Exam 1 Flashcards
What are the differences in organization/neuron types in the ANS? (ex. cholinergic v. adrenergic, preganglionic v. postganglionic)
Cholinergic - Parasympathetic mechanisms
Adrenergic - Sympathetic mechanisms (named because of the adrenal medulla)
Preganglionic - Nicotinic receptor. Neurotransmitter is always ACh.
Postganglionic - For PSNS, neurotransmitter is ACh and receptor is usually muscarinic. For SNS, receptor is adreneric.
What are the major neurotransmitters found in the autonomic nervous system?
ACh - the pre-ganglionic neurotransmitter for everything; Also post-ganglioic neurotransmitter
NE - post-ganglionic for sympathetic pathway
E - post-ganglionic for adrenal sympathetic pathway
What are the major physiological responses under parasympathetic and sympathetic control?
Parasympathetic - Cardiac and smooth muscle, gland cells, nerve terminals
Sympathetic - Sweat glands, cardiac and smooth muscle, gland cells, nerve terminals, renal vascular smooth muscle.
How can you differentiate the sympathetic control of the sweat glands, kidney, and adrenal glands from other areas of the sympathetic nervous system?
Sweat glands - When it’s stress related, the post-ganglionic neurons release NE, but when it’s thermoregulation, post-ganglionic neurons release ACh.
Kidney - Not innervated, so they are not controlled by neurotransmitters that are released by CNS, but neurotransmitters that are released by something else (ex. Dopamine that is produced locally)
Adrenal glands - Preganglionic neurons don’t synapse on paravertebral sympathetic ganglion, but on the adrenal gland itself. Also, adrenal glands release E, not NE.
What are the different describing terms for drugs that effect the autonomic nervous system?
Drugs either mimic or block ACh and NE/E
Receptor agonist - mimic NTs to activate receptors
Receptor antagonist - block NTs and deactivate.
Parasympathomimetic - mimics ACh, muscarinic agonist, cholinergic
Parasympatholytic - blocks ACh, anticholinergic, muscarinic antagonist
Sympathomimetic - mimics NE, adrenergic, adrenergic agonist
Sympatholytic - blocks NE, antiadrenergic, adrenergic antagonist.
What are the major types of neurotransmitter receptors found in the autonomic nervous system organized by structure, signal transduction pathways, tissue distribution, and associated physiological effects?
Muscarinic - M1-5 subtypes. M1-3 are main functional ones. They are GPCRs
Nicotinic - Ligand Gated Ion Channel.
Adrenergic - A1-2, b-,2,3
How can you predict the effects on an organ system or 2nd messenger formation given a specific drug (agonist or antagonist)? Heart, vasculature, lung, genitourinary, penis/vas deferens, GI, liver, kidney
An agonist activates the receptors, antagonist inhibits receptors.
Heart: SNS - Increase rate and force of contraction (mainly b1); PSNS - Decrease rate and force of contraction (m2)
Vasculature: SNS - constriction (a1, a2, b2)
Lung: SNS - dilate (b2) and PSNS (m2,3) constrict
Genitourinary: SNS - halts urination; PSNS - stimulates urination
Penis/vas deferens: Only one where they work together!
GI: SNS inhibits secretion; PSNS increases secretion
Liver: SNS - Glucose production/degradation through a1 and b2
Kidney: SNS - increases renin secreation by b1
What are the signal transduction pathways that are associated with each of the major receptor types in the ANS?
M1,3,5 - Gq pathway (IP3 -> more Ca+; DAG -> PKC)
M2,4 - Gi pathway (inhibits cAMP production and K+ channel opens causing hyperpolarization).
a1 - Gq pathway; Major function is vasoconstriction due to its location (various smooth muscle, heart, liver)
a2 - Gi pathway
b1,2,3 - Gs pathway (increase cAMP through adenylyl cyclase; kinase activity)
What are the differences between the sympathetic and parasympathetic control of the eye (pupillary size, lens refractive power, aqueous humor production and flow)?
Pupillary size - SNS dilates, PSNS constricts
Lens refraction - ??
Aqueous humor secretion- SNS increases aqueous humor through ciliary epithelium (b2)
Aqueous drainage (flow) - SNS ciliary body a2 receptor inhibits production of aqueous humor and increases the outflow of it; PSNS contracts ciliary muscle, increasing flow.
How can you predict the effects of a given drug on pupillary size (miosis v. mydriasis) based on knowledge of the radial and circular muscles?
If the drug is an agonist or antagonist of these receptors, the following things will happen:
Miosis - pupillary constriction through the circular muscle (PSNS); m3 receptor.
Mydriasis - pupillary dilation by radial muscle (SNS); a1 receptor.
What are the major pharmacologic manipulations of the cholinergic system?
Muscarinic receptor agonist
AChE inhibitor
How can you identify the major structural features of a drug to determine what is responsible for its activity? (In terms of charge and structure for AChE binding)
- charged molecules can’t pass BBB
- no acetyl group would ensure that it wouldn’t get hydrolyzed by AChE
- 4º amine ensures it will bind to anionic site in AChE
How can you determine what the effect of a chemical modification will do to a molecule’s activity/sensitivity to acetylcholinesterase?
Acetylcholinesterase hydrolyzes ACh extremely fast, so decreasing ACh’s sensitivity to AChE will increase the binding of ACh to its receptor.
In this case, it’ll further stimulate muscarinic receptors that have various effects.
What is the molecular basis for the interactions of acetylcholine and related drugs with muscarinic receptors (esp. on stereochemical requirements of drugs)?
The muscarinic receptor is steroselective.
ACh assumes a particular formation when it binds to the muscarinic receptor. The derivaties of ACh mimic that stereochemistry (even tho ACh doesn’t have a chiral center, the derivatives do).
How can you choose the appropriate cholinergic agonist to treat various clinical conditions? (Bethanechol, methacholine, carbachol, pilocarpine)
Bethanechol - GI stimulation & treatment of urinary retention
Methacholine - Provocative test for hyperreactive airways
Carbachol - Ocular surgery & glaucoma
Pilocarpine - glaucoma & hypoproduction of saliva
What’s the difference between acetylcholinesterase and plasma cholinesterase?
Plasma ChE has a much broader range of selectivety than AChE (hydrolyzes ACh, Succinylcholine, and local anesthetics)
Plasma ChE is not neuronal (it’s in plasma), but AChE is (in synapse).
What are the direct and indirect mechanisms of acting parasympathomimetic drugs?
Direct - Binds to muscarinic receptor
Indirect - Inhibits AChE
What are the roles that the AAs at the esteratic and anionic sites play in the catalytic steps associated with the actions of acetylcholinesterase?
The 4º amine binds to anionic site, and the ester binds in the catalytic triad. Then, the OH on the serine attacks the ester and the ACh splits. Serine is now attached to acetate. Then, water comes in an attacks the acetate, and it is now released. Once the acetate is release, the enzyme is reactivated and restarts the cycle.
What are the differences between the structures and molecular interactions of the reversible cholinesterase inhibitors with acetylcholinesterase? (Edrophonium, Neostigmine/Pyridostigmine, Pyridostigmine)
Edrophonium - An alcohol and a quat. amine. This binds to the anionic site of AChE, but can’t be hydrolyzed, so it blocks the site.
Pyridostigmine & Neostigmine - A carbamate & quat. amine. Causes covalent modification to AChE. Hydrolyzed slower than ACh, so slows down AChE.
Physostigmine - A carbamate, but no quat. amine, so more likely to cross the BBB. Causes covalent modification to AChE. Hydrolyzed slower than ACh, so slows down AChE. (Still can be pos. charged at phys. pH)
How can you choose the appropriate acetylcholinesterase inhibitor to treat various clinical conditions? (Edrophonium, Pyridostigmine, Neostigmine, Physostigmine)
Edrophonium - Diagnosis of Myasthenia Gravis; Very short acting.
Pyridostigmine - Treatment of MG, pretreatment for potential nerve gas exposure, reversal of non-depolarizing neuromuscular blockade
Neostigmine - MG, reversal of non-depolarizing neuromuscular blockade, post-op urinary retention
Physostigmine - Glaucoma, Alzheimer’s, & Antidote to antimuscarinic poisoning because it can cross the BBB.
What’s the difference between the mechanism of organophosphates (inc. aging effect) and the reversible inhibitors of acetylcholinesterase?
Organophosphates have a phosphate that permanently covalent bond to Serine’s functional group (usually, H2O can come and kick out the covalent bond, but the phosphate bond is too strong).
When the phosphate binds to serine, it can later form an anion (process called aging), which is extremely poisonous.
In the reversible inhibitors, the compounds get hydrolyzed and released as water replaces the transient covalent bond.
What’s the difference in toxicity of Malathion and Diazinon in mammals and insects?
Malathion is rapidly inactivated to its acid form in mammals due to a carboxyesterase enzyme that we have, but insects do not have this capability, so it’s toxic for them.
Diazinon - ??
Why shouldn’t parasympathomimetic drugs be used in asthma, peptic ulcer, or bowel and urinary obstructions?
The parasympathomimetic drugs stimulate the PSNS, which is responsible for bronchoconstriction and for simulating digestion/urination. It increases acid secretion, and increased contractions don’t necessarily remove the obstructions.
What are the signs and symptoms of parasympathomimetic toxicity and how can you determine the appropriate treatment?
Signs/Symptoms - DUMBBELS (essentially consequences of overstimulations of cholinergic receptors); SLUD (salivation, lacrimation, urination, defecation)
2-PAM (Pralidoxime) - Antidote of organophosphate toxicity. Must be combined with atropine for BBB access.
Atropine - Cholinergic receptor antagonist, doesn’t need to be with 2-PAM if it’s not necessary.
What are the cholinergic agents used to treat Alzheimer’s dementia? (4)
All reversible:
Tacrine (Cognex) - Binds to anion site to prevent ACh binding; Enhances cognitive ability, but doesn’t slow the progression of the disease
Rivastigmine (Exelon) - 3º amine; Enhances cognitive ability, but loses effectiveness as disease progresses; Side effects include nausea, vomiting, anorexia, and weight loss.
Galantamine (Razadyne) - Natural product that loses effectiveness as disease progresses
Memantine (Namenda) - NMDA receptor antagonist, which decreases stimulation in CNS by glutamate in areas associated with cognition and memory, which may slow the progression of the disease.
What are the side effects of Cholinergic agonists? DUMBBELS
Diarrhea Urination Miosis Bradycardia Bronchoconstriction Emesis Lacrimation Sweating/Salivation
What are the various clinical uses of antimuscarinic drugs? What are examples of drugs used for each clinical purpose?
Treatment of motion sickness - Scopolamine
Mydriasis, cycloplegia - Homatropine, Tropicamide (short-lasting)
Parkinsons Disease - Benztropine
COPD - 4º amines; Ipratropium
GI disorders - 4º amines; Glycopyrrolate, Probanthine
OAB - Tolterodine
What are the clinical outcomes of antimuscarinic drugs in terms of the functional properties of M1, M2, and M3 muscarinic receptors?
M1 - Responsible for postganglionic functions (depolarization); Not many things target M1
M2 - Responsible for the heart (slowing beat, reducing force); When targeted, pulse raises, force increases.
M3 - Responsible for smooth muscle (contractions), exocrine glands (secretions) and endothelium (relaxation); This can be targeted to reduce constriction (ex. asthma treatment, COPD), reduce secretions (ex. Pre-op GI surgery)
What are the pharmacophore characteristics of antimuscarinic drugs?
Antimuscarinic drugs are mainly tertiary or quaternary amines.
They also have an ester, mimicking the acetyl moiety of ACh.
How does the clinical use of antimuscarinic drugs depend on the drug’s duration of action?
Long acting - Used for longer term issues like Parkinson’s, GI disorders, motion sickness
Short acting - Used in optical applications like cycloplegia and mydriasis
Ex. We don’t want to use a long acting drug on something that’ll affect the patient’s vision.
Why are antimuscarinic drugs with a quaternary amine group suitable for some clinical purposes but not others?
Having a quaternary amine results in a permanent positive charge. A positive charge makes it impossible for the compound to pass the BBB. So, if CNS assess is needed, then a quaternary amine would NOT be suitable.
Quaternary amines are used in GI tract and other peripheral applications, and tertiary amines are used in ocular and CNS appications.
What is the chemical and biological rationale for the anticholinergic effects of drugs that were not designed to target muscarinic receptors?
This one, she said it’s more general like we have to be aware of the anticholinergic effects of drugs to make sure it’s okay to give to the patient.
What are the clinical uses of ganglionic and neuromuscular blockers? What are examples of drugs used in each clinical purpose?
Skeletal muscle relaxation during anesthesia - Tubocurarine (Curare), Succinylcholine
Muscle spasm issues - Botulinum Toxin
HTN - Hexamethonium (not anymore tho)
What are the clinical outcomes of ganglionic and neuromuscular blockers in terms of the functional properties of nicotinic receptors?
N skeletal - Responsible for motor end-plate depolarization and contraction; Can be targeted to prevent the contraction.
N neural - Responsible for depolarization and catecholamine secretion; When targeted, can block SNS and PSNS activity.
What are the pharmacophore characteristics of ganglionic and neuromuscular blockers (ex mono and bis-quaternary motifs)?
Neuromuscular blockers look like ACh, but they don’t have the acetyl group, so they can’t be hydrolyzed by AChE.
What are the different modes of action of depolarizing vs. non-depolarizing ganglionic and neuromuscular blockers?
Depolarizing blockade - Ensures that the channel never resets by keeping the agonist bound to the receptor, so the channel stays inactive. A depolarizing blocker is one that binds and activates nicotinic receptor once, but then blocks it. (ex. Succinylcholine)
Non-depolarizing - Binds to active site of nicotinic receptor and blocks it without every activating it (ex. Tubocurarine)
What are the key structural features of anti-muscarinic drugs and ganglionic and neuromuscular blockers?
They all mimic ACh. They either have 3º or 4º amine.
Anti-muscarinic - have acetyl moiety.
Ganglionic/neuromuscular blockers - Look like ACh, but can’t be hydrolyzed by AChE because they lack the acetyl moiety.
What are the differences between the major pharmacologic mechanisms that alter adrenergic system function?
??
What are the major steps in catecholamine synthesis and metabolism?
- Tyrosine (single -OH, NH2, COOH)
- Tyrosine converted to L-DOPA by tyrosine hydroxylase (Adds an -OH, now is a catechol)
- L-DOPA converted to Dopamine through AA Decarboxylase (Takes off carboxyl (-COOH))
- Dopamine converted to NE by Dopamine b-Hydroxylase (adds -OH to beta carbon)
- NE converted to E by N-methyltransferase (adds CH3)
What are the different adrenergic receptor subtypes (in terms of signaling pathways and location)?
a1 - Gq pathway
a2 - Gi pathway, in CNS
b1 - Gs pathway
b2 - Gs pathway
What is needed in the structure of NE to bind to adrenergic receptors?
NE has one chiral center (R orientation), and that is what is important for direct binding to the adrenergic receptors.
What are the effects of structural changes in an adrenergic receptor agonist w/ regards to receptor selectivity, activity (agonist v. antagonist), mechanism of action (direct v. indirect), lipophilicity, and metabolism?
Receptor selectivity - The bulkier the group (on α carbon), the more likely it’ll bind to b2 receptors (order from least bulky to most bulky: a -> b1 -> b2); Moving one of the -OH from the catechol makes it selective for b2, whereas removing one -OH makes it selective for a1
Activity -
MOA -
Lipophilicity - As the R group on α carbon gets bulkier, it is more likely to be lipophilic (adding more carbons)
Metabolism - As the R group (on α carbon) gets bulkier, the less likely it is to be metabolized by MAO.
How can you determine the receptor selectivity of adrenergic receptor agonists through dose-response curves?
In a dose-response curve, the left-most curve (indicating lowest value) means the drug is most selective for that receptor.
Ex. Phenylephrine will be left-most on a graph that is indicating a1 receptor activation.
Given data on the effects of adrenergic agonists on the CV system, how can you predict what adrenergic receptor(s) the drug is acting on?
b1 receptor is known for cardiac stimulation, which results in increased heart rate and force of contraction
a1 receptor is known to facilitate vasoconstriction; An agonist would cause vasoconstriction, raising BP
b2 receptor is known to facilitate uninnervated vasodilation; Agonist would lead to fall in BP and bronchodilation
What are the pharmacologic properties, adverse effects, and clinical uses of different selective and non-selective a-adrenergic receptor agonists? (NE, E, D, Phenylephrine, Naphazoline/Tetrahydrozoline/Oxymetazoline, Clonidine, Guanabenz/Guanfacine, Methyldopa, Brimonidine, Apraclonidine, Tizanidine)
Norepinephrine - direct, non-selective, raises blood pressure
Epinephrine - direct, non-selective, used for anaphylaxis (b2), glaucoma, and in combination with anesthetics
Dopamine - direct D1, b1, and a1 agonist, used for shock and CHF
Phenylephrine - direct a1, mydriasis, pressor, nasal decongestant
Naphazoline/Tetrahydrozoline/Oxymetazoline - direct a1 partial agonist, used for local vasoconstriction with nasal and ophthalmic decongestants
Clonidine - a2 agonist, used for HTN, opiate withdrawal, and ADHD
Guanabenz/Guanfacine - a2 agonist, used for HTN and ADHD
Methyldopa - a2 agonist (prodrug), active metabolite used for HTN
Brimonidine - a2 agonist, used for glaucoma
Apraclonidine - a2, Glaucoma
Tizanidine - a2, Muscle spasticity
What are the general structural features of imidazoline-based a-adrenergic receptor agonists?
Imidazoline: 5 membered ring with 2 nitrogens
- results in e- dispersion due to resonance, thus stabilizing the charge
- more basic due to this stability
What are the differences in the effects of changes in a2-adrenergic receptor agonist structure on cardiovascular response and receptor affinity?
The a2 receptor is in the CNS and antagonizes the a1 receptor functions. It decreases the release of NE, and therefore decreases the sympathetic tone of the SNS.
In order to increase CNS, you want the pKa to be lower (ex. pKa of 8) so that it’s not protonated (don’t want + charge). The goal is to be non-ionized at physiological pH, but still mimic imidazoline.
What are the differences in pharmacologic properties, adverse effects, and clinical uses of selective and non-selective b-adrenergic receptor agonists? (Isoproterenol, Terbutaline/Metaproterenol, Albuterol/Salmeterol, Formoterol, Dobutamine, Mirabegron)
Isoproterenol - non-selective, used for asthma, COPD, and cardiostimulant
Metaproterenol/Terbutaline - b2 agonist, used for asthma, COPD (terbutaline also used to prevent premature labor)
Albuterol/Salmeterol - b2 agonist, used for asthma, COPD (Salmeterol used for long term asthma)
Formoterol - b2 agonist, used for long term asthma
Dobutamine - mixed b1 (and a1) agonist, strong inotropic effect results in use for acute heart failure and shock
Mirabegron - b3 agonist, used for OAB
What structural changes in b-adrenergic receptor agonists lead to increased b2 receptor selectivity and resistance to MAO and COMT?
- increase in bulky R group off of amine group increases selectivity for b2 receptor and lessens MAO activity
- changing from catechol to resorcinol or meta-hydroxymethyl makes compound selective for b2
How does the racemic mixture of dobutamine lead to a selective inotropic effect on the heart?
The (+) enantiomer is a b1 agonist and an a1 antagonist, and the (-) enantiomer is an a1 agonist and the potency for b receptors is reduced x10. This results in a strong inotropic effect, but little chronotropic effect.
What are the differences in the major mechanisms of indirect-acting sympathomimetics from the direct receptor agonists?
Direct binds to the actual adrenergic receptors.
Indirect-acting sympathomimetics bind to receptors that are in charge of NT reuptake and either inhibit them, or alter the pre-synaptic conc. of the NT. There are also MAOIs that increase the amount of NT circulating by inhibiting MAO, which usually metabolizes the NT.
Ex. NET blocked by cocaine
For amphetamine and related drugs, what are the pharmacologic actions that contribute to and promote release of catecholamines from neurons?
Through the actions of the plasma membrane transporter, the extra drug makes the pre-synaptic cell think there is more NT inside than there actually is, so it pumps out more NT. This results in excess NT in the synapse.
What are the pharmacologic properties, adverse effects, and clinical uses of the different selective and non selective a-adrenergic receptor antagonists? (Phenoxybenzamine, Phentolamine, Terazosin/Doxazosin, Tamsulosin/Prazosin)
Phenoxybenzamine - a1 & a2; Used for pheochromocytoma, hypertensive crisis
Phentolamine - a1 & a2; Used for pheochromocytoma, hypertensive crisis, and male impotence
Terazosin, Doxazosin - a1; Used for HTN, benign prostatic hypertrophy (BPH)
Tamsulosin & Prazosin - a1; Used for HTN, BPH, and Reynaud’s disease
Side effects of a1 receptor antagonists: orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
What is the mechanism by which phenoxybenzamine irreversibly inactivates adrenergic receptors?
Phenoxybenzamine is a b-Haloalkylamine that has a Cl as the X group. This Cl forms a covalent bond with the receptor, making it irreversible.
The covalent bond is formed by making a highly reactive intermediate called Aziridinium ion, which is then used to make the bond with the receptor.
-It also blocks ACh, Histamine, and Serotonin receptors.
What are the general structural features of selective and non-selective a-adrenergic receptor antagonists?
Non-selective: b-Haloalkylamines that have an alkyl group on one end and an aromatic or alkyl attached to the nitrogen on the other end. Also imidazolines (5 membered ring with 2 nitrogens)
a1 selectivity: Quinazolines that have 2 aromatic rings (one with 2 nitrogens, the other has ethers attached)
a2 selectivity: Indole alkaloid
How can you predict effects on dose-response curves of combinations of adrenergic agonists and antagonists?
A competitive antagonist will push the curve to the right (lower affinity).
An irreversible antagonist will lower the max binding, and thus lower potency.
What are the differences in pharmacologic properties, adverse effects, contraindications, and clinical uses of non-selective b-adrenergic receptor antagonists? (Propanolol, Nadolol, Timolol, Pindolol, Carteolol)
b-blockers common indications: decreased CO and HR, reduced renin release (& BP), Increase VLDL, Decrease HDL, Inhibit lipolysis, Inhibit glycogenolysis/glucose release, Increase bronchoconstriction
b-blocker clinical use: HTN, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, CHF.
blocking b2 is contraindicated with asthma due to bronchoconstriction
Propanolol - non-selective, has local anesthetic properties
Nadolol - non-selective, HTN, agina, migraine, contraindicated in kindey disease pts.
Timolol - non-selective, Glaucoma, hypertension, angina, migraine
Pindolol - non-selective, Has intrinsic sympathomimetic activity, making it a partial agonist. It is less likely to cause bradycardia/lipid abnormalities. Used for HTN, angina, migraine.
Carteolol - non-selective, Has ISA, so partial agonist. Used in HTN and glaucoma
What are the general structural features of selective and non-selective b-adrenergic receptor antagonists?
Non-selective: Aryloxypropanolamines which have a non-carbon atom in the side chain attached to an aromatic ring and a bulky alkyl group attached to the nitrogen.
b1 selective: para-substited phenyl derivatives. These have a group on the para position on the aryl group.
How can you differentiate partial agonists from antagonists and full agonists using dose-response curves?
Partial agonists decrease the affinity and potency. An antagonist would take the response to 0%, but the partial could take it from 100 to 50%.
