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Pharmacology and Toxicology > Exam #1 > Flashcards

Exam #1 Flashcards

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1
Q

Explain the differences between efferents, afferents and interneurons

A

efferents: motor neurons that carry signals to the periphery from the CNS (can control voluntary muscles or tissues of the autonomic nervous system)
afferents: sensory neurons - convey information from internal & external environment back to the CNS
interneurons: convey information between other neurons. All of the neurons of CNS are interneurons. Interneurons that carry info between brain regions are projection interneurons, and those that carry signals within a brain region are local interneurons

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2
Q

Describe the role of ion channels in the establishment and maintenance of a membrane potential

A

cell membrane is impermeable to ions, so ion channels allow diffusion of ions into & out of the cell. Passive channels are open all of the time. Voltage gated ion channels open when stimulated by a change in electrical difference between inside & outside of the cell.

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3
Q

List the relative concentrations of Na+, Cl-, K+ and organic ions on the inside & outside of a neuron

A

Na+ greater concentration outside the cell than inside
Cl- greater concentration outside the cell than inside
K+ smaller concentration outside the cell than inside
organic anions all are inside the cell (none are outside)

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4
Q

Explain the role of the sodium-potassium pump with respect to maintenance of the membrane potential

A

Keeps the membrane potential negative, because it pumps 3 Na+ ions out for every 2 K+ ions in (while using up one ATP)

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5
Q

Describe how an action potential is initiated and propogated

A

membrane becomes depolarized by 15-30mV, voltage-gated Na+ channels open & Na+ ions go into the cell. Causes more depolarization and more voltage-gated Na+ channels to open. At peak depolarization, Na+ channels close and voltage-dependent K+ channels open, K+ goes out of the cell. Then Action potential is propagated through axon: adjacent Na+ channels open due to local change in membrane potential & proceeds along the length of the axon in a wave of depolarization whose strength is maintained all the way to the nerve terminal.

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6
Q

Explain what IPSPs and EPSPs are

A

EPSP: Excitatory Postsynaptic Potential: results from neurotransmitters that stimulate opening of specific ligand-gated ion channels that allow influx of positively charged ions (Na+, Ca2+) ~ localized depolarization. (single EPSP does not initiate AP by itself)
IPSP: Inhibitory Postsynaptic Potential: results from other neurotransmitters opening ligand-gated ion channels that lead to either the influx of Cl- ions or the efflux of K+ ions.
both sub-threshold, so not self-sustaining like action potential (decay in a distance-dependent manner)

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7
Q

Describe the two important principles related to summation of signals in the initiation of an action potential

A

Spatial Summation: EPSPs and IPSPs occurring close to one another in the postsynaptic neuron have more of an effect on each other than those that are more distant from one another.
Temporal summation: EPSPs/IPSPs must be close together in time in order to have an effect on one another.

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8
Q

Explain the role of each of the following in neurotransmission: resting membrane potential, synaptic potentials and action potentials

A

resting membrane potential: -70mV ~ no information is being transmitted
synaptic potential can be either inhibitory or excitatory - it is the difference in voltage between the inside and outside of a postsynaptic neuron.
Action potentials is initiated (or not) dependent on the cumulative effect of all incoming EPSPs and IPSPs at any given time.

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9
Q

List the three criteria for a substance to be considered a neurotransmitter

A
  1. substance must be localized to the presynaptic element of an identified synapse
  2. substance must be shown to be released following activation of the presynaptic cell in which it resides
  3. direct application of substance to postsynaptic terminal must have the same effects as stimulation of the presynaptic neuron.
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10
Q

List the differences between classical neurotransmitters and neuropeptide neurotransmitters.

A

Classical neurotransmitters: fewer than 10 carbons, most are amines. Synthesis & degradation takes place mainly near site of release (in presynaptic terminal). Taken up through transporter proteins into synaptic vesicles
Neuropeptide neurotransmitters: more than 10 carbons, range from 3 to 40 amino acids in length - synthesized and packaged in cell body (unlike classical neurotransmitters). Usually cleaved from larger precursor peptides. packaged into dense-cored vesicles in Golgi apparatus & transported to axon. Release & mode of action is similar to classical neurotransmitters.

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11
Q

Identify the 4 main amino acid and the 5 main biogenic amine neurotransmitters and what their precursor molecules are

A 
Amino Acids (precursor molecules in parentheses)
1. GABA (glutamate)
2. Glutamate (glutamate)
3. Glycine (Glycine)
4. Aspartate (Aspartate)
Biogenic amines
1. Dopamine (Tyrosine)
2. Norepinephrine (tyrosine)
3. Epinephrine (tyrosine)
4. 5-Hydroxytryptamine [Serotonin] (Tryptophan)
5. Histamine (Histidine)
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12
Q

Explain how acetylcholine differs from the biogenic amine neurotransmitters

A

amino acid & biogenic amine neurotransmitters are removed by reuptake through transporters. Acetylcholine is enzymatically degraded by acetylcholinesterase.

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13
Q

Explain how nitric oxide differs from other neurotransmitters

A

Not stored (other neurotransmitters are). Diffuses through water & lipid membranes. Half-life of only a few seconds. Does NOT have specific receptor.

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14
Q

Explain the differences & similarities between voltage-gated and ligand-gated ion channels

A

voltage-gated channels open in response to a change in charge.
ligand-gated ion channels

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15
Q

Explain what is meant by direct vs indirect gating of an ion channel

A

direct gating is through neurotransmitter receptors that take on a conformational change when bound by the neurotransmitter (ligand-gated ion channel)
indirect gating is through g protein-coupled receptors that, when bound by neurotransmitter, stimulate intracellular signaling cascades

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16
Q

Describe the structural characteristics of G-protein coupled receptors vs. ligand-gated ion channels

A

Ligand-gated ion channels are composed of 5 subunits that form central pore through membrane (homomeric are all identical, heteromeric are combination of 5 different subunits).
G protein-coupled receptors: one subunit that traverses the membrane 7 times

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17
Q

Describe the general signaling mechanism through which a neurotransmitter interacting with its G-protein coupled receptor activates (or inhibits) an effector protein.

A

Inactive: GDP is bound to alpha subunit of G protein. Neurotransmitter binds to receptor, stimulates exchange of GDP for GTP to alpha subunit. alpha subunit releases from G protein complex. alpha/GTP complex binds to effector protein and either activates or inhibits it. (alpha subunit has GTPase activity, so eventually converts GTP back to GDP & then receptor/G protein/GDP reconfiguration reassociates & receptor is ready for another round of stimulation)

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18
Q 
Describe the following components of chemical neurotransmission: 
• synthesis and storage
• neurotransmitter release
• termination of neurotransmitter action
• regulation of neurotransmission
A
  • synthesis and storage: neuropeptides synthesized like any other protein in nucleus & ER, packaged into dense-cored vesicles. Classical neurotransmitters synthesized in axon terminal, taken up through transporter proteins & stored in synaptic vesicles (sometimes stored with neuropeptides in dense-core vesicles)
  • release: vesicles aggregate in active zone at tip of presynaptic terminal. dock inside of synaptic membrane through interactions between SNAP-25 & syntaxin (synaptic proteins) and VAMP (vesicular protein). when membrane is depolarized, voltage-gated Ca2+ channels open. Ca2+ binds to & activates synaptotagmin (a vesicular protein) which creates a fusion pore via conformational change of synaptotagmin. contents of vesicle flow into synaptic cleft.
  • termination of action: either reuptake back into cell (amino acid & biogenic amine neurotransmitters) or enzymatic degradation (acetylcholine and neuropeptides) extracellulary.
  • regulation: 1. initiation of AP through summation of incoming signals. 2. auto receptors (G protein-coupled) in presynaptic terminal interact w/neurotransmitters in negative feedback loop. 3. modulation of postsynaptic receptors (changes in number or responsiveness)
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19
Q

lidocaine

A

binds to sodium channels & blocks them so that no action potential can be generated.

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20
Q

primary excitatory and inhibitory neurotransmitters of the brain

A 
Glutamate = excitatory
GABA = inhibitory
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21
Q

What nerves have ganglionic synapses?

A

Autonomic

somatic do NOT

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22
Q

Which nerves have voluntary control?

A

Somatic

Autonomic do not

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23
Q

What are the tissues innervated by somatic and autonomic nerves?

A

Somatic: Skeletal muscle
Autonomic: Viscera (GI tract, heart, blood vessels, bladder, glands)

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24
Q

Somatic vs. Autonomic - which are excitatory & which are inhibitory

A

Somatic: excitatory
Autonomic: can be either excitatory OR inhibitory

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25
Q

How are autonomic nerves classified?

A

Anatomic (based on CNS location from which preganglionic nerve emerges)

  • Parasympathetic nerves: cranial (3, 7, 9, 10), sacral (3, 4) spinal
  • Sympathetic: Thoracic lumbar

Neurotransmitter (based on nature of primary neurotransmitter released)

  • Cholinergic: release Acetylcholine = parasympathetic
  • Adrenergic: release catecholamines = sympathetic (e.g., norepinephrine, epinephrine, dopamine)
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26
Q

Which neurotransmitters are released from which types of nerves (sympathetic, parasympathetic, preganglionic, postganglionic)

A

[Somatic: ACh]
Parasympathetic: Pre and post ganglionic release ACh
Sympathetic: Preganglionic release ACh, post ganglionic release Catecholamines mainly, and some release ACh

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27
Q

Which sympathetic nerves are cholinergic?

A

Sympathetic pre-ganglionic nerves

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28
Q

What are different types of autonomic innervation patterns?

A

single: tissue is innervated by either cholinergic or adrenergic nerves (turn on or off for control)

Dual: Innervation by both cholinergic and adrenergic nerves

  • functional antagonism: 2 nerves going to the same cell (e.g., pacemaker cell)
  • physiological antagonism: nerves work on different cells (e.g., eyes: parasympathetic causes pupils to get smaller by contracting circular muscles, sympathetic causes pupils to dilate by contracting radial muscles)
  • Complementary responses: both work together towards same goal (e.g. ejaculation (sympathetic) and erection (parasympathetic))
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29
Q

What are nonadrenergic, noncholinergic nervous systems?

A

Tachykininergic nerves: sensory nerves that release substance P & neurokinin A (tachykinins) when stimulated –> vasodilation and edema locally –> flush, flare, wheal

Nitrergic nerves: when stimulated, Ca++ comes into nerve terminal and forms nitric oxide. NO diffuses into cell & nearby cells triggering vasodilation and smooth muscle relaxation. (also sphincter relaxation)
NO works through activation of cGMP.

Enteric nervous system: located in intestinal wall
intrinsic serotonergic and neuropeptidergic nerves influence coordination of GI movement & secretion
(parasympathetic & sympathetic nerves modulate enteric system function outside of GI tract). Parasympathetic system dominates in this tract

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30
Q

Viagra

A

(Sildenafil)

Promotes penile erection by amplifying NO-dependent signal transduction pathways - prevents the breakdown of cGMP

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31
Q

What types of adrenoceptors are on blood vessels?

A

alpha 1 –> promote vasoconstriction when occupied by norepinephrine
beta 2 –> promote vasodilation when occupied by norepinephrine

alpha 1’s predominate, because sympathetic nervous system causes vasoconstriction

tissues can have more than one adrenoceptor, and the different adrenoceptors have the potential to have opposing effects, but usually one type of receptor dominates.

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32
Q

If a blood vessel is being constricted by a sympathetic nerve, what would you predict a beta-adrenoceptor antagonist would do to the extent of vasoconstriction?

A

It would increase vasoconstriction

prevent the beta receptor from causing vasodilation

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33
Q

What are the steps involved in the synthesis of dopamine?

A
  1. tyrosine is taken up into the nerve terminal
  2. tyrosine hydroxylase converts tyrosine to DOPA
  3. DOPA decarboxylase converts DOPA to Dopamine
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34
Q

How is Norepinephrine synthesized?

A

Dopamine is converted by dopamine-beta-hydroxylase into norepinephrine
dopamine-beta-hydroxylase is located in vesicles

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35
Q

how is epinephrine synthesized?

A

norepinephrine is converted by phenylethanolamine-N-methyl transferase to norepinephrine.
PE-N-methyltransferase is located in adrenal chromaffin cells

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36
Q

alpha-methyldopa

A

inhibits conversion of DOPA to dopamine
competes with DOPA, acts on alpha-2’s
fills up vesicles with “false transmitters” - alpha 2-agonist

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37
Q

Carbidopa

A

prevents conversion of peripheral DOPA to dopamine because it doesn’t enter CNS
allows more DOPA to cross BBB and convert to dopamine in brain (treatment for Parkinson’s disease)

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38
Q

Reserpine

A

Taken up into nerve ending, binds tightly to vesicle & inhibits VMAT-2 which is the transporter for dopamine. Prevents dopamine from entering vesicles, so dopamine gets metabolized by MAO.
causes CCA depletion and destroys vesicles
used to treat high blood pressure
side effect: depression –> prevents serotonin from getting into vesicles

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39
Q

Guanethidine

A

Adrenergic neuron blocking drug (ANBD)
inhibits CCA release by
-CCA depletion: enters terminal via norepinephrine transporter (NET) [NET is part of NE recycling pathway - guanethidine uses this pathway], taken up and concentrated into vesicles, displaces CCAs, CCA depletion. We are turning down the sympathetic nervous system
Initially, turns sympathetic nervous system UP, because more CCAs are in the synapse (ANBD is getting taken back into vesicle instead of some CCAs), but then as CCAs get displaced from vesicles, they get metabolized and depleted.
Eventually, you get adrenoceptor upregulation and/or the receptors start coupling more effectively –> supersensitivity of tissues to CCAs –> exagerrated response to things that would cause an increase in blood pressure, so beware.. medications that contain alpha adrenoceptor agonists (decongestants) - are going to increase blood pressure much more than in typical patient

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40
Q

Describe how various agonists of presynaptic receptors inhibit or facilitate neurotransmitter release

A

alpha 2 presynpatic receptor: inhibits release when bound by CCA
D2: inhibits release when bound by CCA
beta2: facilitates release when bound by CCA
M2: inhibits release when bound by ACh
AT1: facilitates release when bound by angiotensin II
Mu: inhibits release when bound by opiates

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41
Q

how do indirect-acting sympathomimetics work?

A

induce CCA release from sympathetic nerves by displacement
release is not exocycotic
they do NOT act directly on adrenoceptors - released norepinephrine mediates the pharmacological effect

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42
Q

what are some sympathomimetic agents?

A

amphetamine (indirectly acting and non-polar - acts in the CNS)
ephedrine (also directly acting on alpha and beta receptors)
pseudoephedrine (also directly acting on alpha receptors)
tyramine (only indirectly acting - also a MAO/COMT substrate)
-tyramine is found in food (not a drug), but continued exposure to tyramine can result in decreased sympathomimetic pathways - important interactions with MAO inhibitors

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43
Q

What are the mechanisms involved in terminating actions of catecholamines?

A

Uptake (neuronal [NET] and extraneuronal [ENT])
Metabolism (Monoamine oxidase [MOA] and catechol-O-methyl transferase [COMT])

NET is the MOST important mechanism regulating activity of neurally released CCAs

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44
Q

What are inhibitors of neuronal uptake?

A

Cocaine
Tricyclic antidepressants (e.g., desipramine, imipramine)
Phenothiazines (e.g., chlorpromazine)

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45
Q

What would a neuronal uptake inhibitor do to sympathetic nervous effects on the heart?

A

Increase them

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46
Q

With respect to abuse, euphoric effects of cocaine are indistinguishable from amphetamine. Why would you expect this to be the case?

A

Amphetamine is indirectly acting - increases the amount of dopamine. Cocaine at dopaminergic nerve would block reuptake of dopamine so increase dopamine concentration near dopamine receptors inducing euphoric event.
Both will increase the levels of dopamine in neuro-effector junction & will cause sympathetic effects all over the body.

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47
Q

What are the metabolic enzymes responsible for CCA metabolism?

A

Monoamine oxidase (MAO) (most important)
-MAO-A preference for NE, EPI and 5HT
-MAO-B preference for DA, phenylethylamines
-both will metabolize NE, EPI, tyromine and serotonin
catechol-O-methyl transferase (COMT)

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48
Q

where are MAOs located?

A

nerve terminal cytoplasm
GI mucosa
liver

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49
Q

Tyramine

A

oral phenylethylamine: indirectly acting sympathomimetic
normally metabolized by MAO in liver and GI tract
significant portion gets to the liver, not much gets to sympathetic nerves, which prevents it from acting as an indirect acting sympathomimetic
under normal circumstances, tyrosine leads to very little NE release
person treated with MAO inhibitor can get a sympathetic response because there’s nothing to metabolize it effectively.

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50
Q

MAO inhibitors

A

isocarboxazid: irreversible: inhibits A and B
moclobemide: reversible: inhibits A
Selegiline: irreversible: inhibits B

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51
Q

What would happen if a depressed person treated with an irreversible MAO-A inhibitor ate a food containing tyramine?

A

Tyramine will be metabolized in GI mucosa, so you will have significant levels of tyramine in the blood - nerve terminal will uptake it where it will not be metabolized. It will go into VMAT2, get into vesicles and displace CCAs. Those CCAs increase blood pressure, could lead to hypertensive crisis.

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52
Q

entacapone

A

inhibits peripheral COMT
protects L-dopa from being metabolized in the liver which results in more L-Dopa reaching the CNS. (Parkinson’s treatment)
allows lower dose of L-dopa to get desired CNS therapeutic effect
helps avoid L-dopa side effects (L-dopa produces dopamine in sympathetic nerves, goes to norepinephrine - sympathetic side effects)

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53
Q

Why was the development of isoproterenol so important for the identification of adrenoceptor subtypes?

A

ISO allowed us to distinguish the two types of receptors

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54
Q

Where are alpha adrenoceptors located?

A 
blood vessels --> constriction
radial muscle of iris --> pupil dilation
sphincters --> contract
ureter, vas deferens --> increase motility & tone (ejaculation)
nerve endings
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55
Q

Where are alpha 1 adrenoceptors located and what do they do?

A

smooth muscle –> on blood vessels, prostate capsule, bladder neck –> cause contraction

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56
Q

phenylephrine

A

alpha 1 adrenoceptor agonist

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57
Q

prazosin

A

alpha 1 adrenoceptor antagonist

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58
Q

Where are alpha 2 adrenoceptors located?

A

presynaptic nerve endings –> decrease release of NE

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59
Q

Clonidine

A

alpha 2 receptor agonist

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60
Q

Vohimbine

A

alpha 2 adrenoceptor antagonist

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61
Q

How can beta adrenoceptors increase blood pressure?

A

beta 1 in the heart increase heart rate, contractility & conduction
AND in the kidney –> increases renin release –> formation of angiotensin II –> release of aldosterone –> increased blood pressure

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62
Q

What kind of receptors are adrenoceptors?

A

g protein coupled receptors
Beta receptors are Gs linked (Beta 2 also couple to Gi) - linked to adenylate cyclase which increases concentrations of cAMP
alpha 1 couple with Gq and alpha 2 couple with Gi

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63
Q

norepinephrine

A

alpha 1 and 2 agonist

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64
Q

phenylephrine

A

alpha 1 agonist

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65
Q

methoxamine

A

alpha 1 agonist

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66
Q

clonidine

A

alpha 2 agonist

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67
Q

isoproterenol

A

beta 1 and 2 agonist

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68
Q

dobutamine

A

beta 1 agonist

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69
Q

albuterol

A

beta 2 agonist

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70
Q

terbutaline

A

beta 2 agonist

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71
Q

phentolamine

A

alpha 1 and 2 antagonist

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72
Q

prazosin

A

alpha 1 antagonist

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73
Q

terazosin

A

alpha 1 antagonist

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74
Q

yohimbine

A

alpha 2 antagonist

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75
Q

propranolol

A

beta 1 and 2 antagonist

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76
Q

metoprolol

A

beta 1 antagonist

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77
Q

atenolol

A

beta 1 antagonist

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78
Q

butoxamine

A

beta 2 antagonist

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79
Q

How can dopamine elicit effects?

A

dopamine receptors
D1 are in blood vessels, renal tubules, JGA: promote dilation in blood vessels (particularly in kidney) and diuresis (renal excretion) in kidney tubules
D2: presynaptic CNA
D3, D4, D5 (don’t have to know)

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80
Q

epinephrine

A

directly-acting adrenoceptor agonist

alpha 1, 2, beta 1, 2

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81
Q

If phenylephrine was administered i.v., what would happen to heart rate?

A

phenylephrine is alpha 1 directly-acting agonist
blood pressure will increase, body will sense increase in bp & try to decrease it, so body will decrease sympathetic outflow. Heart rate will go down. reflex bradycardia (slow heart rate < 60 bpm)

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82
Q

Should a patient use a nasal decongestant chronically?

A

No. Rebound congestion. If you don’t have a lot of blood going to a tissue, it becomes damaged. Too much vasoconstriction for an extended period of time can damage the tissue leading to more congestion.

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83
Q

How would cocaine promote vasoconstriction?

A

Cocaine blocks reuptake of NE from nerves. If you block reuptake, levels of NE near affected tissues increase, so near blood vessels, it will cause constriction.

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84
Q

Why are alpha 1 adrenoceptor agonists administered topically to the eye?

A

to reduce side effects of hypertension. If given systemically, the dose required to get to the eye would cause increased HTN.
from eye, it is possible to get into systemic circulation through back of nose & into vascular supply, so still be aware of possible systemic side effects when giving topical eye alpha 1 agonists.

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85
Q

Sudden discontinuation of clonidine can lead to headache, sweating, tachycardia, rebound hypertension. What change in sympathetic nervous system activity would cause these symptoms?

A

Clonidine turns down sympathetic activity. When you suddenly take it away, it’s like a sympathetic nervous system rebound - the sympathetic system is no longer being restricted, so the stimulation is suddenly effective

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86
Q

CCAs decrease the effective refractory period of a cardiac cell. Would that increase or decrease the ability of the cell to be stimulated by a fast pacemaker?

A

INCREASE the ability of the cell to be stimulated by a fast pacemaker

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87
Q

CCAs decrease the effective refractory period of the AV node. What would that do to the conduction of impulses from the atria to the ventricle, increase or decrease conduction?

A

If AV node is less refractory, it will pass on every impulse that hits it - in person with atrial fibrillation, this would cause cardiac output to drop because ventricles couldn’t fill with blood fully between contractions.

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88
Q

name receptors and what they do on the eye

A

beta receptors increase aqueous humor production
alpha receptors increase aqueous humor outflow
radial muscle (iris) alpha 1 –> contraction (mydriasis - dilation)
sphincter muscle (iris) M3 –> contraction (miosis - making pupil smaller)
ciliary muscle beta 2 –> relaxation (far vision) and M3 –> contraction (near vision)
lacrimal glands M3 –> increase secretion

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89
Q

name receptors and what they do on the heart

A

SA node: Beta 1 > Beta 2 –> increase rate and M2 –> decrease rate
atria: beta 1 > beta 2 –> increase contractility and increase conduction velocity and M2 –> decrease contractility
AV node: Beta 1 > beta 2 –> increase automaticity and increase conduction velocity AND M2 –> decrease conduction velocity
ventricles: beta 1 > beta 2: increase automaticity, conduction velocity and contractility
beta 3 decreases cardiac contractility

90
Q

name receptors and what they do on arterioles

A

coronary: beta 2 –> dilation > alpha 1 and alpha 2 –> constriction
skin/mucosa: alpha 1 –> constriction AND M3 –> dilation
SKM: beta 2 –> dilation > alpha 1 –> constriction AND M3 –> dilation
cerebral: alpha 1 –> constriction (small)
pulmonary: alpha 1 –> constriction > beta 2 –> dilation
abdominal viscera: alpha 1 –> constriction&raquo_space;> beta 2 –> dilation
salivary glands: alpha 1 and 2 –> constriction AND M3 –> dilation
renal: alpha 1 and 2 –> constriction&raquo_space;> beta 1 and 2 –> dilation

91
Q

name receptors and what they do on veins

A

systemic: alpha 1 and 2 –> constriction&raquo_space;> beta 2 –> dilation

92
Q

name receptors and what they do on lungs

A

airway smooth muscle: beta 2 –> dilation AND cholinergic –> contraction
alpha 1 decrease secretions
beta 2 increase secretions

93
Q

name receptors and what they do on stomach/intestines

A

motility and tone: alpha 1, 2 and beta 2 –> decrease it AND M3 –> increases it (much greater effect than alphas & betas)

sphincters: alpha 1 –> contract AND M3 –> relax
secretion: alpha 2 –> decrease AND M3 –> increase (much more so than alphas decrease)

94
Q

name receptors and what they do for gall bladder and ducts

A

beta 2 –> relax

M –> contract

95
Q

name receptors and what they do for kidneys

A

renin secretion: beta 1 –> increase > alpha 1 –> decrease

96
Q

name receptors and what they do on urinary bladder/prostate gland

A

detrusor muscle: beta 3 –> relax AND M3 > M2 –> contract
trigone & sphincter: alpha 1 –> contract AND M3 > M2 –> relax
prostate capsule: alpha 1 –> contract

97
Q

name receptors and what they do on ureter

A

motility and tone: alpha 1 –> increase it AND M –> increase it

98
Q

name receptors and what they do on uterus

A

pregnant: alpha 1 –> contract, beta 2 –> relax

non-pregnant: beta 2 –> relax

99
Q

name receptors and what they do on male sex organs

A

ejaculation: alpha 1 –> increase
erection: M3 –> increase

100
Q

name receptors and what they do on skin

A

pilomotor muscle: alpha 1 –> contract

sweat glands: alpha 1 –> localized secretion AND M3 –> increase secretion (more so than alpha 1)

101
Q

name receptors and what they do on splenic capsule

A

alpha 1 –> contract&raquo_space; beta 2 –> relax

102
Q

name receptors and what they do on skeletal muscle

A

beta 2 –> increase contractility, increase glycogenolysis, increase K+ uptake
beta 3 –> glycogenolysis

103
Q

name receptors and what they do on liver

A

beta 2 and alpha 1 –> increase glycogenolysis

beta 2 –> increase gluconeogenesis

104
Q

name receptors and what they do on pancreas

A

acini: alpha –> decrease secretion AND M3, M2 –> increase secretion
beta cells: alpha 2 –> decrease insulin secretion&raquo_space; beta 2 –> increase insulin secretion

105
Q

name receptors and what they do on fat cells

A

beta 3 –> lipolysis&raquo_space; alpha 2 –> decrease lipolysis

106
Q

name receptors and what they do on salivary glands

A

alpha 1 –> increase K+, H2O secretion
beta 2 –> amylase secretion
M3, M2 –> increase K+ and H2O secretion (much more than alpha or betas)

107
Q

name receptors and what they do on lacrimal glands

A

alpha –> increase secretion

M3 and M2 –> increase K+, H2O secretion (much more than alpha)

108
Q

name receptors and what they do on nasopharyngeal glands

A

M3, M2 –> increase secretion

109
Q

name receptors and what they do on pineal gland

A

beta –> increase melatonin synthesis

110
Q

name receptors and what they do on posterior pituitary gland

A

beta 1 –> increase ADH secretion

111
Q

Muscarinic antagonists (i.e. atropine-like agents) have been the mainstay of overactive bladder treatment. A purported advantage of the beta 3 agonists is that they won’t have the atropine-like side effects. What side effects do you think patients complain most about when they use a muscarinic antagonist?

A

dry mouth

112
Q

In a patient that has suffered a myocardial infarction, regions of the myocardium may be severely hypoxic. Under such circumstances, how could beta adrenoceptor activation be a problem? How could alpha adrenoceptor activation be a problem?

A

beta activation –> makes myocardium use more oxygen, so could become ischemic
alpha activation –> makes blood vessel caliber smaller, so it makes the heart push blood into constricted vessels. Cardiac output goes down if the vessels are constricted enough. makes heart use more oxygen. increases after-load - pressure against which the heart has to push blood

113
Q

albuterol

A

beta 2 direct acting agonist
used for bronchodilation - may also inhibit mediator release
side effects: increase heart rate (direct via sino-atrial node and indirect via arteriole dilation leading to sympathetic activation to counteract drop in blood pressure), induce muscle tremor

114
Q

amphetamine

A

indirectly-acting adrenoceptor agonist: relies on the release of NE from sympathetic nerves to elicit response
CNS stimulant

115
Q

dopabutamine

A 
beta 1 > beta 2, alpha 1 directly acting agonist
inotropic agent (alters the force of muscular contractions) used to increase cardiac contractility (short term)
when heart is stimulated, makes it use more O2. Can make heart more ischemic in someone with heart failure. Can make infarction larger (infarction is insufficient O2 supply). Like making making a person with a dry cleaning bag on their head do more jumping jacks
can increase AV node conduction which can increase risk of atrial fibrillation --> cause fast ventricular rates (tachyrhythmias) In defibrillation, atria beat at 300+ bpm, don't want each impulse to be conducted
116
Q

clonidine

A

directly-acting alpha 2 agonist
anti-hypertensive by acting on the nerve endings, decreasing NE release and on the CNS by decreasing sympathetic outflow and increasing parasympathetic outflow
side effects: xerostomia and sedation (due to parasympathetic increase from CNS effects)

117
Q

nerve terminal receptors and what they do

A

alpha 2 –> inhibit neurotransmitter release

beta 2 –> facilitate neurotransmitter release

118
Q

cocaine

A

indirect acting adrenoceptor agonist: relies on the release of NE from sympathetic nerves to elicit response
used for hemostasis in surgery: constrict blood vessels to give opportunity for blood clots to form

119
Q

dopamine

A

D1 = D2 > Beta 1 >/= alpha 1 = alpha 2

directly acting agonist

120
Q

ephedrine

A

indirectly acting adrenoceptor agonist: relies on the release of NE from sympathetic nerves to elicit response
directly acting on alpha and beta receptors
mild CNS stimulant

121
Q

epinephrine

A

alpha 1, alpha 2, beta 1 and beta 2 directly acting agonist
increase duration of local anesthetic by constricting nearby blood vesses
-hemostasis in surgery: constrict blood vessels to allow clots to form
- mydriasis for examination of retina
-open angle glaucoma treatment (reducing intraocular pressure)
-cardiac arrest (alpha agonist increases diastolic pressure increasing coronary blood flow & beta effects make heart more susceptible to conversion by electrical counter shock)
-anaphylaxis: reverses hypotension & shock, inhibits further mediator release, decreases itching (beta 2) and swelling of lips, tongue & eyes (alpha 1), decreases edema of glottis (alpha 1), stimulates cardiac output (beta 1)

122
Q

methylphenidate

A

(ritalin)
indirectly-acting adrenoceptor agonist: relies on release of NE from sympathetic nerves to elicit response
mild CNS stimulant

123
Q

mirabegron

A

beta 3 directly acting agonist
used for over-active bladder (relaxes smooth muscle - detrusor muscle - & decreases frequency of rhythmic bladder contractions)

124
Q

norepinephrine

A

alpha 1, alpha 2, beta 1, beta 3 directly acting agonist

125
Q

phenylephrine

A

alpha 1 directly acting agonist
nasal congestion: contract arterioles, allow engorged venous sinusoids to empty, airway opens up
used for examination of retina (mydriasis)
used for paroxysmal atrial tachycardia - taking advantage of the side effect of body decreasing sympathetic output & reving up parasympathetic system, decreasing SA node rate
side effects: reflex bradycardia as body tries to compensate for increased blood pressure

126
Q

psneudoephedrine

A

indirectly-acting adrenoceptor agonist: relies on release of NE from sympathetic nerves to elicit response
directly acting on alpha receptors
nasal congestion: contract arterioles, allow engorged venous sinusoids to empty, airway opens up

127
Q

alpha 1 adrenoceptor agonists

A

constrict arterioles and veins: increase peripheral vascular resistance, increase venous return, increase blood pressure
used for hypotensive conditions
constriction of local blood vessels make these useful for
-1) increase duration of local anesthetic
-2) nasal congestion
-3) hemostasis in surgery
contracts radial muscle of eye: mydriasis & open angle glaucoma (decreasing intraocular pressure by effects on aqueous humor production & outflow)

128
Q

alpha 2 adrenoceptor agonists

A

inhibit neurotransmitter release
cardiovascular system: presynaptic receptors on sympathetic nerves decrease NE release, so decrease blood pressure
receptors in brainstem decrease sympathetic outflow so decrease BP, increase vagal outflow so decrease heart rate
used as anti-hypertensive by acting on the nerve endings (decreasing NE release) and on the CNS by decreasing sympathetic outflow

129
Q

beta 1 adrenoceptor agonists

A

cardiovascular system: increase heart rate by increasing SA node rate
increase cardiac contractility by increasing Ca++ influx into cell, increasing stroke volume & increasing cardiac output
pro-dysrhythmogenic: makes cardiac myocytes more responsive - increases AP propogation
decreases effective refractory period of AV node
used for inotropic - increases cardiac contractility (short term)
increases AV node conduction - can increase risk of atrial fibrillation causing fast ventricular rates (tachyrhythmias)

130
Q

beta 2 adrenoceptor agonists

A
  • airway: relax airway smooth muscle - used for bronchodilation
  • uterus: relaxes uterine smooth muscle - can delay or prevent premature parturition
  • side effects: skeletal muscle tremor (beta 2 acceleration of cystolic Ca++ sequestration & fine hand tremor due to increase muscle spindle discharge), tachycardia (direct effect on heart due to beta 2 receptors on sino atrial node and reflex effect beta 2 receptors on vaso smooth muscle - dilation decreases blood pressure, body activates sympathetic nervous system to bring it back up - increases heart rate
  • tolerance with long term administration: receptors down regulate
131
Q

beta 3 adrenoceptor agonists

A

bladder: relaxes detrusor muscles which decreases pressure inside bladder & makes voiding less likely
decreases frequency of rhythmic bladder contractions
metabolic: induces expression of mitochondrial uncoupling proteins in adipose cells –> lipolysis & fat oxidation, increases non-oxidative glucose metabolism, increases insulin sensitivity of beta cells in pancreas (potential diabetes type 2 treatment), suppresses appetite

132
Q

non-selective adrenoceptor agonists

A

vasoconstriction, increase cardiac output, decrease mediator release from mast cells
used for shock (inadequate perfusion of tissues associated w/hypotension) -increase cardiac contractility and peripheral vascular resistance
used for cardiac dysrhythmias: cardiac arrest: alpha agonists –> vasoconstriction, increases diastolic pressure which increases coronary blood flow. beta effects make ventricular fibrillation more susceptible to external defibrillation
paroxysmal atrial tachycardia –> alpha will increase blood pressure, body compensating will rev up parasympathetic activity & tell SA node to slow down
allergic reaction: agonists will increase blood pressure, decrease bronchoconstriction (beta 2), decrease mast cell mediator release (beta 2), less bronchoconstriction, and less drop in blood pressure

133
Q

phaeochromocytoma is a tumor of the adrenal medulla that results in the release of large amounts of adrenaline into the circulation. What would you predict the cardiovascular symptoms of this disease would be?

A

skyrocketing blood pressure, increased heart rate, vulnerable to dysrhythmias

134
Q

prior to surgical resection of phaeochromocytoma (tumor of adrenal medulla), phenoxybenzamine is administered. What cardiovascular symptoms would this prevent? why would phenoxybenzamine be a better choice than phantolamine?

A

phenoxybenzamine blocks alpha receptors, so it would be blocking vaso-constrictor effects - the alpha 1 effects on arterioles and veins.
phenoxy is better than phentolamine because phenoxy is irreversible - no competition going on. with phentolamine you need high doses, so more potential for adverse side effects

135
Q

Why would you predict beta 1 adrenoceptor antagonists to be more effective antihypertensive agents than non-selective beta adrenoceptor antagonists?

A

if you block beta 2 receptor, peripheral vascular resistance will increase, blocking beta 1s target the sites that are promoting increase in blood pressure. non-selective will also target beta 2s, so blood pressure won’t drop as much.

136
Q

pharmaceutical companies have developed 3rd generation beta adrenoceptor antagonists that induce vascular NO release (nebivolol), block alpha 1-adrenoceptors (labetolol), act as beta 2 adrenoceptor agonists (carteolol), block calcium channels (betaxolol) or activate K+ channels (tilisolol). Why would the companies desire such an action?

A

NO dilates blood vessels, blocking alpha 1 dilates blood vessels
beta 2 stimulation will dilate blood vessels
calcium channel blockage will prevent vasoconstriction, K+ flowing out of the cell will cause hyperpolarization of the membrane making it less likely to contract

blocking beta 1 is good to drop blood pressure, but body tries to compensate by activating sympathetic nervous system. with beta 1 blocker, can’t stimulate heart or renin secretion, but can tell arterioles to constrict, so you need to give something that will prevent the arteriole constriction - dilating arterioles reinforces antihypertensive effects of these agents.

137
Q

beta adrenoceptor antagonists are commonly used by people giving presentation to a large audience. What symptoms of nervousness would they yelp the speaker deal with?

A

tachycardia (racing heart), skeletal muscle tremor

138
Q

hypoglycemia triggers tachycardia and skeletal muscle tremor. This is an important physiological warning sign of hypoglycemia in patients with diabetes. How would beta adrenoceptor antagonists affect these symptoms?

A

beta 1 & beta 1 mediate tachycardia, beta 2 mediates muscle tremor: if patient is taking beta blocker, masking important signs of hypoglycemia

139
Q

beta antagonists are administered in phaeochromocytoma only after an alpha antagonist has been administered. Why?

A

alpha antagonists will lower blood pressure by blocking alpha receptors on blood vessels.
beta antagonists will protect heart from dysrhythmias, decrease conduction, but will also tell blood vessels to constrict.

140
Q

labetalol

A

alpha 1 antagonist
beta non-selective antagonist
used to treat hypertension - advantage to be both beta non-selective and alpha 1 selective

141
Q

metoprolol

A

beta 1 selective antagonist
i.v. used to treat early stages of myocardial infarction: decreases myocardial O2 demand, decreases likelihood of dysrhythmias occurring, decreases plasma FFA concentration
also used to prevent recurrences of acute myocardial infarction

142
Q

phenoxybenzamine

A

alpha non-selective antagonist
irreversible
H1, M, 5HT antagonist

143
Q

phentolamine

A

alpha non-selective antagonist

M1, H1 antagonist

144
Q

prazosin

A

alpha 1 antagonist

used for heart failure and hypertension by blocking sympathetic effects on arterioles

145
Q

propranolol

A

beta non-selective antagonist
used to prevent recurrences of acute myocardial infarction: decreasing myocardial O2 demand, decreasing likelihood of dysrhythmias, decreasing plasma concentration of FFAs

146
Q

tamsulosin

A

alpha 1A antagonist
more selective for prostate - used for impaired bladder emptying by relaxing trigone muscle, bladder neck, prostate capsule, and prostate neck and for prostate obstruction
can be used to treat hypertension & heart failure by blocking sympathetic effects on arterioles
side effects: postural hypotension, abnormal ejaculation (inhibiting regulation of bladder sphincters, so goes into bladder instead of exiting penis)

147
Q

Yohimbine

A

alpha 2 antagonist
used to increase sympathetic outflow from CNS
used to treat erectile dysfunction/impotence by increasing penile blood inflow & decreasing penile blood outflow (not by direct effect in periphery but through CNS)

148
Q

alpha 1 adrenoceptor antagonists

A

dilate arterioles and veins, decrease PVR and venous return, so decrease blood pressure
used for:
-HTN
-heart failure: decreases preload by dilating veins, decreases afterload by dilating arterioles - makes less blood go into the heart & makes it easier to push out blood (not having to work as hard & not using as much O2)
-urinary tract: impaired bladder emptying (by relaxing trigone muscle of bladder, bladder neck, prostate capsule, prostate neck - decreasing resistance to urine outflow)
side effects:
-orthostatic hypotension (first dose phenomenon - gets better with time) & abnormal ejaculation (ejaculate goes into bladder instead of exiting body)

149
Q

alpha 2 adrenoceptor antagonists

A

penile function
increases penile blood inflow, decreases penile blood outflow through CNS NOT by direct effect in periphery
used to treat erectile dysfunction/impotence

150
Q

what are beta adrenoceptor antagonists used for

A
  • hypertension: decrease heart rate, contractility & conduction AND decrease renin secretion, inhibiting angiotensin II & aldosterone
  • exertional angina: beta 1 blockade decreases myocardial O2 demand by decreasing CCA induced heart rate & contractility
  • acute myocardial infarction: decrease myocardial O2 demand so limits size of infarction, decrease likelihood of dysrhythmias occurring
  • long term heart failure: decreasing stress placed on heart by decreasing sympathetic drive - decreases mortality
  • supraventricular dysrhythmias: decreases AV node conduction, increases refractoriness of AV node, decreasing conduction of impulses from atria to ventricles, and decreasing firing rate of SA node
151
Q

cautions with beta adrenoceptor antagonists

A

respiratory system: beta 2 antagonism causes bronchoconstriction
decreases glucose mobilization (beta 2) by decreasing glycogenolysis & gluconeogenesis
beta 3 antagonism decreases generation of FFAs, increases LDLs, decreases HDLs
B2 antagonism decreases CCA induced K+ uptake which can be problem for people with closed head injuries or burn victimes

152
Q

adverse effects with beta adrenoceptor antagonists

A
  • use beta 1 selective for patients w/diabetes, peripheral vascular disease or raynauds phenomenon (if you block beta 2, you make circulation problems even worse)
  • use beta 1 selective for patients w/asthma (beta 2 antagonist prevents airway smooth muscle dilation)
  • may induce heart failure where cardiac performance is supported by sympathetic drive (trying to compensate for sudden bp drop)
  • may induce life threatening bradycardias in patients w/partial or complete AV node defects
  • abrupt discontinuation of long term use may worsen angina or lead to sudden death b/c beta receptors can upregulate & get activated more effectively by CCAs when blockade is removed
  • decrease rate of recovery from insulin-produced hypoglycemia AND cover signs. use with care in diabetics prone to hypoglycemic episodes
153
Q

What would happen if you blocked the effects of Acetylcholine at ganglia? at neuroeffector cell? at SKM?

A

ganglia: you would block autonomic responses
neuroeffector cell: You would block parasympathetic effects and sympathetic post ganglionic cholinergic responses
SKM: paralysis-ville

154
Q

Tetrodotoxin (from puffer fish gland) blocks fast Na+ channels. Omega-conotoxin from Conus Geographicus, a fish-hunting snail, blocks N-type Ca++ channels. What would be an obvious symptom of poisoning with these agents?

A

If you block Na+ channels, AP will be blocked. Ca++ channel blockade will block transmitter release.
paralysis (or muscle weakness).
also would shut down autonomic responses b/c they need action potentials. bradycardia, drop in blood pressure, dry mouth, blurred vision

155
Q

black widow spider venom toxin (alpha-latrotoxin) embeds itself in the cholinergic nerve terminal membrane & forms a Ca++ channel. What would be an obvious symptom of poisoning with this toxin?

A

vesicles start fusing w/membrane and massive release of ACh - parasympathetic effects: secretions, bronchodilation, urination, defecation, muscle spasms
no more vesicles inside terminal
receptors that respond to ACh on SKM undergo desensitization, so initially they spasm, and then you get paraylsis

156
Q

Neostigmine and physostigmine have been used in nerve gases. (Cholinesterase inhibitors). What would signs of toxicity be?

Lipid soluble drugs are more deadly. Why?

A

parasympathetic: amplified secretions, diarrhea, bronchoconstriction
SKM: (somatic) muscle spasms, too much ACh in NMJ, over time you lapse into paralysis
CNS: respiratory depression

Lipid soluble drugs: get into your body more quickly, get into CNS more readily & promote paralysis & respiratory depression.

157
Q

What are the sympathetic cholinergic nerves?

A

sweat glands, superficial vessels of face and neck

158
Q

what kinds of peripheral nerves leave the CNS?

A

cholinergic
released ACh acts on nicotinic receptors
the peripheral nerves can be autonomic or somatic

159
Q

Consider the effects of blockade of the different cholinoceptor subtypes. Which nerves would be blocked by:
Nn antagonist
Nm antagonist
M antagonist

A

Nn antagonist: post-ganglionic.–> all autonomic nerves (sympathetic and parasympathetic)
Nm antagonist: somatic nerves
M antagonist: parasympathetic and sympathetic cholinergic nerves

160
Q

acetylcholine

A

can inhibit its own release by binding to M2 presynaptic receptors
Nm, Nn and M cholinoceptor agonist

161
Q

atropine

A

M cholinoceptor antagonist

162
Q

botulinum toxin

A

inhibitor of ACh exocytosis
binds to synaptobrevin (in vesicle membrane)
causes SKM weakness and paralysis
irreversible: in order for transmission to occur you have to get more synaptobrevin generated
Used for: spasmodic ocular movements or dystonia
cosmetic purposes
excessive sweating
migraine

163
Q

Hexamethonium

A

Nn cholinoceptor antagonist

164
Q

muscarine

A

M cholinoceptor agonist

165
Q

neostigmine

A

cholinesterase inhibitor: inhibit the metabolism of ACh so enhances ACh-mediated responses & increases cholinergic nerve responses
indirectly acting cholinomimetic
used therapeutically to enhance cholinergic nerve-mediated responses

166
Q

nicotine

A

Nm and Nn cholinceptor agonist

167
Q

physostigmine

A

cholinesterase inhibitor: inhibit the metabolism of ACh so enhances ACh-mediated responses & increases cholinergic nerve responses
indirectly acting cholinomemetic
used therapeutically to enhance cholinergic nerve-mediated responses

168
Q

tubocurarine

A

Nm cholinoceptor antagonist

169
Q

how is acetylcholine synthesized?

A

choline is taken up into nerve terminal by carrier mediated process (Na+ dependent - this is the rate limiting step)
acetylation is catalyzed by choline acetyltransferase (once choline is in the nerve terminal)

170
Q

How is ACh stored?

A

taken up into nerve terminal vesicle by VAChT) (along with other stuff)

171
Q

how is ACh released?

A

depolarization at nerve terminal induces Ca++ influx
vesicles migrate and fuse with terminal membrane: synaptobrevin (vesicular protein) interacts with syntaxin (nerve terminal membrane protein) then synaptobrevin interacts with SNAP 25 (another nerve terminal membrane protein) - need interaction of all 3 proteins for exocytosis
presynaptic receptors located on nerve terminal inhibit or facilitate release:
-M2 inhibits ACh release when bound by ACh
-alpha 2 inhibits ACh release when bound by CCA
-Mu inhibits ACh release when bound by opiate

172
Q

list the mechanisms involved in termination of cholinergic transmission

A

ACh has to be rapidly degraded to prevent over activation of receptors - to allow fine muscle control
cholinesterase (ChE) hydrolyzes ACh –> choline + acetic acid
ChE levels differ between tissues: NMJ>NEJ>ganglion
2 types: acetylcholinesterase: on pre or post junctional membranes of cholinergic NEJ or NMJ
butyrylcholinesterase (pseudo or non-specific ChE): in plasma, liver & other places

173
Q

What are the types of cholinoceptors?

A 
muscarinic (g protein coupled receptors)
and nicotinic (ligand gated ion channels)
174
Q

What are the subtypes of nicotinic receptors and where are they located?

A

located on postganglionic nerve cell bodies, adrenal medulla cells and SKM muscles
generally excitatory, so they depolarize the cell membrane
Nm (muscle nicotinic) on SKM cells
Nn (neuronal or ganglionic nicotinic) on postganglionic cells and adrenal medullary cells

175
Q

what is the structure of nicotinic receptors?

A

pentameric
Nm and Nn have 2 alpha subunits, but differ in beta, gamma or delta subunits
both alphas have to be bound by ACh for ion channel to open
both kinds get desensitized when stimulated too much - lose responsiveness, so instead of contracting muscle more forcefully, you get paralysis

176
Q

What are the subtypes of muscarinic receptors and where are they located?

A

located on autonomic effector tissues that are sensitive to ACh (effector tissues of parasympathetic nerves)
can be excitatory or inhibitory
M1: autonomic ganglia (post ganglionic cells), gastric glands
M2: heart, presynaptic
M3: smooth muscle, secretory glands
M4 & M5: don’t have to worry about

177
Q

What is the mechanism that muscarinic receptors activate signal transduction pathways?

A

M1, M3 and M5: g-protein linked transduction mechanism: stimulation of phospholipase C
M2 and M4: g-protein linked transduction mechanism: K+ channel activation, inhibition of adenylate cyclase- makes it harder to reach membrane potential - slows things down - decreases cAMP

178
Q

Acetylcholine is released from:

A

all preganglionic nerves
all somatic nerves
all parasympathetic postganglionic nerves
some sympathetic postganglionic nerves

179
Q

which cells are stimulated by activation of the following cholinoceptors?

A

Nn –> stimulation of neuronal nicotinic receptors: ganglionic cell bodies
Nm –> stimulation of muscle nicotinic receptors: skeletal muscle
M –> stimulation of muscarinic receptors: cells that respond to parasympathetic nervous system & cells that respond to ACh coming from parasympathetic & sympathetic post neuronal nerves

180
Q

between acetylcholine, methacholine, bethanechol, and carbachol, which agents would be potentiated by a cholinesterase inhibitor?

A

methacholine and acetylcholine - a cholinesterase inhibitor would amplify their effects

181
Q

based upon its tissue selectivity, what side effects would be predicted to occur with bethanechol?

A

diarrhea, urinary urgency at lowest concentrations
at higher concentrations, you would start to see effects on the eye –> pupil constriction, blurred vision
urinary urgency is most likely SE

182
Q

carbachol has a similar tissue selectivity as bethanechol. Why is its use less preferable for the treatment of gastrointestinal atony?

A

carbechol is also a nicotinic agonist, so you invite sympathetic side effects because you are stimulating sympathetic ganglia.

183
Q

Why would muscarinic agonists be contraindicated in peptic ulcer disease?

A

because they could stimulate acid secretion (through stimulation of M1 receptor). You want to suppress acid secretion in PUD

184
Q

Why isn’t bethanechol used instead of methacholine for bronchial provocation?

A

it’s totally selective for muscarinic receptors, given as an aerosol, so unless they swallow a lot, the systemic side effects would not be great. Methacholine is metabolized more quickly, you don’t want bronchoconstriction to be long lasting. methacholine has shorter half life because it’s broken down by cholinesterase.

185
Q

in the production of miosis, acetylcholine or carbachol have different duration of action. Why?

A

ACh has short duration because it is broken down by ChE, carbachol is not.

186
Q

Why would cholinesterase inhibition later cause depression at autonomic ganglia and neuromuscular junction?

A

at all of these sites, you have nicotinic receptors. If you stimulate a nicotinic receptor too much or too long, it can undergo desensitization where it no longer responds to ACh, so it’s like blocking that neuromuscular junction.

187
Q

Why don’t cholinesterase inhibitors induce vasodilation by amplifying the effects of cholinergic nerves on blood vessels?

A

There ARE no cholinergic nerves going to blood vessels. (except superficial vessels on face and neck). Sympathetic adrenergic nerves are the ones that go to blood vessels

188
Q

Excessive cholinesterase inhibitor will actually aggravate and mimic myasthenia gravis. Why might you expect this to happen?

A

concentrations of ACh will increase in NMJ, if increase too much or for too long, nicotinic receptors will desensitize. Muscle strength will start to decrease. So you want to increase concentration to normal healthy person level, without increasing it too much.

189
Q

Why would we use physostigmine to treat anticholinergic drug toxicity and neostigmine to reverse paralysis?

A

Physostigmine is lipid soluble - we need lipid solubility to get into the CNS. We don’t need lipid solubility to get to the neuromuscular junction to treat paralysis - we are targeting skeletal muscle.
with toxicity, some of that involves blocking muscarinic receptors in the brain, so you use physostigmine to out compete anticholinergic drug in the brain.

190
Q

GI side effects (diarrhea, N/V) are common side effects associated with the oral administration of anticholinesterase agents targeted for CNS actions (e.g., rivastigmine). Other routes, such as transdermal and intranasal are used to reduce GI side effects. Why would these routes of administration reduce GI affects vs. oral?

A

when you are targeting a ChE inhibitor, you are going to get lots of side effects, because you are amplifying parasympathetic effects in the GI tract. with patch, you might get sweating. With intranasal, you would get runny nose - side effects depend on site of administration
(sweat glands are sympathetic cholinergic - don’t forget)

191
Q

in general, cholinomimetics have identical effects as parasympathetic nervous activation. There are two exceptions to this observation. What are they?

A

sweat glands and vasodilation associated with flushing –> sympathetic cholinergic effects

192
Q

What are the actions of cholinomimetics in the periphery?

A

eye: contract sphincter muscles (miosis), contract ciliary muscle (near vision)
heart: decrease heart rate, decrease atrial AP duration & refractoriness, decrease AV node conduction
blood vessels: relaxation (dilation) (endothelium NO)
lung: ASM contraction (bronchospasm), increase secretions
GI tract: increase motility & tone, relax sphincters, increase secretions
gall bladder & ducts: increase secretions
pancreatic acini: increase secretions
salivary glands: increase secretions
lacrimal glands: increase secretions
nasopharyngeal glands: increase secretions
sweat glands: increase secretion
urinary bladder: contract detrusor muscle, relax sphincters
nerve terminals: inhibit neurotransmitter release

193
Q

acetylcholine

A 
cholinomimetic
\+++cholinesterase sensitivity
\+++muscarinic activity
\+++nictonic activity
CV=GI=bladder > eye
used for induction of miosis (short duration)
194
Q

bethanechol

A 
cholinomimetic
- cholinesterase sensitivity
\+++muscarinic activity
- nicotinic activity
GI=bladder > eye >> CV
used to treat GI atony b/c more selective for GI tract, and no nicotinic activity (so no sympathetic side effects)
used to treat urinary retention
side effects: diarrhea
195
Q

carbachol

A 
cholinomimetic
- cholinesterase sensitivity
\+++muscarinic activity
\+++nicotinic activity
GI=bladder > eye > CV
used for induction of miosis (prolonged action)
196
Q

donepezil

A 
reversible anticholinesterase agent
enters CNS (designed to amplify cholinergic pathways in CNS for alzheimer's disease)
197
Q

echothiphate

A 
irreversible anticholinesterase agent
low toxicity
positively charged, low volatility
safe drug, even though it's irreversible
used to treat open-angle glaucoma
lipid soluble
198
Q

edrophonium

A

reversible anticholinesterase agent
short-acting
rapid renal elimination
used for diagnosis of myasthenia gravis: increases strength in mg patients, decreases strength & causes lingual fasciculations in healthy patients

199
Q

malathion

A

irreversible anticholinesterase agent
insecticide
lipid-soluble - pro-drug - converted to active ChE inhibitor, malaoxon, metabolized quickly in vertebrates, Insects can’t metabolize it, so they have ChE inhibition & that’s how they die

200
Q

methacholine (acetyl-beta-methylcholine)

A 
cholinomimetic
\+ cholinesterase sensitivity
\+++ muscarinic activity
\+ nicotinic activity
CV > GI = bladder > eye
used for bronchial provocation test b/c muscarinic-selective --> fewer side effects
201
Q

neostigmine

A 
reversible anticholinesterase agent
cholinergic agonist
direct nicotinic agonist
used to treat GI atony: chosen over other cholinesterase inhibitors b/c less lipid soluble so less likely to get CNS side effects
also used to treat urinary retention
202
Q

obidoxime

A

cholinesterase reactivator
acts as nucleophilic agent & accelerates the release of irreversible inhibitors (if you get there early enough - you can prevent covalent attachment)
most effective when given soon (within minutes) after exposure to irreversible ChE inhibitor

203
Q

physostigmine

A

reversible anticholinesterase agent
lipid soluble (has easier access to CNS)
used to treat narrow-angle and open-angle glaucoma

204
Q

pralidoxime

A

cholinesterase reactivator
acts as nucleophilic agent & accelerates the release of irreversible inhibitors (if you get there early enough, you can prevent covalent attachment)
most effective when given within minutes after exposure to irreversible ChE inhibitor

205
Q

pyridostigmine

A

reversible anticholinesterase agent

206
Q

What do cholinomimetics do?

A

mimic effects of parasympathetic nerve stimulation
pharmacological actions are mediated mainly through actions on muscarinic cholinoceptors:
-heart: decrease rate, increase refractory period of AV node (through K+ channel activation), fewer impulses get through
-blood vessels: relax smooth muscle through endothelium/NO mechanism, inhibition of NE release from adrenergic nerves (less constriction)
-blood pressure: decrease HR, decrease cardiac output, vasodilation –> decrease peripheral resistance –> decrease BP
-GI system: revs it up: contract GI smooth muscle, increase amplitude of contractions, increase peristaltic activity, increase motility, relax sphincters, (SE: cramps, diarrhea, vomiting)
-glands: increase secretion (xerostomia treatment)
-Urinary tract: increase peristalsis, contract detrusor muscle, relax trigone, (urinary retention treatment)
-airways: contract airway smooth muscle, promotes mucus secretion (bronchial provocation test)
-eye: contract sphincter muscle of iris (miosis), contract ciliary muscle, (narrow angle & open angle glaucoma treatment)

207
Q

What do anticholinesterase agents do?

A

Inhibit ChE by binding to enzyme at active site or peripheral anionic site
amplify cholinergic nerve mediated responses
Heart: slows
blood vessels: dilate (vaso motor center of CNS)
blood pressure: decrease (decrease HR, CO, contractility & vascular resistance all through decreased sympathetic outflow in CNS)
GI system: same actions as cholinomimetics
eye: same as directly acting cholinomimetics: induce miosis, used to treat glaucoma
urinary tract: same as directly acting cholinomimetics (treat urinary retention)
NMJ: stronger contractions, decrease decay of ACh, can cause depolarization of motor end plate, antidromic impulses, fasciculations of motor unit, asynchronous excitation fibrillation (used for neuromuscular disorders like myasthenia gravis and lambert-eaton syndrome)
glands, airways: same as directly-acting cholinomimetics
used for anticholinergic drug intoxication

208
Q

What effects does the parasympathetic nervous system have on heart (rate, contractility, conduction), blood vessels and blood pressure?

A

heart: decreases rate, neutral effect on contractility, decreases conduction
BVs: there are no parasympathetic nerves in blood vessels, does nothing to blood vessels
BP: by effects on heart, it may decrease it, but in general, the effects are kind of neutral. The biggest change in BP comes from affecting blood vessels.

209
Q

Tissue susceptibility to atropine is dose-dependent. Which tissues are most sensitive?

A

salivary = bronchial = sweat glands > eye = heart > bladder = GI > GI secretions

210
Q

The ability of atropine-like drugs to delay gastric emptying may aggravate gastric ulcer. How might this happen?

A

damaged tissue is exposed to noxious stimuli for longer period of time.

211
Q

atropine-like drugs can cause a patient’s skin to become dry and hot. This may result in the patient’s body temperature increasing when the environmental temperature is high. What would cause this?

A

Preventing sweating - sweating is an important regulatory mechanism.

212
Q

Why would sandy or dry eyes be a side effect of muscarinic antagonists?

A

eyes can’t constrict, so when you go outside, too much light comes in. (photophobia)
muscarinic antagonists inhibit tear formation, so less lubrication of the eye.

213
Q

Why wouldn’t a muscarinic antagonist reverse the neuromuscular effects of anticholinesterase poisoning?

A

because the receptors at the NMJ are nicotinic, not muscarinic.
You need parasympathetic drive to see effects of antimuscarinic agents.

214
Q

What are the actions of muscarinic cholinoceptor antagonism?

A

eye: relax sphincter muscle (mydriasis), relax ciliary muscle (far vision)
heart: increase heart rate, increase AV node conduction
arterioles: little effect (no parasympathetic innervation)
lung: airway smooth muscle relaxation (bronchodilation), decrease secretions
GI tract: decrease motility and tone, contract sphincters, decrease secretions
gall bladder & ducts: decrease secretions
salivary glands: decrease secretions
lacrimal glands: decrease secretions
nasopharyngeal glands: decrease secretions
sweat glands: decrease secretions
urinary bladder: relax detrusor muscle
nerve terminals: facilitate neurotransmitter release

215
Q

atropine

A 
muscarinic antagonist
used for pupil dilation
CNS: depression, anti-tremor
decrease salivation
increase AV node conduction
used for ChE inhibitor toxicity
used for anesthetic premedication: tranquilizing and amnesiac effects + inhibition of salivation & respiratory secretions
216
Q

dicyclomine

A

muscarinic antagonist

used to decrease GI motility (antispasmodic)

217
Q

ipratropium

A

muscarinic antagonist
very poor absorption, no decrease in Mucociliary clearance
used in airways as bronchodilator

218
Q

oxybutynin

A

muscarinic antagonist
antispasmodic
urologic-specific (increase bladder capacity)
used for dry mouth

219
Q

scopolamine

A 
muscarinic antagonist
CNS activity
used for pupil dilation
CNS: for depression, anti-tremor
decrease salivation
used for anesthetic premedication: tranquilizing and amnesia effects + inhibition of salivation & respiratory secretions
used for motion sickness (sedation & dry  mouth side effects)
anti-tremor medication
220
Q

tiotropium

A

muscarinic antagonist
M1/M3 antagonist
long duration
used in airways as bronchodilator

221
Q

tropicamide

A

muscarinic antagonist
short duration
less cycloplegia
used for pupil dilation

Pharmacology and Toxicology (1 decks)

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