Pharmacology Flashcards
(321 cards)
1
Q
what is potency? how is it measured?
A
the amount of drug necessary to produce an effect of a given magnitude
measured by EC50 (decreased EC50 = more potent)
2
Q
what is efficacy? how is it measured?
A
ability of a drug to elicit a response when it interacts with a receptor
measured by Emax
assumes all receptors are occupied by drug and no increase in response will be observed if more drugs added –> this is not true for spare receptors!!
3
Q
describe a competitive antagonist. what effect does it have on log-dose response curve?
A
reversibly binds orthosteric site (same site as agonist), can be overcome by increasing [agonist] to outcompete, often has complimentary shape to receptor agonists
R shift on log-dose response curve (increase EC50, no change in efficacy)
4
Q
what type of inhibitor is represented by the purple curve?
A
non-competitive inhibitor
5
Q
what type of inhibitor is represented by the green curve?
A
competitive inhibitor
6
Q
describe a noncompetitive antagonist. what effect does it have on log-dose response curve?
A
inhibition that cannot be overcome with increased [agonist]. can either be 1) antagonist irreversibly binds to agonist binding site (orthosteric site) OR 2) antagonist binds to another site (allosteric site) and prevents receptor activation.
Log-dose response curve: no change in EC50 (potency), decreased efficacy (Emax)
7
Q
describe an uncompetitive antagonist. what effect does it have on log-dose response curve?
A
an antagonist that doesn’t antagonize unless receptor is activated (ie need formation of agonist-receptor complex)
Log-dose response curve: decrease efficacy (Emax) and EC50 (ie increase potency)
8
Q
where do all agonists bind?
A
orthosteric site
9
Q
when does EC50 = Kd?
A
for binding, especially for antagonists
(Kd= equilibrium dissociation constant)
10
Q
what are the two important properties of a partial agonist?
A
- does not yield max biological response
- can act as competitive inhibitor of a full agonist
11
Q
describe the concept of spare receptors
A
when responses are due to complex amplification system, low doses of antagonist will produce R shift on log-dose response curve. This is because even if only a small proportion of receptors bound to full agonist, will still be able to reach max response even though most receptors aren’t bound (ie unoccupied or spare receptors)
12
Q
when does EC50 NOT EQUAL Kd?
A
when spare receptors
13
Q
in a biological system, how can you distinguish from competitive inhibitor versus other antagonist given spare receptors?
A
if increase [noncompetitive antagonist], will eventually see a decrease in Emax response to full agonist
14
Q
under what two conditions are constitutive receptor activity observed?
A
- tumors
- experimental artificial expression systems
15
Q
what is ED50?
A
median effective dose, dose at which half of individuals get desired drug effect
16
Q
what is LD50?
A
median lethal dose that produces death for 50% of experimental animals in the study
17
Q
how to calculate therapeutic index
A
TI = toxic ED50/beneficial ED50
18
Q
what do inverse agonists do?
A
reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists
19
Q
what is warfarin? what is it’s therapeutic index?
A
blocks VCORC1 to inhibit synthesis of clotting factors, used to prevent clots after surgery and to tx atrial fibrillation
TI is very low at ~1 –> this means can be dangerous. sweet spot is 2-3x increase in clotting time to prevent stroke and excessive bleeding
20
Q
what is diazepam? what is its therapeutic index?
A
allosteric activator of GABAA receptors to increase Cl- current by increasing frequency of channel openings
used to produce sedation, sleep, tx anxiety and muscle spasms
high TI: ~100
side effects: oversedation, dizziness, confusion, memory loss
21
Q
drugs ending in …azopam or …azolam are _________ and act by ________
A
benzodiazepenes
bind to a site other than the site that binds the inhibitory transmitter GABA (“allo” in allosteric=other). This benzo binding increases the frequency of opening of GABAA-gated Cl- channels and enhances synaptic inhibition
22
Q
describe the features of the Na/K ATPase pump
A
makes inside of cell slightly negative
23
Q
which direction do sodium and potassium leak channels flow?
A
Na+ leaks into cell –> depolarizes (more pos)
K+ leak leaves cell –> hyperpolarizes (more neg)
24
Q
what is equilibrium potential?
A
membrane potential that is just sufficient to oppose the chemical potential for a specific ion
25
what graded potential(s) exist(s) in neurons?
EPSP (excitatory post synaptic potential)
IPSP (inhibitory post synaptic potential)
26
what graded potential(s) exist(s) at the neuromuscular junction?
end plate potential
27
what is the mechanism of EPSPs?
ionotropic glutamate receptors, conduct Na+ or Na+/Ca2+ (mostly monovalent cation channels)
depolarize membrane
28
what is the mechanism of IPSPs?
GABA receptors, conduct Cl-
in developing neuron, depolarize
in mature neuron, hyperpolarize
29
describe the developmental switch in GABAnergic neurons
in developing neuron: active Na-K-2Cl transporter so high intracellular Cl-. GABA receptor removes Cl- from cell, depolarizing membrane
in mature neuron: Na-K-2Cl transporter inactive but active K-Cl transporter which exports Cl-, so low intracellular Cl-. GABA receptor brings Cl- in to hyperpolarize the cell
30
what is the mechanism of the end plate potential (EPP)?
acetylcholine receptors, conducts Na+ or Na+/Ca2+, depolarizes membrane
31
what channels are responsible for absolute refractory period?
Na+ channel inactivation
32
what channels are responsible for the relative refractory period?
incomplete Na+ channel recovery and residual K+ opening
33
name two major differences between neuronal, muscle, and cardiac action potentials
speed: nerve/skeletal are fast, cardiac is slow
diff ion channels: cardiac also uses Ca2+
34
describe the components of an action potential
35
how can cooperativity occur for receptors? (3 ways)
1. binding of one agonist molecule influences the binding of another (rarely happens for receptors)
2. binding of each molecule is independent, but you need more than one molecule bound to activate
3. the relationship between binding and response is cooperative (multiple/ranges of active states are possible)
36
describe the constrained subunits model for receptors (Monod-Wyman-Changeux)
there are only two states of receptors: active and inactive
agonists can only bind to the active conformation, and shift the equilibrium toward the active conformation
37
describe the sequential activation model for receptors (Koshland-Nemthy-Filmer)
receptors undergo sequential changes to a multitude of different possible conformations
different ligands induce specific/different conformational states
38
name an example of a receptor that follows the constrained subunit model
nicotinic Ach receptor
39
name two examples of receptors that follow the sequential changes/activation model
1. ionotropic glutamate receptors
2. GPCRs
40
what is primary active transport?
ATP-mediated transport
| (ATPases)
41
what is secondary active transport?
coupled transport driven by potential energy stored in a concentration gradient
(move one ion down its conc gradient and the other against its conc gradient)
42
what are the two types of secondary active transporters?
symporters (co-transport)
antiporters (counter-transport)
43
what are some examples of voltage-gated channels?
the Na+, K+, Ca2+, and Cl- channels that mediate electrical signaling
44
what are some examples of ligand-gated channels that are activated by extracellular ligands?
1. Ach-gated channels
2. GABA-gated channels
3. ATP gated-channels
4. exogenous substance-gated channels (i.e. capsaicin)
45
what are some examples intracellular ligands that activate ligand-gated channels?
1. IP3
2. Ca2+
3. cAMP/cGMP
46
what do leak channels do?
mediate passive movement of ions
47
what are leak channels for water called?
aquaporins
48
what are the two categories of ATPases and what are examples of each?
1. V-type: proton pumps
2. P-type: Na/K ATPases, Ca-ATPases, H/K ATPases
49
describe how a uniporter works
uniporters enable facilitated diffusion by moving a solute down a concentration gradient
50
how many subunits does an inward rectifier channel have?
4
it's a tetramer!
51
what are the 2 types of subunits of KATP channels?
1. channel-forming subunits
2. regulatory subunits (sulfonylurea receptors)
52
describe why sulfonylureas can be used to treat diabetes
sulfonlyureas inactivate the KATP channel --\> Vm is depolarized --\> voltage-gated Ca2+ channel opens --\> insulin is released from pancreatic B cells
(triggers insulin release without glucose stimulation)
53
does ATP activate or inhibit KATP channels?
inhibit! presence of ATP causes them to close
54
when ATP is present, will KATP channels in smooth muscle cause vasoconstriction or vasodilation?
vasoconstriction
ATP inactivates KATP channels --\> Ca2+ channels open --\> vaosconstriction
55
what does minoxidil treat and what's its mech of action?
anti-hypertensive
activates KATP channels, causes membrane hyperpolarization and closure of Ca2+ channels
(therefore causes vasodilation!)
56
what are the two domains in a voltage-gated K+ channel?
1. voltage sensing domain (in particular the S4 helix)
2. pore domain (S5-S6 helices)
57
how does the S4 helix of the voltage gated K+ channel determine whether the channel is open or closed?
S4 is a partially charged voltage sensor--when the membrane is depolarized, the S4 portion is pushed in an outward direction, opening the channel
when the membrane is hyperpolarized, the S4 portion is pulled pack into the cell, which triggers a conformational change & closes pore
58
describe N-type and C-type inactivation of K+ voltage gated channels
N type inactivation: the NTD of one of the channel helices plugs the inner mouth of the pore shut (like a ball and chain)
C type inactivation: collapse of the channel
59
how many subunits does the twin pore channel have?
2
| (it is a dimer!)
60
what is the mechanism of action for a local anesthetic like lidocaine?
blocks Na+ voltage-gated channels, preferenitally binds to inactivated state of the channel
61
describe use-dependent or frequency-dependent block
means that the degree of channel block is proportional to the rate of nerve stimulation (degree of block is enhanced during repetitive stimulation)
important for fast-firing neurons
62
what channel do neurotoxins like tetrodotoxin, saxitoxin, and brevotoxin block?
Na+ voltage gated channels
63
where are L-type voltage-gated Ca2+ channels active?
the heart
64
where are P/Q, R, and N-type Ca2+ voltage gated channels active?
the nervous system
65
where are T-type Ca2+ voltage gated channels active?
both the heart and the nervous system
66
what does it mean for a channel to be high voltage activated?
which Ca2+ voltage-gated channels are high voltage activated?
it means that the cell needs to be HIGHLY depolarized for the channels to be activated
include L, P/Q, N, and R-type channels
67
what does it mean for a channel to be low voltage activated?
which Ca2+ voltage-gated channels are low voltage activated?
it means that the channel just needs a little depolarization nudge to be activated (easily activated)
includes T-type channels
68
what are some diseases that Ca2+ channel blockers are used to treat?
hypertension, angina, arrhythmia
69
how to Na+ channel blockers affect heart rhythm?
Na+ channels block initial upstroke, therefore slowing conductance of AP through heart
70
how do Ca2+ channel blockers affect heart rhythm?
don’t affect rate of rise, but do affect plateau phase (make it easier to repolarize the heart, shortens AP)
71
how do K+ channel blockers affect heart rhythm?
K+ channel blockers impair repolarization, therefore lengthen AP
(need to find a balance with these between fixing arrhythmia and causing long QT syndrome)
72
what happens to heart rhythm when the hERG K+ channel is inactiaved?
there is a lenghtening of action potential due to longer repolarization time
73
why did people unexpectedly die after taking the antihistamine **terfenadine**?
terfenadine has an off-target effect of blocking hERG channels and causing arrhythmia (long QT)
74
describe epithelial cells
monolayer sheets, polarized cells: apical and basolateral aspects. often have brush border morphology @ apical side
imp for drugs in intestinal lining (absorption), renal tubules (elimination), intrahepatic biliary (elmination)
75
what role do TJs play in the epithelial barrier?
polarize the cell by separating membrane into two compartments (apical and basolateral), asymmetrical distribution of membrane proteins
76
what is the difference between the cellular pathway and the paracellular pathway in epithelial cells?
cellular- molecule goes through cell on both apical and basolateral sides using diff membrane proteins to travel between lumen and interstitium
paracelluluar- molecule goes between cells through TJs, solutes and water and dissolved drugs can do this
77
what is the difference between a tight and leaky epithelium?
leaky- bulk movement of fluid, low resistance to flow of charged ions so voltage doesn't build up (ex. small intestine, proximal renal tubule)
tight- high resistance, resists flow of charged ions so voltage builds up, doesn't let as much through (ex colon, renal collecting duct)
78
describe the three types of vascular endothelial cells. which are the most important for drug transport?
\*\*continuous- snug connections, have TJs, can be tight or leaky, BBB
\*\*fenestrated- holes in cell cytoplasm, more leaky, most capillaries including gut and kidney
sinusoidal- intercellular gaps and incomplete basement membrane, incomplete barriers, whole cells can get through, in spleen and bone marrow
79
drugs are designed to be ____ soluble
lipid
80
in which form do lipid soluble drugs diffuse across the cell membrane?
uncharged (they are weak acids and bases, but uncharged form is what crosses)
81
describe the concept of ion trapping across the gastric cell membrane
drugs can only get into lumen when uncharged, then rapidly convert back to charged form inside lumen so essentially "trapped"
82
what is the henderson hasselbach equation?
gross.
but also it's log[HA]/[A-] = pKa - pH
83
describe ABC transporters
mediate active transport, use ATP, contain nucleotide binding domain (NBD) to bind ATP, most often for efflux, some can mediate anticancer drug resistance
84
what is p-glycoprotein?
an ABC transporter, drug exporter, can pump out chemotherapy drugs, imp in both cancer resistance and normal physiology --\> eliminates drugs from brain, reduce GI absorption, excrete drugs in bile and urine
85
what is an SLC transporter?
mediate secondary active transport (don't use ATP directly but use gradient formed via ATP active transport) and facilitated diffusion (via alternating access and conformational change), can have coupled co-transport (Na and glucose)
ex. neurotransmitters
86
what is the role of neurotransmitter transporters at the synaptic cleft?
after neurotransmitters activate receptor on post-synaptic membrane, get taken back up into presynaptic terminal via transport to shut down signaling
87
SLC6A2
norepinephrine transporter
clears norepi from synapse
target of cocaine, ADHD drugs
88
SLC6A3
dopamine transporter
clears dopamine from synapse
target of cocaine, amphetamines
89
SLC6A4
serotonin transporter
clears serotonin from synapse
target of antidepressants (SSRIs)
90
what is transcytosis?
vesicle is formed on one side of the membrane to capture substance to be transported, next vesicle and its contents are shuttled inside the cell to reach an opposing membrane. cells can use vesicles to transport substances across PM either into or out of cell
91
what is vectorial transport?
net, directional transfer of a solute across epithelial or endothelial cells, imp for efficient transfer of nutrients across epithelial or endothelial barriers, drug absorption and elimination
transcytosis may also be used here
92
what is drug absorption?
transfer of drug from its site of administration to systemic circulation
most drugs need this to happen to reach their target
93
name three factors that impact drug absorption
route of administration
bioavailability
bioequivalence
94
what is the main criteria for drug administration?
bioavailability
95
what are the fastest routes of drug administration? what are the slowest?
intravenous, intraosseous (in pediatrics), endotracheal
intramuscular, subcutaneous, oral (varies widely), transdermal
96
list advantages and disadvantages for oral drug administration (brief)
advantages: easy, expensive, safe, preferred by pts
disadvantages: slow time to effect, consciousness required, requires functional gut, bioavailability can be limited
97
what are advantages and disadvantages of rectal drug administration
advantages: easy, good absorption, no first pass metabolism, good for infants and children
disadvantages: not preferred by pts
98
what are advantages and disadvantages of intravenous drug administration?
advantages- rapid onset, dependable, 100% bioavailability!!!!!
disadvantages- requires IV cannula, expensive, labor intensive, pain, risk of infection, bleeding
99
what are advantages and disadvantages of IM/Subcutaneous drug administration?
advantages: relatively fast onset, no first pass metabolism
disadvantages: absorption can be unpredictable, pain, risk of bruising/bleeding
100
what are some advantages and disadvantages of transdermal drug administration?
advantages: easy, non-invasive, high pt satisfaction
disadvantage: slow time to effect, most drugs not absorbed through skin
101
what are some advantages and disadvantages of inhalation drug administration?
advantages: rapid absorption, limited systemic delivery
disadvantages: effectiveness depends on pt technique
102
name some factors to consider when choosing route of drug administration
clinical urgency, type and properties of drug including bioavailability, condition of pt including age and mental status, pt preference
103
define bioavailability
fraction of administered dose of unchanged drug that reaches systemic circulation
ie how well a drug is absorbed, usually with respect to oral administration
104
what is the bioavailability of IV drugs?
100%
105
what is bioequivalence
related to the manufacturing of the drug, same rates (pharmacokinetics) and extents of bioavailability of active ingredient
(TLDR; same amt active ingredient delivered in same amt time)
a generic drug must have 8-%-125% bioequivalence of brand-name drug without identical formulation
106
what is pharmaceutical equivalence?
contain same active ingredients, are identical in strength or concentration, dosage form, and route of administration
107
name some factors affecting oral absorption of drugs
intrinsic chemical and physical properties, bioavailability (high efficient absorption), gastric acidity and digestive enzymes, gastric emptying time, relationship to food intake, drug metab by intestinal epithelium (CYP3A4), drug efflux from intestinal epithelial cells (p-gp), inhibitors of CYP3A4 and drug transporters
108
why is ibuprofen largely absorbed from the intestine
surface area in intestine far outweighs the driver for absorption
109
what is first pass metabolism?
for oral drugs, metabolism in either intestinal wall or liver before the drug can reach systemic circulation reduces bioavailability
110
what receptor is largely responsible for 1st pass metabolism?
CYP3A
111
what are some drugs with low bioavailability? which are NOT administered orally?
morphine, demerol, lidocaine, nitroglycerin = not administered orally
propranolol- oral administration bc wide therapeutic window
112
what effect does grapefruit juice have on bioavailability? how does it achieve this?
furanocoumarins in grapefruit juice (and pomegranate) INHIBIT CYP3A4 and p-gp --\> this increases bioavailability for some meds by decreasing 1st pass metabolism, can cause toxic elevation of plasma drug concentration
113
how do generic drugs differ from brand named drugs?
A generic drug must conform to 80 to 125% of bioequivalence of the brand-name drug, but it must not be identically formulated.
3 criteria: pharmaceutical equivalence, bioequivalence, effective and safe
114
what should be the same if looking at a time-concentration curve for generic and brand name drug in order for generic drug to be manufactured?
should have same Cmax peak at same time point and same AUC (area under the curve) which represents how much drug the body gets
115
what is drug distribution?
reversible transfer of drug between systemic circulation and extravascular (interstitial) fluids and tissues
116
what does perfusion-limited tissue distribution mean?
initial rate of drug distribution depends on blood flow to tissue
first phase: brain, heart, liver, kidney
second phase: muscle, most organs, skin and fat (have moderate blood flow)
117
what does permeability-limited tissue distribution mean?
certain compartments have restricted access, for ex blood brain barrier (BBB), placenta
118
how does drug accumulation in tissues impact volume of distribution (Vd)?
if more drug accumulates in tissues, higher Vd
119
what is the mechanism of termination of thiopental?
redistribution, when removed from plasma and redistributed from brain to other tissues, that's why it's so short lasting
120
describe the blood brain barrier (BBB)
no fenestrations, limited extracellular space due to other cells and basement membrane, TJs
lots of efflux transporters to send things out of the brain (MRPs and p-gp)
121
what can p-gp KO studies tell us?
if KO increases drug penetration in BBB, we know it's normally pumped out of CNS by p-gp
ex. quinidine gets pumped out, ritonavir does not
122
how can we leverage the BBB to increase drug delivery? (two ways)
1. inhibit p-gp
2. utilize blood-CSF interfact to bypass BBB with interthecal lumbar puncture
123
what type of endothelial cells are the choroid plexus capillaries?
fenestrated
124
albumin binds \_\_\_\_\_\_
drugs that are weak acids
125
alpha-acid glycoprotein binds \_\_\_\_\_\_\_
drugs that are weak bases
126
how does protein binding impact drug activity?
bound drug is inactive, free drug is active and can equilibrate across diff fluid spaces.
protein binding lowers effective concentration and slows distribution to extravascular sites bc less is metabolized, increased half life
127
what is hypoalbuminemia?
disease affecting protein binding of drugs, affects free drug concentration without affecting total plasma concentration
128
name an example of a drug that can compete for protein binding to cause drug displacement
sodium valproate (displaces phenytoin from albumin and increases free phenytoin concentration)
129
List the basic signaling processes used by pharmacological receptors (from the fastest to the slowest)
1. Ligand-gated channels (fastest)
2. G-protein coupled receptors
3. Transmembrane enzymes (RTKs and related molecules)
4. Cytoplasmic and nuclear receptors (slowest)
130
name the 4 excitatory receptors
1. Ach-nicotinic receptors
2. Serotonin 5HT3 receptors
3. P2X ATP receptors
4. Glutamate (AMPA/kainite receptors and NMDA receptors)
131
name the 2 inhibitory receptors
1. GABA-A receptors
2. Glycine receptors
132
name the 4 CYS-loop receptors
1. Ach (nicotinic)
2. 5-HT3 (serotonin)
3. GABA-A
4. glycine
133
name the non-cys loop receptors (2)
1. glutamate
2. P2X ATP receptors
134
what does Ondansetron (Zofran) do?
competitive inh at 5HT3 receptors- treat nausea and vomiting
135
what channels have benzodiazepine binding sites?
GABA-A
136
what effect does penicillin have on GABA-A channels?
what negative physiologic effect does it cause?
they are open channel blockers
causes seizures!
137
which neurotransmitter works only on ligand-gated channels? (hint: all other NTs also work on GPCRs)
glycine!
138
what is the mech of action of Strychnine?
it's a competitve inhibitor at glycine receptors (prevents an inhibitory effect)
causes spasticity
139
what is the mech of action of tetanus toxin?
blocks glycine release (so it won't bind to receptors), causes spasticity
140
what is hyperekplexia?
familial startle disease
alpha subunits of glycine receptors are mutated, channel can’t bind glycine and therefore won’t open…no inhibitory effect in spinal cord :(
141
what are the types of channels in the glutamate channel family?
NMDA, AMPA, Kainate
142
what to nicotinic Ach receptors do?
1. Initiate action potential in skeletal muscle and ganglionic transmission in peripheral NS
2. Perform excitatory func in CNS
143
what does the 5-HT3 serotonin receptor do?
it's an excitatory receptor in CNS
causes emesis and GI activity
144
is GABA-A excitatory or inhibitory?
What kind of channel does is it a ligand for?
inhibitory in CNS
opens ligand-gated Cl- channel
145
is glycine inhibitory or excitatory?
where does it act?
inhibitory, in spinal cord
146
what is the normal role of the NMDA receptor?
what disease can it cause when it's letting too much calcium into the cell?
1. Important in learning & memory (w/ normal to high Ca2+ levels)
2. can cause Alzheimer's when too much Ca2+ in cell
147
what does memantine treat? what's it's mech of action?
open channel blocker of NMDA receptors, tx for Alzheimer’s
148
List the three main types of signaling used by G-protein coupled receptors (GPCRs) from the fastest onset to the slowest
1. Milliseconds: direct membrane effects (i.e. activation/inhibition of ion channels) by B/Y subunits of G-protein
2. Seconds: second messenger synthesis (or block of synthesis by inh alpha subunits)
3. Minutes: phosphorylation via protein kinase A after cAMP activation or protein kinase C after DAG activation
149
what is the scaffold protein for RTKs when the ligand is a growth factor?
growth receptor bound protein 2
150
EGF (and other growth factors) trigger which downstream signaling pathway?
Ras/MAPK
hint: **mitogen-activated** protein kinase
mitogen = GF!
151
what is the scaffold protein for RTKs when insulin is the ligand?
IRS (insulin receptor substrate)
152
what signaling cascade does insulin RTK trigger?
PI3K/AKT/mTOR
| (metabolic)
153
what signaling cascade do cytokines trigger?
JAK/STAT
154
what are the main differences between RTKs for insulin and growth factors vs RTKs for cytokines?
(2 differences)
1. for cytokine receptors, the TM domain does not have kinase activity (JAK serves as the kinase)
2. for cytokine receptors, there is not a separate scaffold protein (JAK acts as the scaffold protein that recruits STAT)
155
how to glucocorticoids work?
steroid binds receptor --\> inhibitory HSP90 dissociates from glucocorticoid receptor --\> ligand-bound receptors dimerize and enter nucleus, where they bind to DNA and trigger ∆s in gene TC --\> causes inhibition of inflammatory cells & synthesis/release of inflammatory mediators
156
how are GPCRs desensitized via GRKs?
GPCRs are phosphorylated on the cytoplasmic tail of receptor by GRKs (G-prot receptor kinases)
phosphorylated site binds B-arrestin, arrests signaling, which causes desensitization and receptor internalization
157
what happens when you give repetitive doses of a competitive antagonist?
1. Continual use leads to upregulation of receptors
2. Discontinuation can cause rebound effects (esp with GPCRs)
158
do allosteric activators increase or decrease likelihood of receptor desensitization?
decrease
159
what are biased ligands and how do they differ from classical (balanced) ligands?
1. Classical balanced signaling ligands (like endogenous substances) elicit their effects globally…
2. **Biased ligands** can direct their effects toward one mechanism (such as GPCR signaling) vs another (arrestins)
160
Why do we need drug metabolizing enzymes?
to rid the body of xenobiotics (which are sometimes cometabolized with endogenous agents), to make drugs more polar so they can be made inactive and excreted
161
What family of proteins carry out the majority of Phase I metabolizing reactions?
the CYPS (cytochrome p450 monooxygenases). (They carry out 80% of phase I rxns)
162
Which CYP is the most prevalent in Phase I rxns?
CYP3A4- (carries out about 60% of Phase I rxns)
163
What is the purpose of Phase I drug metabolism reactions?
To provide a reactive site on the molecule where Phase II rxns can made modifications
164
What is the most common rxn scheme for drug metabolism?
Phase I oxidation by CYP3A4, Phase II glucuronidation
165
What is Midazolam, and how is it fully metabolized? (include which CYP is involved)
Mizadolam (Versed) is a benzodiazepine- a sedative used prior to surgery/procedures. Allosteric activator of GABA channels.
It undergoes Phase I metabolism by **CYP3A4**, and then Phase II glucuronidation.
166
All benzodiazepines are metabolized by _____ in Phase II.
Glucuronidation
167
What is a common structural element of all benzodiazepines?
a 7 membered diazepine ring, containing 2 N atoms
168
Oxidations & hydrations constitute Phase ____ metabolism reactions.
Phase I
169
What is a cosubstrate, and why is it important?
In a Phase I CYP-dependent metabolism reaction, a cosubstrate is a second enzyme besides CYPs that is needed for the reaction to occur.
In Phase I reactions, this enzyme is **NADPH cytochrome p450 reductase**- it supplies electrons and protons to activate oxygen, creating a reactive oxygen species needed for the rxn to finish successfully.
170
Where are the CYPs and cosubstrate located within the cell and within the body?
On the cytoplasmic side of the smooth ER, in the liver and intestine
171
Describe aliphatic hydroxylations. Give a substrate example.
Phase I rxn where CYP will add an OH group to an aliphatic carbon. Ex. Midazolam
172
Describe aromatic hydroxylations. Give a substrate example.
Phase I rxn where a CYP will add an OH group to a carbon in a ring. Ex. Propanolol
173
Describe propanolol, its therapeutic intent, its mechanism of action, and which CYP it is metabolized by.
**-lol= beta blocker**
anti-hypertensive, anti-arrhythmic, reduces HR and cardiac contraction
Blocks beta1 adrenoreceptors which mediate HR and cardiac contraction
Metabolized by **CYP2C19**
174
Describe S-oxidations. Give an example of a substrate.
Phase I rxn where a CYP adds an O to an S atom on a drug. Ex. Cimetidine (Tagamet)
175
Describe Cimetidine- it's therapeutic effect, mechanism of action, and any other special properties.
Cimetidine (Tagamet) suppresses acid secretion. It's used to treat heartburn, acid reflux, and ulcerative GI condtions.
Mechanism of action: competitive inhibitor of histamine @ H2 receptors (normally histamine, released from paracrine cells as a result of gastrin signaling, will bind to parietal cell H2 receptors causing HCl secretion)
Cimetidine is also an **inhibitor of all the CYPs** (except CYP2E1).
176
Describe how drug interactions may affect CYP metabolism.
One drug substrate for a CYP may act as a competitive inhibitor of another, if the first drug has such high affinity for the CYP that it is unable to let go.
177
Describe N-oxidations. Give an example of a substrate.
Phase I rxns where CYP adds an O group to an N atom on the drug. Ex. Diphenhydramine (Benadryl)
178
Describe diphenhydramine (Benadryl)- it's therapeutic effect, & mechanism of action
Used to treat mild allergic reactions.
Mechanism of action: competitive inhibitor of histamine @H1 receptors. (Normally, histamine released from mast cells binds to H1 receptors and causes mild allergies)
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Describe N-dealkylation, and list common substrates.
CYP removes an alkyl (-CH2) group from an N. Ex. methylxanthines (caffeine, theophylline), diazepam (Valium)
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At low doses, how do caffeine & theophylline act? At high doses, how do they act?
At low doses, caffeine & theophylline (methylxanthines) are **competitive inhibitors of adenosine receptors**. They will inhibit cell function.
At high doses, they inhibit phosphodiesterases, increasing cAMP.
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What is theophylline used to treat?
It's a last resort drug to treat asthma & COPD
182
What is diazepam (valium) used to treat? Describe its metabolism.
Diazepam is a benzodiazepine used to treat seizures, anxiety, muscle spasms, etc.
It's metabolized by **CYP3A4** and **CYP2C19** into 2 active metabolites, 1 being very long acting. Then, it is glucuronidated in Phase II metabolism.
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Describe O-dealkylation. List common substrates.
Phase I rxn where CYP removes an alkyl group from O. Ex. Codeine, hydrocodone
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What are the two CYP-independent Phase I oxidation rxns? (list, no need to describe)
Dehydrogenase rxns (ethanol breakdown), and oxidative deamination
185
Describe ethanol metabolism.
Ethanol ------\> acetaldehyde ------\> acetate.
The enzyme in the first step is **alcohol dehydrogenase** (found in liver and stomach), and it uses an NAD+ and produces an NADH.
The enzyme in the second step is **aldehyde dehydrogenase**, and it also uses an NAD+ and produces an NADH.
**Acetaldehyde buildup** causes nausea, headache, dizziness, facial flush.
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What substrate builds up and causes toxicity in chronic alcoholics?
NADH. NADH is produced in both steps of ethanol metabolism. NADH buildup causes metabolic disorders, an increase in reactive oxygen species, and liver destruction.
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Describe Phase I hydrolysis rxns. What are the enzymes involved, and what are common substrates?
Addition of H2O, catalyzed by esterases and hydrolases.
Ex. acetylcholine, succinylcholine
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What are the reactions of Phase II metabolism? (list, don't describe). Which is the most common?
SAGGMeth: sulfation, acetylation, glutathione, glucuronidation, methylation.
Glucuronidation is the most common.
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Describe sulfation. What are common substrates?
Sulfation is the addition of a sulfate group to an OH. Occurs via **sulfotransferases** (found in the cytosol.) These require **PAPS (ADP-Sulfate)** to function.
Ex. Albuterol, Acetaminophen. Acetaminophen doesn't require Phase I metabolism bc it already has a free OH. Sulfation will metabolize it into a nontoxic sulfate.
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What is special about acetylation?
Unlike all other metabolism reactions, acetylation makes drugs less polar (more lipid-soluble) but still inactive.
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Describe glucuronidation. What are common substrates?
Glucuronidation is the addition of a glucuronide molecule to the drug. It occurs via **UDP Glucuronyl Transferase (UGT**), found in the smooth ER. It requires **UDP glucuronic acid** as a substrate along with the drug.
Ex. Lorazepam (Ativan). It already has an OH group so therefore doesn't need Phase I metabolism. UGT will turn it into lorazepam glucuronide.
Ex. Acetaminophen. In addition to sulfation, glucuronidation is another way to inactive acetaminophen.
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Why is lorazepam (Ativan) a good drug for the elderly?
Lorazepam is a useful benzo for the elderly because glucuronidation does not decline in the elderly. Other benzos require CYPs in Phase I, and CYP function declines substantially in the elderly.
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Describe glutathione. What is an example substrate?
Glutathione reactions protect against electrophiles. The transfer of an electrophile to an HS site on glutathione is catalyzed by **Glutathione-S transferase (GST)**.
ex. Benzoapyrene (epoxide) can be neutralized by glutathione reactions.
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What is special about tumor cells and glutathione reactions?
Some tumors express high levels of glutathione S-transferase (GST), causing tumor cells to proliferate and be resistant to cancer chemo drugs.
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What are some substrates of CYP3A4?
Most drugs are metabolized by CYP3A4. These include Diazepam, Midazolam (-azolam benzos), oral contraceptive, lidocaine, etc.
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What makes CYP3A4 have so many substrates?
It has a very large active site and accepts a large number of ligands (shape does not matter).
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What are 2 inhibitors of CYP3A4?
Ketoconazole (-conazole) and erythromycin. These are 2 very different looking molecules- another example of how shape doesnt matter with CYP3A4
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Which CYP is most commonly involved in genetic polymorphisms?
CYP2D6
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What is a prodrug? Give 2 examples.
A prodrug is a drug that needs to be metabolized to be activated.
Ex. **Codeine** (analgesic, CYP2D6 will metabolize it to morphine), **clopidogrel** (anti-platelet drug, CYP2C19 will metabolize it to be active)
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What is an example of a drug that is already active but metabolized into other active intermediates?
Diazepam- metabolized by CYP3A4 and CYP2C19 into 2 other active intermediates, resulting in long lasting effects
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Describe how acetaminophen can be metabolized into a toxic intermediate. What are the steps taken after this intermediate is produced?
At low doses, acetaminophen is metabolized by sulfation and glucuronidation into nontoxic metabolites.
At high doses, **CYP2E1** and **CYP3A4** will metabolize it into a toxic electrophile called **NAPQI**.
After this, there are 2 choices: glutathione can rescue the molecule by neutralizing NAPQI, or, if glutathione is low, cell death will occur.
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How can we address the issue of acetaminophen toxicity if glutathione is low?
Glutathione cannot be adminstered because it does not cross cell membranes well. Instead, we use **N-acetylcysteine (NAC)**. Its structurally similar to glutathione and can act in the same way.
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List the 3 CYPs most relevant to polymorphisms.
CYP2D6, CYP2C19, CYP2C9
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Describe the genetic variations seen in CYP2D6. Which populations are most affected?
_Poor metabolizers_: 2 mutant CYP2D6 alleles. Little to no enzyme function. Will need to lower drug dose to avoid toxicity. (8-10% of **Caucasians**)
_Rapid/Ultrarapid metabolizers_: duplification/amplification of functional CYP2D6 alleles. Will need to increase drug dose so it can reach therapeutic levels. (30% of **North Africans**)
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What are some CYP2D6 substrates?
Beta- blockers, and lots of CNS drugs- ex. opioids (codeine, hydrocodone), antidepressants, amphetamines.
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Describe metoprolol & its mechanism of action. Describe how metoprolol dosing may need to be adjusted based on individual polymorphisms.
Metoprolol is a beta blocker (-lol). It blocks B1 adrenoreceptors, making it an anti hypertensive, anti arrhythmic, anti anginal drug.
It is metabolized by **CYP2D6**. Poor metabolizers will require lower doses to avoid toxicity. Rapid/Ultrarapid metabolizers will require higher doses to achieve therapeutic levels.
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What is the difference between metoprolol and propanolol?
They are both beta blockers (-lol). Metoprolol acts to block B1 adrenoreceptors, and propanlol acts to block B1 and B2 adrenoreceptors. B2 agonists relax the airways, making metoprolol the better choice for patients with _asthma_ and _COPD_.
(also, metoprolol is metabolized by CYP2D6 while propanlol is metabolized by CYP2C19)
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Describe how the dosing of codeine may need to be adjusted to account for individual polymorphisms.
Codeine is a prodrug, metabolized by **CYP2D6** into active morphine.
Poor metabolizers: drug should be avoided because it's not useful/therapeutic.
Rapid/Ultrarapid metabolizers: require lower doses (to avoid morphine toxicity)
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What is the common polymorphism seen in CYP2C19? What population is the most affected?
Poor metabolizer polymorphisms- 15-25% of the **Asian population**
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What are important substrates of CYP2C19?
Diazepam and other -azepam (long-acting) benzodiazepines, omeprazole (-prazole: proton pump inhibitors), clopidogrel, propanolol
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Describe how diazepam metabolism is affected for CYP2C19 poor metabolizers.
Diazepam is metabolized by CYP3A4 and CYP2C19. It is metabolized into 2 long acting intermediates. For poor metabolizers, the _half life of diazepam will be increased greatly_.
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Describe the common variation seen in CYP2C9. Which population is most affected?
Poor metabolizers- 10-35% of **Caucasian pop**
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What are important substrates of CYP2C9?
Warfarin, NSAIDs (non-steroidal anti inflammatory drugs) including iburprofen & celecoxib
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How is warfarin metabolism affected in CYP2C9 poor metabolizers?
Warfarin is an anticoagulant often used post surgery. It has a very narrow TI. Poor metabolizers will show reduced warfarin clearance, changing (reducing) the number of days required to reach stable anticoagulation.
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What is the difference between ibuprofen and celecoxib (both NSAIDs)?
Ibuprofen and celecoxib are both pain relievers & anti-inflammatory. Ibuprofen inhibits both COX1 (housekeeping protein, used to maintain normal kidney and GI function) and COX2 (causes pain). Celecoxib inhibits only COX2. This makes it a better choice for post op pain, because it doesn't affect the kidney or GI.
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How does NSAID dosing need to be adjusted for CYP2C9 poor metabolizers?
CYP2C9 poor metabolizers will require lower doses of NSAIDs
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Describe variations in the enzymes involved in ethanol metabolism. What accumulates as a result of these variations? What population is most affected?
Both increases in the amount of alcohol dehydrogenase (90% of **Chinese pop**) and decreases in the amount of aldehyde dehydrogenase (30-50% of **Chinese/Japanese pop**) will cause accumulation of acetaldehyde.
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What is the effect of mu and theta genotypes of glutathione S-transferase (GST)?
Glutathione is needed to neutralize evil electrophiles. Mu and theta genotypes have null alleles of GST. This leads ot an increased risk of cancer and increased toxicity of chemo drugs.
Mu genotype- 50% of **Caucasian** pop
Theta genotype- 60% of **Chinese/Korean** pop
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Explain how ethanol + acetaminophen interaction is toxic.
At high doses, acetaminophen is metabolized by CYP2E1 and CYP3A4 into the toxic electrophile NAPQI.
High doses of ethanol cause **induction of CYP2E1**, helping create NAPQI, and also **reduced glutathione**, preventing rescue from NAPQI.
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Charbroiled foods + environmental pollutants induce \_\_\_\_\_, causing epoxide formation.
CYP1A2
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What is Ginkgo used for? What are its effects on the CYPs?
Ginkgo is a herbal remedy used to enhance memory. It induces CYP3A4, CYP2C9, and CYP2C19.
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What is Echinacea? What effects does it have on the CYPs?
Echinacea is a herbal remedy used to enhance the immune system (ex. treat colds). It induces CYP3A4 and inhibits CYP1A2.
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What is St. Johns wort? What are its effects on the CYPs? How does it work to cause these effects?
St. Johns wort is a herbal remedy used to treat mild depression. It induces CYP3A4, CYP2C9, CYP2C19, and CYP2E1.
It goes straight to the nucleus and binds to receptors + coactivators, causing increased CYP gene transcription.
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what are the 3 processes for drug elimination through the kidneys?
1. glomerular filtration
2. tubular secretion
3. passive tubular reabsorption
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will protein-bound drugs be secreted through the glomerulus? how about through the proximal tubule?
NO
only unbound drugs will be secreted
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excretion through the glomerulus is proportional to:
(2 things)
1. glomerular filtration rate (GFR)
2. concentration of free drug in plasma
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for which groups should we decrease doses of drugs that are exclusively renally-excreted?
old people
people with kidney damage/disease
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where does tubular secretion of drugs occur?
in the proximal tubule of the kidney
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what transporters are used for renal excretion of weak bases?
weak acids?
organic cation transporters (OCTs) for bases
organic anion transporters (OATs) for acids
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why/how does probenecid increase the half life of penicillin?
probenecid and penicillin use the same transporter to be secreted. probenecid will competitively bind to that transporter and prevent penicillin from being secreted, therefore increasing the amount of penicillin in the body and increasing its half life
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explain how tubular pH can be manipulated to promote or impair reabsorption
(hint: this is used for drug overdoses!)
acidifying tubule prevents reabsorption of weak bases by causing them to be protonated (this enhances excretion). example = meth
alkalinizing tubule prevents reabsorption of weak acids by causing them to be deprotonated. ex = phenobarbital/other barbituates
**ionized drugs will not cross the membrane!**
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how does the glomerulus achieve size sensitivity?
it has 3 layers of membranes, all with varying sizes of fenestrations/pores/slits.
the endothelial layer has medium-sized fenestrations
the basement membrane has larger pores
the podocyte layer has tiny filtration slits
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how does the glomerulus achieve charge sensitivity?
endothelial cells and podocytes are lined with negatively charged glycoproteins
(negatively charged particles such as albumin are not filtered)
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which transporter mediates secretion of conjugated metabolites like glucuronides, sulfates, and glutathione in the kidney?
MRP2
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what is hepatic clearance determined by?
hepatic blood flow and extraction ratio
(extraction ratio tells you liver's metabolic capacity)
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in terms of hepatic clearance, what are high extraction drugs limited by?
hepatic blood flow
(they can be metabolized rapidly, so that won't hold them up)
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in terms of hepatic clearance, what are low extraction drugs limited by?
liver's metabolic capacity and fraction of free drug
(they are metabolized very slowly, so the liver is already overwhelmed trying to clear these drugs out. increased blood flow won't make much of a difference since the rate is already slow)
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how are drugs handled through biliary excretion eliminated?
through feces
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what does the OATP1B1/SLCO1B1 transporter do?
what happens when you have genetic variants of this transporter?
it's an organic anion transporter that transports statin into hepatocytes
when you have the genetic variant, you are predisposed to muscle toxicity
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what is enterohepatic circulation?
reabsorption of drug from bile once the bile reaches the gut lumen
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how are conjugated drugs liberated back into their native state to be reabsorbed during enterohepatic circulation?
intestinal bacterial B-glucuroindases liberate them
242
if you have malignant hyperthermia susceptibility, which drugs should you NOT take?
volatile anesthetics
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glucose-6-phosphate dehydrogenase deficiency leads to acute hemolysis when you take which drugs?
anti-malarial drugs
sulfonamides
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what is succinylcholine normally used for?
what happens if you take it when you have pseudocholinesterase deficiency?
it's a transient paralytic used during surgery/intubation
if you have pseudocholinesterase deficiency, it will cause **persistent** paralysis
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which CYP metabolizes warfarin?
CYP2C9
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what's affected when you have VKORC1 variants?
warfarin efficacy changes
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are pharmacogenomic inheritance patterns traceable in families??
no
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which CYP2D6 alleles have normal levels of activity?
\*1, \*2, \*4
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which CYP2D6 alleles have intermediate/poor levels of metabolic activity?
\*3, \*5, \*10
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how do you get ultra-rapid metabolism of CYP2D6?
duplication/amplification of CYP2D6\*1
251
what's the difference between a standard drug and a prodrug?
a standard drug is administered in its active form
a prodrug has to be activated through metabolism
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what happens when poor metabolizers take a standard drug?
they have decreased elimination rate and increased toxicity risk because they can't effectively clear the drug
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what happens when poor metabolizers take a prodrug?
they have decreased activation and reduced effectiveness of the drug
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what happens when ultra-rapid metabolizers take a standard drug?
they have increased elimination rate and reduced effectiveness of drug
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what happens when ultra-rapid metabolizers take a prodrug?
they have increased activation and therefore increased toxicity risk
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what happens when intermediate metabolizers take a standard drug?
they have potential for increased toxicity (eliminate the drug a bit slower than normal)
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what happens when intermediate metabolizers take a prodrug?
they have possible reduced effectiveness (aren't transformed to active drug as quickly)
258
which CYP metabolizes codeine?
CYP2D6
259
which CYP metabolizes clopidogrel?
CYP2C19
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what happens if you take clopidogrel and you have CYP2C19\*2 or \*3 alleles?
you won't metabolize prodrug clopidogrel to its active form
therefore you won't get anticoagulative effects, so you're at higher risk of clotting, cardiovascular complications, death, MI, etc
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what happens when you have genetic variants for TMPT and need to take an anti-cancer drug?
how is this avoided?
you won't break down and excrete thiopurines as effectively, putting you at risk for bone marrow toxicity
testing for variants is done to dose correctly and avoid toxicity
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what happens if you have CYP2C9\*2 or \*3 alleles and take warfarin?
you will have slowed elimination of warfarin and increased anticoagulative effects
this puts you at risk for bleeding
263
how can we monitor anticoagulative activity of warfarin?
do a prothrombin assay and look at the INR
264
what happens if you have an INR that is higher than the therapeutic window for warfarin?
you get increased bleeding
265
usually we see germline variants in pharmacogenomics. where do we see an example of somatic pharmacogenomic variants?
cancer!
specifically, non small cell lung cancers with hyperactive EGFR are more sensitive to EGFR inhibitors like gefitinib and erlotinib
266
What is the equation for apparent volume of distribution?
267
What is the clearance? What is the equation for it? When is it constant, and when does it change?
Clearance is the volume of plasma cleared of a drug per unit time. In 1st order drugs, its constant. For zero order drugs, it changes (rate of elimination remains constant/plateaued).
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1st order drug clearance= constant ______ of drug eliminated per unit time, while zero order clearance= constant ______ of drug eliminated per unit time.
Fraction, amount
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What is the equation for loading dose?
LD= Vd\*Css
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True/False: the patient's weight affects the apparent volume of distribution and must be accounted for.
True
271
What is the equation for maintenance dose?
Maintenance dose= CL\*Css
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What is Css?
Steady state, desired plasma concentration of drug
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What is the equation for Css in a continuous infusion?
Css= infusion rate/CL
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What is the equation for Css for a multiple dose drug?
Css= dose/(dosing interval \* CL)
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What is the equation for half life?
t(1/2)= 0.693Vd/CL
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How many half lives does it take to reach 90% steady state (considered good enough)?
3.3
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What is the equation for loading dose if bioavailability is not 100%?
F\*LD= Vd\*Css
278
Describe what happens with parasympathetic innervation of the heart.
Acetylcholine is released onto muscarinic receptors. This causes an inhibitor, membrane delimited GPCR response through activating K+ channels. This slows the heart rate.
279
What is the effect of multivalent cations (except Ca2+) and aminoglycoside antibiotics on skeletal muscle?
They are competitive inhibitors of voltage gated Ca2+ channels- blocking Ca2+ from entering- making it so vesicles can't release content.
280
What is the effect of botulinum toxin type A on skeletal muscle? What can it be used to treat?
Cleaves SNAP-25 of SNARE. This blocks secretion of Ach into the neuromuscular junction. It can be used to treat spasticity (blepharospasm- a disease of eye closure due to spastic eye muscle contraction)
281
Describe what happens at the somatic neuromuscular junction to cause skeletal movement.
There is a vesicle full of ACh. It's connected to the Ca2+ channels in the presynaptic plasma membrane via the Fusion Machine. SNARES on the fusion machine are responsible for priming the vesicles. SNAREs have Ca2+ sensors.
If there is an AP, it will propagate down the presynaptic membrane, and voltage gated Ca2+ channels will respond and open. Ca2+ will flow into the cell, binding Ca2+ sensors on the Fusion Machine, allowing vesicles to release ACh by exocytosis into the neuromuscular junction.
ACh will bind to nicotinic ACh receptors and cause Na+ influx, which produces the EPP. EPP will generate an action potential via voltage gated Na+ channels opening.
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What is the role of TTX?
At the skeletal neuromuscular junction, it blocks voltage gated Na+ channels from the outside, preventing initiation of AP in nerve and skeletal muscle.
It blocks the input to synapses (intial AP needed for Ca2+ influx) and the output ( the production of AP from the EPP).
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What are the -curoniums? What are they used for?
Rocuronium and vecuronium- nondepolarizing blockers. Competitive inhibitors at skeletal neuromuscular junction. Used to relax skeletal muscle during surgical procedures.
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What is Sux (succinylcholine) used for?
Used to relax skeletal muscles for intubation. It's a depolarizing blocker because it binds to nicotinic receptors and depolarizes/activates the muscle before it blocks. Very fast acting.
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What is neostigmine?
A reversible inhibitor of acetycholinesterase, making it so ACh has to remain in the cleft longer, improving transmission when nicotinic and muscarinic receptors are impaired (ex. after surgery and to treat disease of muscle fatigue).
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Fight or flight is the ______ division of the ANS, while rest and digest is the ______ division.
Sympathetic, parasympathetic
287
Where are preganglionic fibers located for sympathetic nerves?
Thoracic and lumbar regions of the spinal cord
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Where are preganglionic fibers located for the parasympathetic division of the ANS?
Cranial and sacral regions of CNS
289
Muscarinic receptors are ______ (GPCRs/Ligand gated ion channels).
GPCR
290
How is norepinephrine action terminated?
Reuptake by SLC into presynaptic membrane (SLC6A2)
291
What is the therapeutic use of atropine? How does it act?
Atropine is used to increase heart rate during spinal anesthesia. It is a competitive inhibitor of Ach at muscarinic receptors.
292
Describe what happens after ACh binds to a receptor in the parasymapthetic nerve terminal for cardiac muscle.
Parasympathetic= rest/digest.
ACh binds to muscarinic receptors on postsynaptic membrane, these are GPCRs. It acts via a membrane delimited process- beta gamma subunits of G protein break off and activate K+ channels, inhibiting cardiac muscle (reducing heart rate and contraction).
293
How does Ach released by parasympathetic nerve endings constrict airways?
Parasympathetic= rest+ digest.
Ach binds to muscarinic receptors, causing the alpha subunit of the G protein to break off and activate Phospholipase C. The water soluble arm of this involves PIP2 synthesizing IP3, which releases Ca2+ from storage sites. This causes smooth muscle contracition- constriction of airways.
294
What is the mechanism of action of ipratropium and tiotropium? What are they used for clinically?
Used to treat airway disorders (asthma, COPD). They are competitive inhibitors of ACh at muscarinic receptors- inhibiting the inhibiton of airway opening.
295
How does norepinephrine released by sympathetic nerve endings onto alpha1 receptors constrict blood vessels?
NE binds to alpha1 adrenoreceptors (GPCR), which works through the Phospholipase C inhibitory pathway. Ca2+ release causes smooth muscle contraction via alpha1 adrenoreceptors.
296
What is phenylephrine used for?
It's an agonist of alpha1 adrenoreceptors. Can be used to relieve nasal congestion by constricting blood vessels in nasal passages, and increase blood pressure during surgery.
297
What is the neurotransmitter that increases heart rate and contractile force in the sympathetic NS? How does it work?
Epinephrine or norepinephrine.
Binds to B1 receptors, which are GPCRs- causes alpha subunit to dissociate and stimulate adenylyl cyclase, causing cAMP formation. This leads to activated PKA and protein phosphorylation.
298
Where are beta2 receptors located?
Smooth muscle- blood vessels and bronchioles
299
What happens to smooth muscle when B2 agonists bind to their receptors?
Smooth muscle relaxation-- happens via adenylyl cyclase activation and cAMP synthesis
300
How does cAMP work in cardiac muscle?
increases Ca2+ entry and increases stores of Ca2+, causing contraction
301
how does cAMP work in smooth muscle?
decreases cellular Ca2+ concentrations, making it so less is available for contration, causing relaxation. Increases calcium removal/reduces its entry
302
What is the mecahnism of action of beta blockers like propanolol and metoprolol?
Competitive inhibitors of NE at beta1 receptors in the heart.
303
What is the mechanism of action of albuterol (-erols)?
What are they used for?
Used to treat asthma and COPD.
They are agonists of B2 receptors, relaxing smooth muscle and opening airways.
304
The control of blood vessel ____ is the major determinant of blood pressure.
Radius
305
Describe sympathetic tone and the constriction/dilation of blood vessels.
Increasing the tonic firing of AP of the sympathetic nerve will cause an increase in the amount of norepi release onto A1 receptors of blood vessels, causing vasodilation.
Decreasing the firing of AP of the sympathetic nerve will cause a decrease in the amount of norepi released, causing vasoconstriction.
This is the major determinant of blood pressure- controlling radius of the vessel.
306
Norepinephrine does not activate\_\_\_\_ receptors.
B2
307
\_\_\_\_\_\_ can activate all catecholamine receptors(a1, a2, B1, B2)
Epinephrine
308
B2 receptors on blood vessels are _____ (innervated/not innervated)
not innervated. NE cannot activate B2 receptors.
309
What activates B2 receptors on blood vessels? What is the effect?
Epi released from adrenal medulla. Happens during emergency situations. Vasodilation
310
What are the receptors on the heart, and what effects do their agonists have?
parasympathetic: muscarinic Ach receptors. Ach increases K+ conductance, slowing heart rate.
Sympathetic: B1. Epinephrine binds. Increases heart rate and cardiac contraction via cAMP/PKA pathway.
311
What are the receptors on blood vessels? What effects do their agonists have?
Sympathetic: B2- not innervated. Epi from bloodstream causes vasodiation via cAMP increases during emergencies.
Sympathetic: A1- Norepi and epi are agonists. Bind and cause smooth muscle contraction via Ca2+ release from Phospholipase C activation.
312
What are the receptors on the airways? What effects do their agonists have?
Parasympathetic: muscarinic. ACh constricts airways using smooth muscle contraction.
Sympathetic: B2. Receptor activation by -erol drugs causes airway smooth muscle relaxation
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