aminoalcohols such as procyclidine (Kemadrin) and Trihexyphenidyl (Artane) lack an O or N on the "X" position of SAR but do have a carbon thus: A. More lipophillic B. More hydrophillic

A

An acetylcholinesterase inhibitor is a chemical or a drug that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. A. True B. False

A

Any neuron releasing or producing Acetylcholine (ACh) is? A. Cholinergic B. Adrenergic

A

Any neuron releasing or producing Norepinephrine (NE) is? A. Cholinergic B. Adrenergic

A

Atracurium undergoes non-enzymatic breakdown through a process known as Hoffman elimination thus is safer for patients with decreased kidney or renal function. A. True B. False

A

Atropine is contraindicated in patients with? A. Narrow angle glaucoma B. Wide angle glaucoma

A

Auto-receptors are: A. Muscarinic B. Nicotinic

A

Beta-1 blockers ONLY decrease the sympathetic tone and have no effect on the tone at rest (you cannot lower someone's normal tone even lower). A. True B. False

A

Beta-1 blockers inhibit the release of renin from the kidney. A. True B. False

A

Carvedilol, a non-selective beta-blocker & alpha-1 blocker increases the healing process of the heart after a heart attack. A. True B. False

A

Cholinergic receptors can be both nicotinic and muscarinic. A. True B. False

A

Clonidine was found to cause a drop in blood pressure by binding to alpha 2 receptors in the CNS (brain - lipophillic) & as a result caused a decrease in sympathomimetic tone. A. True B. False

A

Cocaine acts by blocking the import of Norepinephrine. A. True B. False

A

Dobutamine is used for the treatment of heart failure and can result in an increased risk of cardiac contraction that increases the heart's need for oxygen. A. True B. False

A

Due to ______ hydrolysis (since you inactivate the enzyme for 15 minutes and it cannot accept a molecule of ACh), the enzyme cannot hydrolyze ACh. A. Slow B. Fast

A

Epinephrine and Norepinephrine are known as catecholamines because they contain a catechol ring (benzene ring with 2 hydroxyl groups ortho/next to each other). A. True B. False

A

Labetalol and Carvedilol also inhibit alpha receptors thus are less likely to cause peripheral resistance (vasoconstriction). A. True B. False

A

Lacrimal glands are innervated by parasympathetic fibers which results in tear release but since atropine blocks parasympathetic activity, it results in dry eyes. A. True B. False

A

Long term use of non-selective beta blockers results in a risk of atherosclerosis due to a change in the lipid profile (Increase in serum triglycerides, increase in LDL and decrease in HDL). A. True B. False

A

Methacholine binds to the muscarinic receptors and mimics the effects of Acetylcholine. A. True B. False

A

Most of the Norepinephrine is recycled and stored through the uptake process & within the neurons, excess NE is degraded. A. True B. False

A

Muscarinic receptor agonist drugs mimic the effects of Acetylcholine at muscarinic receptors. Examples include methacholine, carbachol, bethanechol, cevimeline and pilocarpine. A. True B. False

A

Nicotinic receptors are present in all ganglions. A. True B. False

A

Nicotinic receptors result in opening on sodium channels are excreting an "excitatory signal". A. True B. False

A

Norepinephrine and Epinephrine bind to GPCR through a 7-transmembrane receptor. A. True B. False

A

Out of the 7-transmembrane receptors; Only 3 are critical in forming interactions with epinephrine. "TM5" contains 2 Serine residues that form hydrogen bonds with the 2 hydroxyl groups on the catechol ring. A. True B. False

A

Oxybutynin is metabolized by which of the following enzyme? A. CYP3A4 B. CYP1A2 C. CYP2C9 D. CYP2C19 E. CYP2D6

A

Parasympathetic system releases? A. Acetylcholine B. Norepinephrine C. Acetylcholine & Norepinephrine

A

Patients with a deficiency in CYP2D6 and are also taking grapefruit juice (or any inhibitor of CYP3A4) could have an increase in side effects of the drug (Tolterodine/Detrol). A. True B. False

A

Post-ganglionic fibers can release both ACh (parasympathetic) and Norepinephrine (sympathetic). A. True B. False

A

Prazosin/Minipress will bind almost entirely to alpha receptors in the smooth muscle of the blood to reduce blood pressure & have little affinity for the smooth muscle in the prostate. A. True B. False

A

Preganglionic fibers release? A. Acetylcholine B. Norepinephrine

A

Question from class: (Be able to identify the structure differences between Beta 1 selective vs Non-selective) In addition to the required Aryloxypropanolamine group; an aryl ring infused to a second ring & a bulky amine group are common in? A. Non-selective beta blockers B. Beta-1 selective blockers C. Non-selective beta blockers + alpha blockers

A

The carbazole ring is responsible for the anti-oxidant activity of? A. Carvedilol B. Timolol C. Esmolol D. Labetalol E. Propranolol

A

The dose-dependent CNS effects of scopolamine are as a result of blocking of the parasympathetic responses. A. True B. False *Effects include:* -Restlessness -Confusion -Excitement -Hallucinations -Dizziness -CV collapse and respiratory failure -"Twilight sleep" - conscious but no free will -Coma -Death

A

The main difference between an alpha receptor and a beta receptor is that a beta receptor has an extended hydrophobic pocket as compared to an alpha receptor. A. True B. False

A

The peripheral nervous system is composed of the autonomic and somatic nervous system. A. True B. False

A

There are 22 pairs of sympathetic ganglia many of them preganglionic fibers that synapse with a single ganglia resulting in diffused effects. A. True B. False

A

This receptor sub-type is mostly found in smooth muscles that make up blood vessels (vascular & heart) and are activated by NE resulting in an increase in BP (vascular constriction) and increased blood sugar (gluconeogenesis-liver) when activated. (This receptor sub-type increases sympathetic response) A. Alpha 1 B. Alpha 2 C. Beta 1 D. Beta 2

A

Which of the following acetylcholinesterase domains captures acetylcholine mainly by an interaction known as Pi-cation & using tryptophan (aromatic amino acid) to hold it in place? A. Peripheral binding site B. Narrow Gorge C. Active site

A

Which of the following enantiomer of albuterol is more active & potent? A. R-enantiomer B. S-enantiomer

A

Which of the following is the correct indication for Edrophonium due to its short duration of action (10-30 minutes)? A. Myasthenia gravis diagnosis B. Alzheimer's disease

A

Which of the following systems does the following description correctly match: "Involuntary, maintains homeostasis, smooth muscle control & two-neuron efferent pathway"? A. Autonomic nervous system B. Somatic nervous system

A

_______ converts amine group into carboxylic acid resulting in inactivation of NE (Vanillylmandelic acid).. A. MAO B. COMT

A

________ has less affinity for beta 2 but has a greater affinity for the rest of the receptors (a1, a2, b1); more affinity for alpha receptors than beta. A. Norepinephrine B. Epinephrine

A

M1, M2, M3, M4 & M5 are all sub-types of Muscarinic receptors all expressed widely through periphery & CNS (brain). A. True B. False

A *They are evenly distributed in the brain but some show selectivity for certain subtypes*

Beta-blockers should not be discontinued abruptly after long term therapy. They should be tapered down. A. True B. False

A *Abrupt stopping has resulted in deaths b/c your body gets a sudden increase in stimulation of those receptors once beta-blockers are discontinued*

Oxybutynin/Ditropan a tertiary amine is used for the treatment of urinary incontinence & excessive sweating. A. True B. False

A *Adverse effects include: dry mouth, constipation, nausea, blurred vision, drowsiness* *Urinary incontinence: where the bladder and sphincter both relax letting the urine out uncontrollably*

Benztropine (Cogentin) a tertiary amine is used for the treatment of Parkinson's disease and dystonia (involuntary muscle contractions). A. True B. False

A *Adverse effects: dry mouth, nausea, vomiting, constipation, tachycardia, blurry vision, psychosis (overdose)*

Xylometazoline and Naphazoline are highly ionic and are topically used as nasal decongestants & eye drops. A. True B. False

A *As eye drops; Naphazoline works by constricting the blood vessel in the eye to reduce redness* *Nasal decongestants can cause rebound congestion (persistent congestion) so dont' use for more than 3 days*

Muscle relaxation results from blocking nicotinic receptors. A. True B. False

A *Basically; we have an action potential that comes in triggering the release of ACh from the synaptic vesicles; this results in ACh binding to the N1 receptor (neuromuscular junction) causing muscle contraction but if the N1 receptor is blocked, ACh cannot bind which means that your muscles will relax*

Methacholine is 3 times more stable than Acetylcholine and is also resistant to acetylcholinesterase. A. True B. False

A *But is still hydrolyzed in the stomach*

Atropine is a tertiary amine thus is able to cross the blood brain barrier but not all muscarinic antagonists cross the blood brain barrier equally well. A. True B. False

A *Centrally acting anticholinergincs/antimuscarinics reduce tremors (caused by ACh increase) associated with Parkinson's disease (imbalance of dopamine & ACh); how? by replenishing dopamine and reducing ACh to normal levels*

Diphenhydramine, Doxylamine and Orphenadrine (Norflex) are drugs with anticholinergic side effects (ex: dry mouth, constipation) since they bind to muscarinic receptors & fulfill SAR rules but are not typically used as anticholinergics. A. True B. False

A *Diphenydramine & Doxylamine are antihistamines that bind to H1 & M receptors while Orphenadrine a muscle relaxant binds to H1, M and NMDA receptors*

Dobutamine is made up of racemic mixtures of positive and negative isomers & is known to be a mixed agonist because it activates both beta 1 and alpha 1 agonist (with the beta effect more dominant). A. True B. False

A *Dobutamine is similar to 2 structures of dopamine combined except 1 does not have a catechol ring*

Mivacurium chloride, a Tetrahydroisoquinoline-based neuromuscular blocker is safer than succinylcholine & does not undergo Hoffman elimination but is similar to Atracurium in that its broken down by esterases in the body (butrylcholinesterase) thus would be safer in patients with decreased hepatic and renal functions. A. True B. False

A *Don't worry about the structure just be able to identify its a Tetrahydroisoquinoline-based neuromuscular blocker based on the location of the rings and the ester groups separating the rings*

Donepezil (Aricept) shows greater selectivity at the brain/CNS for ACHE inhibition (slowing down the breakdown of ACh). A. True B. False

A *Enters the blood brain barrier since its a tertiary amine* *Binds to both the peripheral site and active site simultaneously*

Atropine, Scopalamine and Hyoscyamine all contain a tropic acid which in turn becomes a tropic ester once its merged with a tropic ring. A. True B. False

A *Esters are easily hydrolyzed in the liver and eliminated in the kidney*

Fesoterodine (Toviaz) is a pro-drug (inactive drug) that is activated by esterases into active metabolite 5-Hydroxy-tolterodine. A. True B. False

A *Fesosterodine can be converted to the active metabolite of Tolterodine (which is 5-Hydroxy-tolterodine)*

Rivastigmine shows reduced side effects compared to the other 3 reversible carbamate inhibitors since it does not accumulate. A. True B. False

A *Has a short half-life*

Which of the following hydrolysis process is slower? A. Carbamoyl group from carbamylated ACHE B. Acetyl group from acetylcholine

A *Hydrolysis half-life of carbamoyl enzyme is 15 minutes compared to 0.2 milliseconds for acetylated enzyme.*

Looking at a concentration curve of ACh binding to muscarinic receptors; if you have ACh by itself, it binds to the receptor at very low concentrations but when atropine is added; the concentration of ACh______ resulting in competitive antagonism. A. Shifts right B. Shifts left

A *In Competitive antagonism, you would need higher concentrations of ACh to reach the same binding status as before.*

Organophosphates undergo similar mechanisms to carbamylation but instead of an ester or carbamoyl, you have a phosphate (phosphoester). A. True B. False

A *Insecticides have a sulfur group instead of oxygen*

Amphetamine and Methamphetamine lack hydroxyl groups thus are less polar & more lipophillic resulting in greater CNS effects. A. True B. False

A *Lack of hydroxyl group is the reason for more CNS effects; Pseudoephedrine (with hydroxyl group) can easily be converted to Methamphetamine by removal of hydroxyl*

Methacholine, Carbachol and Bethanechol all have quaternary ions thus will not cross the blood brain barrier. A. True B. False

A *Minimal CNS effects*

GPCR signalling: In the parasympathetic system, nicotinic receptors are ligand gated and muscarinic receptors are GPCR's. In the sympathetic system, all adrenergic receptors are GPCR's and contain a 7 transmembrane domain and are associated with different types of G-proteins. A. True B. False

A *NE binds to the GPCR & the alpha subunit exchanges GDP for GTP*

Norepinephrine and Epinephrine have shorter half-lives due to the fact that they are easily degraded by the enzymes COMT (catechol ring) & MAO (amine group). A. True B. False

A *NOTE: Norepinephrine binds to a1, a2, b1 & to some extent b2 but is not specific to a certain receptor & Epinephrine is also not specific to certain receptors but to some extent beta selective at low concentrations*

Ligand-gated ion channels respond to ACh and as a result, the channels open up and we get an influx of sodium which triggers depolarization (contraction) of the target muscle. A. True B. False

A *Neuromuscular blockers bind to N1 receptors & block ACh from binding which results in complete muscle relaxation*

Atropine is non-selective so differences in atropine effects are not due to varying affinity for M receptors subtypes but due to the overall regulation of target by parasympathetic tone & other regulatory factors. A. True B. False

A *Not all effects occur at the same dose; first after increasing dose is blocking salivation = dry mouth, then blocking urination (relax bladder muscle & contract sphincter); then increased HR (since ACh is blocked) at much higher doses, low doses, atropine causes bradycardia we see accommodation on the eye (where its dilated).*

Atropine (an anticholinergic) affects the salivary glands by causing dry mouth & affects the GI tract by inhibiting peristalsis (resulting in nausea, bloating, constipation) and acid secretions only at higher concentrations. (Atropine does not completely inhibit these processes since gastric hormones and histamine also stimulate gastric motility & secretions). A. True B. False

A *Pancreatic secretions are under hormonal control and will NOT be affected by atropine*

Phenylephrine is commonly used as a decongestant, for mydriasis with tropicamide, hypotension (vasopressor) and as treatment for priapism while Metaraminol is commonly used as treatment for hypotension and priapism. A. True B. False

A *Priapism is the prolonged erection of the penis long after stimulation has ended*

Catecholamine-O-methyl transferase (COMT) & Monoamine oxidase (MAO) are critical enzymes for NE synthesis, are responsible for NE's short half-life and regulate the amount of catecholamine in the blood. A. True B. False

A *Responsible for acting on catecholamines - COMT* *Acts on the amine portion of a catecholamine - MAO* *Overall; they break down catecholamines*

Pyridostigmine (Mestinon) is used more for the diagnosis of myasthenia gravis b/c it does not last long, tends to be slower than Neostigmine & acts longer. A. True B. False

A *Similar adverse effects to neostigmine*

The ester of carbamic acid (carbamate) mimics the acetyl group of acetylcholine and instead of a methyl group, we have an amine group. A. True B. False

A *The carbamate group is attacked by the serine in the active site resulting in a carbamylated serine thus a carbamylated ACHE*

Alpha-1A (a1A) drugs are highly selective for? A. Smooth muscle in the prostate B. Smooth muscle in the blood vessels

A *These drugs are more selective for the prostate & less for blood pressure*

Muscarinic antagonists also known as muscarinic blockers, anticholinergics or parasympatholytics: A. Compete with acetylcholine for binding to muscarinic receptors B. Mimic the effects of ACh by binding specifically to the muscarinic receptors at various sites.

A *They generally bind to all receptors (M1, M2, M3, M4, M5) but some drugs show some selectivity -- These drugs DO NOT bind to nicotinic receptors*

With beta-blockers, when we decrease HR, the body compensates by activating alpha receptors and constricting the blood vessels resulting in an increase in BP (NOT initially, but after long term use). A. True B. False

A *This is why we use 3rd generation beta blockers because they block both Beta response and Alpha response; so when you decrease HR, your BP does not increase* --> Drugs in this class include: Carvedilol and Labetalol

Tyrosine is converted to Tyramine through fermentation and the carboxylic acid is removed through the process of decarboxylase resulting in non-receptor binding and displacement of NE (indirect sympathomimetic). A. True B. False

A *Tyramine is too polar for CNS effects*

Pralidoxime (antidote) should be administered _______ the aging process begins (the timing depends on the nerve agent) because once the isobutyl is replaced with the hydroxyl group; its completely irreversible and results in death. A. Before B. After

A *Why is the antidote used instead of water? b/c water speeds up the aging process*

The pre-synaptic fibers of both sympathetic and parasympathetic produce ACh into the synaptic gap which then acts on the post-synaptic fiber through nicotinic receptors/cholinergic receptors. For sympathetic, the post-synaptic fibers always produce _______ which then binds to the adrenergic receptors at the target organ. A. Norepinephrine B. Acetylcholine

A *With the exception of sweat glands which produce ACh instead of Norepinephrine*

Xylometazoline and Naphazoline are nicknamed imidazole derivatives due to the methyline bridge leading to the Imidazoline ring. A. True B. False

A *Xylometazoline and Naphazoline are RESISTANT to COMT & MAO*

Which of the following enantiomers of epinephrine is more active? A. R-epinephrine B. S-epinephrine

A *b/c the R is close enough to the asparagine (blue circle) to form a hydrogen bond with the beta-hydroxyl group*

Beta-1 receptor specificity requires additional hydrogen bonding. A. True B. False

A To identify Beta-1 selective: 1) Look for the Aryloxypropanolamine group 2) Look for a less bulky group on nitrogen (like Isopropyl) 3) look for a para-substituted group capable of hydrogen bonding.

Which of the following adverse events are more likely experienced in patients taking Phenylephrine or Metaraminol (alpha 1-selective agonists)? *Select all that apply* A. Hypertension B. Reflex bradycardia C. CNS penetration

A & B *No CNS penetration for Phenylephrine or Metaraminol due to high polarity*

Which 2 amino acids within the active site are very critical for the breakdown of acetylcholine (catalysis)? *Select 2* A. Histidine B. Tryptophan C. Serine

A & C

Atropine a tropic ester is mostly replaced by tropicamide, a tropic amide for ophthalmic use. Which of the following are the correct reasons? *Select 2* A. Tropicamide has less affinity for melanin in the eye B. Atropine has less affinity for melanin in the eye C. Atropine has a shorter duration of effect D. Tropicamide has a shorter duration of effect

A & D *1) Tropicamide has less affinity for melanin in the eye so it goes directly to eye muscles unlike atropine that has a very high affinity for melanin* *2) Tropicamide has a shorter duration of effect (upto 15-60 minutes) thus would be most effective for eye exams as compared to atropine which has a longer duration of effect (takes upto 5-7 days to wear off)*

Which of the following structures/drugs will most likely penetrate the CNS/BBB? *Select all that apply* A. Physostigmine B. Neostigmine C. Pyridostigmine D. Rivastigmine

A & D *Why? b/c the have tertiary amines* *These 4 modify the enzyme*

Which of the following drugs are considered to be choline esters? *Select all that apply* A. Methacholine B. Carbachol C. Bethanechol D. Pilocarpine E. Cevimeline

A, B, C *They are all quaternary ions & do not cross the blood brain barrier*

These receptors subtypes tend to be on the target organs & are also known as G-protein coupled receptors (GPCR): *select all that apply* A. a1 (alpha-1) B. a2 (alpha-2) C. b1 (beta-1) D. b2 (beta-2)

A, C, D

M2, M4 result in?

ACh inhibition *Nicotinic receptor: Ligand gated ion channels* *M2 & M4 are auto-receptors present on pre-synaptic neurons*

Botulinum toxin inhibits fusion of synaptic vesicle with membrane & prevents release of/exocytosis?

Acetylcholine

The SAR (Structure-Activity Relationship) of Muscarinic Agonists is?

Acetylcholine

The enzyme that catalyzes the breakdown of acetylcholine and of some other choline esters that function as neurotransmitters into choline and acetate is known as?

Acetylcholinesterase

The effects of acetylcholine are short-lived because its quickly hydrolyzed back into choline and acetate by the enzyme known as?

Acetylcholinesterase *Choline is recycled back into the pre-synaptic fiber and is re-synthesized into the synaptic vesicles*

Drugs that block adrenergic signals or sympathetic pathways are called?

Adrenergic blockers

Alpha-1A blockers include:

Alfuzosin/Urozatral Tamsulosin/Flomax Silodosin/Rapaflo

In regards to scopolamine having more serious CNS effects than atropine, are the following statements true or false? 1. The only structural difference between scopolamine and atropine is the epoxide on the scopolamine. 2. Both scopolamine and atropine are tertiary amines 3. The epoxide group (electron withdrawing group) lowers the pKa of scopolamine 4. Scopalamine due to its lower pKa is a weaker base compared to atropine 5. Atropine is more likely to undergo protonation because its a stronger base than scopolamine 6. Ionized drugs are less likely to cross the BBB but unionized drugs are more likely to cross the BBB. (Scopolamine is more unionized) 7. Scopolamine reaches the vestibular system at lower doses and CNS penetration at higher doses.

All true

Ipratropium bromide (Atrovent) and Tiotropium bromide (Spiriva) are both used for the treatment of?

Asthma & COPD *Adverse effects include: dry mouth, stuffy nose, nausea, constipation, dizziness, headache* - its a muscarinic antagonist = blocks parasympathetic fibers resulting the above side effects*

Beta-1 selective (2nd generation) beta blockers block beta-1 receptors mostly found in the heart. Which of the following drugs fit the description of beta-1 selective beta blockers? *Select all that apply*

Atenolol Metoprolol Acebutalol Betaxolol Esmolol Bisoprolol

A single neuronal fiber connects the CNS to the skeletal muscle (through the neuromuscular junction): A. Autonomic nervous system B. Somatic nervous system *Neuromuscular junction: area between neuron and skeletal muscle*

B

Auto-receptors regulate the amount of neurotransmitter released. Which of the following adrenergic subtypes is considered an auto-receptor? A. a1 (alpha-1) B. a2 (alpha-2) C. b1 (beta-1) D. b2 (beta-2)

B

Carbachol binds to M receptors on constrictor & ciliary causing pupillary constriction. The ligaments then relax, lens thickens (near vision) and access to canal opens. The fluid drains into the canal resulting in a/an ________ intraocular pressure. A. Increase B. Decrease

B

Epinephrine synthesis occurs mostly in the? A. Neurons B. Adrenal medulla

B

Neuromuscular blockers are used for? A. Skeletal muscle contraction during surgery B. Skeletal muscle relaxation during surgery

B

The process of norepinephrine to epinephrine involves an enzyme known as ______ that basically just sticks on a methyl group to Norepinephrine & it becomes epinephrine. A. Dopamine-B-Hydoxylase B. Phenylethanolamine-N-methyltransferase C. Tyrosine hydroxylase D. Aromatic L-Amino Acid Decarboxylase

B

There is no specific or direct parasympathetic innervation with smooth muscles of the arteries but parasympathetic fibers stimulate nitric oxide (NO) production that results in vasorelaxation but atropine blocks the parasympathetic response resulting in a shift in favor of? A. Vasodilation B. Vasoconstriction

B

Where is the M2 sub-type likely to be found? A. CNS B. Myocardium (heart) C. Glandular and smooth muscle cells (arteries)

B

Which amino acid in the active site is responsible for the Pi-cation interaction & keeps acetylcholine anchored in place? A. Histidine B. Tryptophan C. Serine

B

Which of the following alkaloids is MORE selective for M1 and M3 receptor subtypes? A. Pilocarpine B. Cevimeline

B

Which of the following choline esters activates both N & M (Nicotinic & Muscarinic) receptors? A. Methacholine B. Carbachol C. Bethanechol

B

Which of the following systems does the following description correctly match: "Voluntary, intentional movement, skeletal muscle control & single-neuron efferent pathway"? A. Autonomic nervous system B. Somatic nervous system

B

Which of the pairs below stimulate Nitric Oxide production leading to vasodilation & less resistance? A. Labetalol and Carvedilol B. Carteolol and Nebivolol

B

Xylometazoline and Naphazoline have a high affinity for _____ due the hydroxy group on the benzyl ring being replaced with lipophilic/hydrophobic groups. A. Beta receptors B. Alpha receptors

B

________ has a greater affinity for beta 2 receptors at low concentrations compared to the rest of the receptors (a1, a2, b1) at high concentrations; more affinity for beta receptors than alpha. A. Norepinephrine B. Epinephrine

B

Which of the following is the correct indication for Galantamine (Razadyne)? A. Myasthenia gravis diagnosis B. Alzheimer's disease & other mild dementias

B *Adverse effects include: GI (cramps, N/V, diarrhea) & BRADYCARDIA*

Which of the following is the correct indication for Donepezil (Aricept)? A. Myasthenia gravis diagnosis B. Alzheimer's disease

B *Adverse effects include: Nausea, vomiting, cramps, diarrhea & sleep problems - due to CNS entry*

This reversible carbamate inhibitor is used in myasthenia gravis patients to increase muscle tone and is also used to reverse the effects of neuromuscular blockers? A. Physostigmine B. Neostigmine C. Pyridostigmine D. Rivastigmine

B *Adverse effects include: blurred vision, bradycardia & GI effects (cramps, diarrhea & nausea);* *Increases the effects of ACh = increase in adverse effects*

You can overcome the effect of atropine by increasing the concentration of the _____. A. Antagonist B. Agonist

B *Agonist is ACh; Antagonist atropine* *Atropine antagonizes muscarinic receptors* *Atropine is a tertiary amine = CNS effects & binds to all M receptors*

Question from class: Which group is removed as a result of activation of prodrug (inactive) Fesosteridine to active metabolite? A. Hydroxyl B. Ester C. Methyl D. Benzyl ring

B *Almost always is an ester; ester to hydroxyl*

Question from class: (Be able to identify the structure differences between Beta 1 selective vs Non-selective) In addition to the required Aryloxypropanolamine group; a single ring, an Isopropyl group on the amine & a para substituted group are common in? A. Non-selective beta blockers B. Beta-1 selective blockers C. Non-selective beta blockers + alpha blockers

B *Bigger groups on the amine will bind to beta-2 instead of beta-1* *Para substituted groups capable of hydrogen bonding are critical for beta-1 binding*

Which of the following groups increases beta selectivity? A. Hydroxyl groups B. Alkyl groups C. Hydrogen groups

B *Examples include: methyl groups, isopropyl groups*

The only way to get rid of Tyramine is through the enzyme? A. COMT B. MAO

B *If a patient is taking MAOI's (antidepressants), the patient is inhibiting the MAO enzyme and cannot get rid of Tyramine rich foods (pickles, cheese, wine, soy sauce, yogurt, chocolate) which can eventually lead to vasoconstriction and increased BP.*

Which of the 2 fit the following description correctly: "contains 2 rings (thiophene), fits into the hydrophobic pocket of the receptor very well thus dissociates from the receptor much slower & is more potent due to that" A. Ipratropium bromide (Atrovent) B. Tiotropium bromide (Spiriva)

B *Know the structures*

This receptor sub-type plays a role in the brain/CNS & neuronal auto receptors by decreasing sympathetic response thus decreasing NE release & decrease in BP when activated. (This receptor sub-type contains the drug clonidine) A. Alpha 1 B. Alpha 2 C. Beta 1 D. Beta 2

B *Known as alpha 2 agonists*

Which of the following class of neuromuscular blockers are NOT dependent on the kidney and liver for their elimination? A. Steroid-based neuromuscular blockers B. Tetrahydroisoquinoline-based neuromuscular blockers

B *Onset & Duration are short in all Tetrahydroisoquinoline-based neuromuscular blockers since they contain ester groups = easily hydrolyzed*

Atropine (used for eye exams) ______ causing your pupil to remain dilated (mydriasis) & paralyzes ciliary muscles resulting in fluid drainage being blocked. A. Blocks sympathetic signals (dilation) B. Blocks parasympathetic signals (constriction)

B *PROBLEM with atropine in people with darker eye colors: the dark eye color tends to absorb the atropine due to the melanin resulting in a need for more atropine for dilation compared to lighter eye colored people but people needing more atropine will take longer to recover from dilation*

1) Its a depolarizing agent that binds and stays at the receptor preventing ACh from binding & to keep muscle in a depolarized state which eventually leads to muscle relaxation & inability to re-polarize (lack of ACh response to contract again) 2) Mimics two molecules of ACh linked end on (with 2 quaternary amines) 3) Has a short duration of action in the body due to the presence of ester groups (hydrolyzed easily by butyrylcholineesterase in the body) 4) Can trigger potassium release & cardiomycytes leading to arrhythmias. Which of the following drugs fit the above description? A. Decamethonium B. Succinylcholine

B *Patients with lower levels of butyrylcholinesterase in the body when succinylcholine is administered at normal levels can lead to overdose/respiratory paralysis*

________ converts one of the hydroxyl groups into a methoxy group resulting in inactivation of NE (Vanillylmandelic acid). A. MAO B. COMT

B *The enzyme COMT will only work on a catechol ring (with 2 hydroxyl groups) NOT a phenyl ring (with 1 hydroxyl group)*

Amphetamine and Methamphetamine are considered: A) Direct sympathomimetics B) Indirect sympathomimetics C) Mixed sympathomimetics

B *They displace both NE and dopamine resulting in an increase in NE & Dopamine b/c it doesn't bind to a receptor*

In the Methacholine structure, the methyl group is substituted in which of the following carbons? A. Alpha-carbon B. Beta-carbon

B *Why? b/c the beta-substitution increases selectivity for muscarinic receptors resulting in similar potency to ACh & also to shield the carbonyl carbon from a nucleophillic attack*

Too much ACh results in binding to ______ for inhibition. *Select all that apply* A. M1 B. M2 C. M3 D. M4 E. M5

B & D

Tolterodine (Detrol) also used for urinary incontinence is? *Select 3* A. Receptor selective B. Not receptor selective C. A tertiary amine & can get into the CNS but is mostly concentrated in the bladder D. A quaternary amine & can get into the CNS but is mostly concentrated in the bladder E. Better tolerated & more patient accepted

B, C, E *Better tolerated since its not receptor selective; its *more tissue selective* thus is mostly confined to the bladder and other tissues* *Oxybutynin is receptor selective BUT Tolterodine is NOT*

Why are Beta-1 selective receptors preferred in diabetic patients?

Beta-1 selective beta blockers are safer in diabetic patients compared to non-selective b/c non-selective blockers will bind to both beta-1 & beta-2 & by binding to beta-2, it results in blocking beta-2 in skeletal muscle thus reducing energy utilization (glucose). ALSO non-selective blockers tend to increase insulin resistance

contraindications of Muscarinic agonists: Asthma

Bronchoconstriction, mucus production

Carbachol is considered to have limited value orally because it binds to ______ resulting in severe side effects. A. N receptors B. M receptors C. Both N & M receptors

C

Question from class: Which of the following groups is necessary for a drug to be considered a beta blocker? A. Hydroxyl group B. Imidazole ring C. Aryloxypropanolamine group

C

The following steps occur when Acetylcholine is released into the synaptic cleft. 1. Presynaptic action potential 2. Opening of calcium channel 3. Calcium influx 4. Fusion of vesicle with membrane 5. Diffusion of ACh in synaptic cleft 6. Binding of ACh with post- synaptic receptors Which 2 steps does the Botulinum toxin inhibit? A. Steps 1 & 2 B. Steps 2 & 3 C. Steps 4 & 5 D. Steps 5 & 6

C

This receptor sub-type plays a role in the heart by increasing chronotropy (rate) & inotropy (strength) and a role in the kidney (increasing renin). This receptor results in a higher heart rate (HR) and BP when activated. A. Alpha 1 B. Alpha 2 C. Beta 1 D. Beta 2

C

Where is the M3 sub-type likely to be found? A. CNS B. Myocardium (heart) C. Glandular and smooth muscle cells (arteries)

C

Which amino acid is critical in carrying out a nucleophilic attack on the phosphate (organophosphates) in the active site? A. Tryptophan B. Arginine C. Serine D. Histidine

C

Which of the following minerals is required for fusion of synaptic vesicles when NE action potential enters the cell? A. Potassium B. Sodium C. Calcium D. Phosphorus

C

Question from class: If a patient about to go into surgery has compromised kidneys, which of the following choices would you recommend as a steroid-based neuromuscular blocker? A. Pancuronium B. Vecuronium C. Rocuronium

C *Both Pancuronium and Vecuronium are contraindicated in patients with compromised kidneys*

Which of the following is the correct indication for Physostigmine? A. Myasthenia gravis B. Urinary retention C. Glaucoma D. Dementia associated with Alzheimer's disease

C *Causes miosis*

Procyclidine (Kemadrin) and Trihexyphenidyl (Artane) are: A. Primary amines B. Secondary amines C. Tertiary amines D. Quaternary amines

C *Cross the BBB*

Solifenacin/Vesicare and Darifenacin/Enablex are both indicated for urinary incontinence. These drugs have an increased selectivity for ______ sub-type muscarinic receptors. A. M1 B. M2 C. M3 D. M4 E. M5

C *M3 = Bladder receptors* *Due to the selectivity, side effects tend to be less* *NOTE from class: don't worry about structures*

Oxybutynin binds to all M receptors but is slightly selective for? A. M1 B. M2 C. M3 D. M4 E. M5

C *M3: Bladder*

Alfuzosin, Tamsulosin, and Silodosin are antagonists highly selective for a1A receptors in the prostate and are considered 1st line treatment drugs for BPH. Which of the 3 is the most selective for a1A receptors? A. Alfuzosin B. Tamsulosin C. Silodosin

C *MOA: They work by blocking a1A receptors found in the bladder neck & prostate causing relaxation & increased urinary flow*

Which of the following is the actual "alpha-2 agonist"? A. Methyldopa B. Methyldopamine C. Methylnorepinephrine

C *Methylnorepinephrine is not usually used due to high polarity but Methyldopa is also polar BUT is able to go through the brain with the help of a transporter*

Which of the following is TRUE regarding Neostigmine and Physostigmine? A. They are both used to treat the same condition B. They result in different adverse effects C. Neostigmine is a quaternary amine while Physostigmine is a tertiary amine

C *Neostigmine is a quaternary amine meaning it will NOT penetrate the blood brain barrier*

Sympathetic system releases? A. Acetylcholine B. Norepinephrine C. Acetylcholine & Norepinephrine

C *Pre-synaptic (ACh & Cholinergic) & Post-synaptic (Norepinephrine & Adrenergic)*

Ephedrine and Pseudoephedrine are considered: A) Direct sympathomimetics B) Indirect sympathomimetics C) Mixed sympathomimetics

C *They show affinity for adrenergic receptors & also displace NE from synaptic vesicles (don't bind)*

Physostigmine is a? A. Primary amine B. Secondary amine C. Tertiary amine D. Quaternary amine

C *Thus can cross the blood brain barrier; was explored as a possible treatment for Alzheimer's disease but was found to be too toxic* *Results in an increase of both Nicotinic and Muscarinic receptors*

Rivastigmine (Exelon) is a? A. Primary amine B. Secondary amine C. Tertiary amine D. Quaternary amine

C *Thus is able to cross the CNS*

Galantamine (Razadyne) is a? A. Primary amine B. Secondary amine C. Tertiary amine D. Quaternary amine

C *Thus will cross the blood brain barrier* *Galantamine blocks the active site particularly using a Pi-cation interaction & inhibits ACHE resulting in a slower breakdown of ACh*

The sympathetic ganglia are within or close to the?

CNS/Spinal cord

Most common uses of Beta-blockers:

CVD Glaucoma Migraine Tremors Performance anxiety

What is the rate limiting step in Acetylcholine (ACh) synthesis?

Choline Import *Choline is recycled & acetate diffuses away*

Acetyl CoA and Choline (mostly recycled) are transferred into the synaptic gap by which enzyme?

Choline acetyltransferase resulting in Acetylcholine (ACh)

Drugs that block cholinergic signals or parasympathetic pathways are called?

Cholinergic blockers

ACHE (Acetylcholinesterase) inhibitors have?

Cholinergic effects

Question from class: Be able to differentiate between the clonidine structure vs alpha-1 structures:

Clonidine has a benzene ring with 2 chloride groups but Alpha-1 structures do not

The parasympathetic system is also known as the:

Craniosacral system

Methyldopa, an alpha-2 selective agonist is used for the treatment of hypertension. Which of the following groups of people is Methyldopa 1st line for due to fewer adverse effects? A. Children B. Elderly C. Infants D. Pregnacy E. None of the above

D

This non-selective beta-blocker (antagonist) was the first ever beta blocker in the market and was first used for angina pectoris. It is now used for the treatment of hypertension & cardiac arrhthymias. A. Atenolol B. Metoprolol C. Timolol D. Propranolol E. Labetalol

D

This receptor sub-type plays a role in the smooth muscle found in the lungs (bronchial relaxation) and skeletal muscles (vasodilation; increase blood flow into muscle, potassium intake, glycogenolysis) resulting in bronchodilation, vasodilation and energy utilization (opening of airways, increase skeletal muscle perfusion & conversion of glucose to glycogen). A. Alpha 1 B. Alpha 2 C. Beta 1 D. Beta 2

D

Which of the following are indications of Alpha-2 selective agonist drugs? A. Hypertension B. ADHD C. Addiction-related withdrawal symptoms D. All the above

D

Which of the following are reasons why epinephrine and norepinephrine will be ionized at physiological pH? A. Its basic B. The nitrogen will be protonated and have a positive charge C. Have a relatively high pKa D. All the above

D

This reversible carbamate inhibitor shows some selectivity for the enzyme in the brain and is most commonly indicated for mild to moderate dementia associated with Alzheimer's disease or Parkinson's disease? A. Physostigmine B. Neostigmine C. Pyridostigmine D. Rivastigmine

D *Adverse effects include: Nausea, vomiting, abdominal cramps*

With other beta-blockers, when we decrease HR, the body compensates by constricting the blood vessels resulting in an increase in BP. Which of the following drugs decreases HR and prevents constriction of the blood vessels resulting in a lower BP (blocks both the responses of alpha-1 and beta-1)? A. Metoprolol B. Timolol C. Esmolol D. Labetalol E. Propranolol

D *Labetalol is composed of a racemic mixture of 2 chiral centers --> 4 diastereomers* *Labetalol is also a partial beta-2 agonist & is capable of vasodilating the skeletal muscle resulting in a further decrease in BP*

Glycopyrrolate (Robinul) is a? A. Primary amine B. Secondary amine C. Tertiary amine D. Quaternary amine

D *Minimal BBB penetration = No CNS effects* *Satisfies the SAR rules for muscarinic antagonists*

Ipratropium bromide (Atrovent) and Tiotropium bromide (Spiriva) are both? A. Primary amines B. Secondary amines C. Tertiary amines D. Quaternary amines

D *Quaternary = NO CNS effects* *There is also less absorption orally compared to atropine so its perfect for inhaler use*

Norepinephrine synthesis in postganglionic neurons steps: 1) Production of NE begins with? Tyrosine 2) Tyrosine is hydroxylated by an enzyme known as hydroxylase to? L-Dopa 3) L-Dopa undergoes decarboxylation and is catalyzed by an enzyme known as decarboxylase to? Dopamine 4) Dopamine is transported into the synaptic vesicle using a transporter known as? VMAT (Vesicular Monoamine Transporter) 5) Within the synaptic vesicles, an enzyme known as dopamine hydroxylase converts dopamine to? Norepinephrine Which of the steps of norepinephrine synthesis in postganglionic neurons would be affected by Reserpine (a drug used previously to lower blood pressure)? A) 1 B) 2 C) 3 D) 4 E) 5

D *Reserpine was used previously to lower blood pressure and it would inhibit transport (VMAT) of dopamine into the synaptic vesicle & if you can't import enough dopamine, it means that you can't produce enough NE; thus you get a lower sympathetic response. *

Methacholine is a? A. Primary amine B. Secondary amine C. Tertiary amine D. Quaternary amine

D *So? it will not penetrate the blood brain barrier thus chances of affecting the CNS are minimal*

Edrophonium contains a? A. Primary ion B. Secondary ion C. Tertiary ion D. Quaternary ion

D *Thus does not cross the blood brain barrier*

Pyridostigmine (Mestinon) is a? A. Primary amine B. Secondary amine C. Tertiary amine D. Quaternary amine

D *Thus will not cross the blood brain barrier & will have minimal CNS effects*

Which of the following drugs are considered alkaloids? *Select all that apply* A. Methacholine B. Carbachol C. Bethanechol D. Pilocarpine E. Cevimeline

D & E *Are tertiary ions and can cross with blood brain barrier resulting in cortical arousal effects*

Examples include: Succinylcholine and Decamethonium

Depolarizing -These neuromuscular blockers will bind to the receptor, mimic the effects of ACh for a moment and then cause depolarization. They also prevent reactivation/repolarization (inability for muscle to respond to ACh).

Aclidinium (Tudorza-Pressair) is also used for asthma/COPD similarly to Ipratropium & Tiotropium. What are some of the advantages? A. Binds to all M receptors but has more M3 selectivity (dissociates from receptor 6 times slower than Tiotropium) B. More easily hydrolyzed in the plasma compared to Ipratropium and Tiotropium C. Less peripheral side effects since its delivered directly into the lungs D. The benzene ring bound to the phenoxy-propyl extension binds with another site on the receptor making an even tighter linkage compared to Ipratropium & Tiotropium E. All the above are advantages

E

Alpha-2 selective agonists are prone to: A. Bind to alpha-2 receptors in the brain B. Bind to Imidazoline receptors (I-1 receptors) in the brain C. Bind to Serotonin & GABA receptors D. Bind to peripheral alpha-2 receptors resulting in lowering of BP E. All the above

E

Beta-1 blockers work by: A. Decreasing heart contractility B. Decreasing ionotropic & chronotropic effects (lowering heart beat & HR) C. Inhibition of AV node D. Decreasing myocardial oxygen demand thus relieving ischemia & angina E. All the above

E

The S-enantiomer of albuterol accumulates leading to more side effects. Therefore, a pure R enantiomer is marketed with fewer side effects & more specific effects. Which of the following characterizes the above statement? A. Isoproterenol B. Colterol C. Terbutaline D. Albuterol R E. Levalbuterol/Xopenex

E

The bronchi are innervated by both sympathetic (release of NE) and parasympathetic (release of ACh). Which of the following is TRUE regarding atropine's effect on ventilation? A. Atropine blocks/prevents parasympathetic activity B. Atropine blocks bronchoconstriction produced by the vagus or M3 receptor C. Atropine DOES NOT trigger bronchodilation D. Atropine does NOT prevent the bronchoconstriction produced by histamine or prostaglandins E. All the above are true regarding atropine's effect on ventilation

E

Which of the following drug is classified as a "tetrahydroisoquinoline-based neuromuscular blocker"? A. Pancuronium B. Vecuronium C. Rocuronium D. Malouetine E. Atracurium besylate/Tracrium

E

Which of the following drugs are considered Beta-2 Selective Adrenergic Agonists? A. Isoproterenol/Isoprenaline B. Colterol C. Terbutaline D. Albuterol E. All the above

E

Which of the following is FALSE regarding carbachol? A. Amino group is a bioisostere of methyl B. Carbachol is more resistant to hydrolysis by gastric acid & esterases C. Carbachol is the carbamic acid ester (carbamate) of choline D. Carbachol binds to both N & M receptors resulting in severe drug effects if used orally E. None of the above statements are false.

E

Which of the following is TRUE regarding Cevimeline? A. Cevimeline is more resistant to hydrolysis compared to pilocarpine since it lacks an ester group but is inactivated by CYP3A4 and CYP2D6 enzymes B. Cevimeline is a muscarinic agonist that shows selectivity for M1 (CNS) and M3 (Salivary glands) receptors C. Cevimeline contains a tertiary amine thus will cross the blood brain barrier D. Cevimeline is used to increase salivation & as a treatment for dry mouth/xerostomia (replacement for pilocarpine) E. All the above are true regarding cevimeline

E

Which of the following is TRUE regarding atropine's effects on the urinary bladder? A. Direct innervation of the parasympathetic fibers with muscles of the urinary bladder and sphincter. B. Parasympathetic fibers release ACh that binds to M3 receptors causing bladder muscle to contract and sphincter to relax C. Atropine blocks the parasympathetic fibers in the muscles of the bladder & sphincter resulting in relaxation of the muscle & contraction of the sphincter D. Atropine will cause urinary retention E. All the above are true regarding atropine's effect on the urinary bladder

E

Which of the following is TRUE regarding bethanechol? A. More resistant to hydrolysis compared to carbachol B. Is selective to muscarinic receptors due to the methyl group on the beta carbon C. Shields the carbonyl carbon from a nucleophillic attack (steric shielding) D. Has a quaternary ion meaning it will not cross the blood brain barrier E. All the above is true

E

Which of the following is TRUE regarding pilocarpine? A. Pilocarpine is sensitive to hydrolysis due to the lactone "ester" and imidazole ring B. Pilocarpine ONLY binds to muscarinic receptors C. Pilocarpine contains a tertiary nitrogen thus crosses the blood brain barrier D. Pilocarpine is used for xerostomia/dry mouth caused by radiation and is available as ophthalmic drops & tablets E. All the above are true regarding pilocarpine

E

Which of the following is a limitation (s) of Acetylcholine as a drug? A. Its non-specific (it will bind to everything -- acts/binds to both nicotinic and muscarinic receptors) B. It has poor absorption (cannot easily cross lipid membranes due to the quaternary amine) C. It is unstable (can be hydrolyzed in the stomach & is easily degraded by esterases in the blood) D. It is very susceptible to a nucleophillic attack due to the carbonyl carbon E. All the above are limitations of acetylcholine as a drug

E

Which of the following statements is FALSE regarding Terazosin & Doxazosin? A. They are considered alpha-1 adrenergic receptor antagonists B. They are less susceptible to metabolism C. They have longer half-lives thus are used once a day D. They show affinity for both prostate and blood vessel smooth muscle thus can lead to cardiovascular side effects when used for BPH E. They are considered alpha-1A adrenergic receptor antagonists

E

Which of the following statements is/are true regarding Albuterol/Salbutamol? A. Its more selective for beta-2 receptors (Selective Beta 2 Adrenergic Agonist) B. Its not hydrolyzed by COMT due to the lack of a catechol ring & presence of a hydroxylmethyl group C. Its marketed as a racemic mixture of R and S enantiomers D. A pure R enantiomer is marketed as Levalbuterol/Xopenex E. All the above

E

Which of the following statements is/are true regarding Ephedrine and Pseudoephedrine? A) They are diasteriomers B) They are traditionally used as bronchodilators & stimulants. C) They are not catecholamines thus cannot be metabolized by COMT but are metabolized by MAO D) Adverse effects include: Increased BP and HR, irritability & confusion E) All the above

E

Which of the following statements is/are true regarding Terbutaline? A. It binds to beta-2 more than it does beta 1 B. Its not easily broken down by MAO due to steric hindrance (big bulky group on the nitrogen) C. Its not hydrolyzed by COMT due to the lack of a catechol ring & presence of a resorcinol ring D. Its used as a bronchodilator (opens up airways) with minimal effects on the heart E. All the above are true

E

Which of the following statements is/are true regarding scopolamine and methyscopolamine (Muscarinic Antagonists)? A. Methyscopolamine is a quaternary amine while scopolamine is a tertiary amine B. The difference between the scopolamine and methyscopolamine structure is the methyl group on methyscopolamine C. Scopolamine is used to treat nausea, vomiting and motion sickness while methyscopolamine is used to treat ulcers and cold/allergy symptoms D. Methyscopolamine is more ionized thus cannot cross the BBB while scopolamine is more unionized and can cross the BBB E. All the above statements about scopolamine and methyscopolamine are TRUE

E

Which of the following statements is/are true regarding Colterol? A. It binds to beta-2 more than it does to beta 1 B. Its short lasting due to degradation by COMT enzyme C. Its not easily broken down by MAO due to steric hindrance (big bulky group on the nitrogen) D. One NE hydrogen on the amine group is replaced with a a bulky tertiary butyl group. E. All the above are true

E *Addition of tert-butyl group on the nitrogen*

Which of the following is TRUE regarding atropine's effect on the heart? A. Vagal input in the heart has an overall parasympathetic activity B. Atropine blocks the vagal input in the heart resulting in an increased HR C. Atropine is responsible for blocking parasympathetic input (which is supposed to slow down HR) D. At lower doses, atropine binds to auto-receptors resulting in an increased release of ACh that binds to the M receptors (M2) of the heart resulting in a decrease in HR (bradycardia) but when the dose is increased, atropine begins to have a direct effect on the heart tissue resulting in an increased HR E. All the above are true regarding atropine's effect on the heart

E *At high doses, atropine causes tachycardia but at low doses, atropine causes bradycardia*

Which of the following is TRUE regarding atropine's effects on sweat glands? A. Sympathetic innervation using the neurotransmitter ACh B. Binds to M receptors C. Atropine reduces sweat production D. Atropine can induce hyperthermia E. All the above are true

E *Atropine reduces sweat production b/c sympathetically, sweat production is supposed to increase but since atropine is blocking the sympathetic innervation, sweat production decreases*

Which of the following drugs are classified as "steroid-based neuromuscular blocking agents"? A. Pancuronium B. Vecuronium C. Rocuronium D. Malouetine E. All the above

E *Hint: "ronium" & malouetine* *Recognize the 4 ring steroidal structure that separates the 2 quaternary nitrogen's at the right distance* *Different blockers have different R groups attached; both R groups do not need to be quaternary amines*

Which of the following statements is/are TRUE regarding Tubocurarine use as a non-depolarizing neuromuscular blocker? A. Structure contains 2 nitrogen's that are separated by a distance of 10-12 carbons B. Binds better than ACh due to the nature of 2 quaternary amines as compared to 1 quaternary amine in ACh C. Used parenterally as an injection D. Blocks neuromuscular junctions everywhere including respiratory muscles which is a safety issue E. All the above statements are TRUE

E *NO CNS effects*

Which of the following statements is/are true regarding Isoproterenol? A. Its a non-selective beta adrenergic agonist (binds to both b1 & b2) B. Its degraded by the COMT enzyme & MAO enzyme to an extent C. Its beta selective thus increases HR & diastolic BP - Increasing contractility (Beta 1) and decreases systolic BP due to decreased vascular resistance on the skeletal muscle (vasodilation - B2) D. One NE hydrogen on the amine group is replaced with a bulky Isopropyl group E. All the above are true

E *Not much degradation by MAO due to the bulky isopropyl group*

Which of the following are examples of organophosphates? A. Parathion B. Malathion C. Sarin D. Soman E. All the above

E *Parathion & Malathion are insecticides while sarin & soman are chemical weapons*

Which of the following statements is/are true regarding Phenylephrine and Metaraminol? A. Para hydroxyl is absent (no longer a catechol ring; only one hydroxyl group is present on the ring) B. They're more alpha 1 selective C. Will not be metabolized by COMT due to the lack of a catechol ring D. Will be metabolized by MAO due to lack of bulky group on nitrogen thus will have short half-lives. E. All the above is true

E *Removing a hydroxyl group lowers the affinity for all receptors but affects more beta receptors than alpha thus drug becomes more alpha selective*

Which of the following are considered the minimum basic requirements for receptor binding? A. Catechol ring (Benzene ring with 2 hydroxyl groups next to each other) B. Beta hydroxyl group C. 2 carbon bridge between the catechol ring and nitrogen D. Nitrogen with a positive charge in-vivo E. All the above are requirements for receptor binding

E *Structure is of Epinephrine*

What are the contraindications of Muscarinic agonists? A. Asthma B. Peptic ulcer disease C. Coronary heart disease D. Hyperthyrodism E. All the above

E 1) Asthma: Bronchoconstriction, mucus production 2) Peptic ulcer disease: Increased gastric secretions worsen the disease 3) Coronary heart disease: Hypotensive effects may reduce blood flow 4) Hyperthyroidism: May increase the risk of atrial fibrillation

What is the major adverse event seen in patients on alpha-1A selective adrenergic receptor antagonists?

Ejaculation dysfunction

M1, M3, M5 result in?

Excitation *Muscarinic receptor: G-Protein Coupled Receptors*

Gq results in?

Excitatory post-synaptic potential (EPSP)

Adverse effects of beta blockers:

For cold extremities: Beta 2 receptors are good for keeping the body warm so intake of a beta 2 blockers causes peripheral vascular constriction

Muscarinic M receptors are?

G-Protein-Coupled receptors (GPCR)

Question from class: Which of the following is a structure of a Tetrahydroisoquinoline-based Neuromuscular blocker?

He will most likely mix in steroid based so know that Tetrahydroisoquinoline has 2 "tetrahydroisoquinione rings on both ends & are separated by spacer groups containing ester groups.

contraindications of Muscarinic agonists: Coronary heart disease:

Hypotensive effects may reduce blood flow

contraindications of Muscarinic agonists: Peptic ulcer disease:

Increased gastric secretions worsen the disease

Gi results in?

Inhibition (decreased activity of target)

M2 sub-type is most likely to be?

Inhibitory

Which of the following class of acetylcholinesterase inhibitors satisfy the following requirements: 1. Covalently modify the enzyme 2. Enzyme is impossible to regenerate after an "aging" process 3. Examples of drugs in this class include: Organophosphates "nerve gases"/poisons

Irreversible inhibitors

Question from class: Which of the following is a structure of a steroid based neuromuscular blocker?

Know answer based on the 4 ring structure found in all steroid-based neuromusuclar blocking agents.

Non-selective beta + alpha 1 blockers (3rd generation) beta blockers block both beta 1- receptors and beta-2 receptors and also block alpha 1-receptors. Which of the following drugs fit the description of Non-selective beta + alpha 1 blockers?

Labetalol Carvedilol *Labetalol has Beta-2 agonistic effects* *Carvedilol has anti-oxidant effects*

What is the most notable function of M receptors in the CNS (relevance to Alzheimer's)?

Learning and memory

Nicotinic N receptors are?

Ligand-gated ion channels

contraindications of Muscarinic agonists: Hyperthyroidism:

May increase the risk of atrial fibrillation

Asthma patients are contraindicated for?

Muscarinic agonists

N1 (Nm) and N2 (Nn) are the 2 major subgroups of nicotinic receptors. Which of the 2 includes neuromuscular junctions?

N1 (Nm)

Pancuronium, tubocuratine and vercuronium are examples of neuromuscular blockers/antagonists used during surgery. These drugs act on the?

N1 (Nm) - neuromuscular junction

N1 (Nm) and N2 (Nn) are the 2 major subgroups of nicotinic receptors. Which of the 2 includes autonomic ganglia, adrenal medulla and CNS?

N2 (Nn)

Ganglionic blockade/antagonist drugs reduce blood pressure in patients with aortic dissection & result in many adverse effects. These drugs act on the?

N2 (Nn) - autonomic ganglia *They DON'T act on the adrenal medulla*

Carbachol comes in an optic formulation, causes miosis (constriction of the pupil) and is indicated for?

Narrow angle glaucoma

Scopolamine patches are indicated for?

Nausea & Vomiting and Motion sickness (at lower doses) -Zombie drug and should be used at low doses

Which of the following drugs work by blocking/inhibiting the enzyme acetylcholinesterase?

Neostigmine Physostigmine Organophosphates (nerve agents)

Which of the following class of acetylcholinesterase inhibitors satisfy the following requirements: 1. Interact with the active site 2. No covalent modification of enzyme (just sits in the active site & blocks ACh from entering) 3. Examples of drugs in this class would be: edrophonium, donepezil, galantamine

Non-covalent inhibitors *lack the carbamoyl group thus do not modify the enzyme*

Examples include: Tubocurarine, Pancuronium, Vecuronium, Pipecuronium, Rocuronium, Mivacurium, Atracurium

Non-depolarizing -These neuromuscular blockers are also competitive antagonists that will bind and occupy the receptor & prevent ACh from binding to the receptor

Which of the following drugs are considered to be "semi-synthetic or synthetic" muscarinic antagonists derived from natural products?

Oxybutynin Glycopyrrolate Procyclidine Benzatropine Solifenacin *Others include: Trihexyphenidyl, darifenacin, orphendarine*

What are considered antagonists of the somatic nervous system?

Pancuronium Tubocurarine Vecuronium Rocuronium Mivacurium

Methacholine will mimic the effects of what pathway? (Example: bronchospasm/bronchoconstriction)

Parasympathetic

The autonomic nervous system can be divided into the sympathetic and parasympathetic nervous systems. Which of the 2 is known as the "rest & digest" system?

Parasympathetic

Which of the following drugs are considered Alpha-1 Selective Adrenergic Agonists?

Phenylephrine Metaraminol Xylometazoline Naphazoline

Question from class: A drug that treats tremors and spasms should be able to penetrate the brain. Which of the following drugs would be used to treat tremors and spasms? *Answers in structure form*

Pick the tertiary amine

Phosphor-adduct is stuck on the enzyme after a nucleophillic attack. Water was originally sufficient to regenerate the enzyme in acetylation & carbamylation but cannot regenerate the enzyme for organophosphates. What is the other option we could use that is a stronger nucleophile compared to oxygen (water)?

Pralidoxime (antidote) -- CHEMICAL ANTAGONIST *Delivered SC or IV within a few minutes to hours depending on the nerve agent* *This will be able to reverse & regenerate the enzyme and also hydrolyze the hydroxyl group so it could take out the phosphor-adduct*

Alpha-1 blockers include:

Prazosin/Minipress Terazosin/Hytrin Doxazosin/Cardura *Prazosin is an exclusive anti-hypertensive* *Terazosin & Doxazosin show affinity for both prostate receptors & blood vessel receptors*

Non-selective (1st generation) beta-blockers block both beta-1 receptors and beta-2 receptors. Which of the following drugs fit the description of non-selective beta blockers? *Select all that apply*

Propanolol Nadolol Pindolol Timolol Carteolol Bunolol *A Non-selective drug would not be good in asthma patients or similar conditions due to the fact that it also blocks beta-2 which can lead to constriction= Bronchospasm of the airways in the lungs*

Glycopyrrolate (Robinul) is used parenterally before surgery to?

Reduce salivary/GI secretions *Adverse effects include: Xerostomia, photophobia, blurry vision, tachycardia*

Which of the following class of acetylcholinesterase inhibitors satisfy the following requirements: 1. Mimic Acetylcholine 2. Covalently modify the enzyme 3. Takes longer to regenerate the enzyme compared to Acetylcholine 4. Examples of drugs in this class would be: Neostigmine, Physostigmine, Pyridostigmine, Rivastigmine

Reversible carbamate inhibitors *have a carbamate group instead of acetylcholine* *You should be able to identify a drug in a way that modifies the enzyme. These 4 modify the enzyme -- analyze the structure & know them + know which structures are likely to penetrate the CNS/BBB*

Which of the following drugs are considered to be "alkaloidal" muscarinic antagonists isolated from natural products?

Scopalamine Atropine Ipratropoium Tiotropium *Others include: Hyoscyamine, Methoscopolamine*

Question from class: If you have a *short duration* surgery, which of the following would be the most appropriate option for use as a steroid-based neuromuscular blocker? A. Pancuronium B. Vecuronium C. Rocuronium *Long duration?*

Short = Rocuronium Long = Pancuronium *NO CNS effects since they are quaternary*

The autonomic nervous system can be divided into the sympathetic and parasympathetic nervous systems. Which of the 2 is known as the "fright & flight" system?

Sympathetic

The parasympathetic ganglia are within or close to the?

Target organ

Why is atropine an antagonist if it still binds to the receptor?

The ring has to do with the reason why atropine is a muscarinic antagonist of the receptor. You have to have at least 1 aromatic ring for compounds to have antagonistic effects & it has to fit in the hydrophobic pocket of the receptor (this is KEY). Acetylcholine does not fit in the hydrophobic pocket of the receptor nor does it have an aromatic ring. *Atropine prevents Acetylcholine from binding to the receptor since it (atropine) binds to all M receptors equally*

The sympathetic system is also known as the:

Thoracolumbar system

T/F: Mechanism of beta blockers interfere with metabolic pathways.

True

This neuromuscular blocking agent was long used by South American natives as arrow poison in the form of "Curare" to cause muscle paralysis in animals?

Tubocurarine

Which of the following is considered an indication of bethanechol?

Urinary retention and abdominal distention (post-surgical & post-partum)

Methacholine (parasympathetic)

asthma diagnosis & bronchoconstriction

Why should non-selective beta blockers be avoided in asthma/COPD patients?

b/c non-selective beta blockers act on both beta-1 receptors and beta-2 receptors. Beta-2 receptor stimulation results in bronchodilation. Non-selective beta-blockers act on beta-2 receptors and will result in bronchoconstriction = bronchospasm.

Bethanechol (parasympathetic)

bladder contraction (treatment of urinary retention)

Muscarinic antagonists (more sympathetic)

compete with ACh to bind to muscarinic receptors & also antagonize the effects of ACh.

Acetylcholinesterase inhibitors

enhance ACh by preventing decomposition/breakdown of ACh.

Cevimeline (parasympathetic)

increases salivation

Muscarinic agonists (more parasympathetic)

mimic the effects of ACh by binding specifically to the muscarinic receptors at various sites

Carbachol(parasympathetic)

miosis & cataract surgery

Pilocarpine(parasympathetic)

treatment of dry mouth/xerostomia

Innervation of adrenal medulla

where you have 1 fiber instead of 2 (no synaptic gap); the fiber from the CNS to the adrenal medulla produces ACh & in a way its like the pre-synaptic fiber and the cells (known as chromaffin cells are like postganglionic neurons) that produce epinephrine and NE as a result of the stimulation are very much related to post-synaptic neurons producing mostly epinephrine (80%) and some norepinephrine (20%) which is released into circulation*

Exceptions to the general rule: Sympathetic innervation of adrenal medulla & sweat glands

•Epi (~80%) & NE (~20%)>>> circulation •Hormonal response •"Reinforces" the neuronal sympathetic response