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PMCOL 200 > Midterm I: Drug Targets - Blood Pressure Regulation > Flashcards

Midterm I: Drug Targets - Blood Pressure Regulation Flashcards

1
Q

agonist

A

substance or drug that binds to a receptor and generates an effect

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2
Q

antagonist

A

substance that generates no biological effect on its own but influences receptor response to an agonist

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3
Q

prodrug

A

a substance that is converted to the active form of the drug via liver metabolism

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4
Q

Gi signaling cascade

A
  • inhibit activity of adenylate cyclase, leading to decreased cAMP production, inactivating cAMP dependent protein kinases and substrates are not phosphorylated
  • responses are generally quick and mediate moment to moment control of many physiol functions
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5
Q

pharmacokinetics

A

subfield focused on the specific details of drugs and the molecular-level receptor interactions

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6
Q

ligand gated ion channel

A
  • open or close in response to binding of small signaling molecules (various AAs, NTs)
  • play important role in CNS synapses as common drugs for psychiatric conditions target them
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7
Q

voltage gated ion channel

A
  • transmembrane receptors
  • rapidly respond to changes in membrane velocity
  • movements of charged AAs the TM electric field change position in response to to changes in voltage, allowing the protein to open or close rapidly
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8
Q

EC50

A

in the context of a conc-response curve, refers to the conc of a drug that yields 50% of its maximal biological effect

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9
Q

potency

A

refers to concentration dependence (the smaller the EC50 of a drug, the less of it is needed to produce a given response, and the more potent it is)

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10
Q

Emax

A

the maximal biological effect observed from a drug

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11
Q

efficacy

A

term referring to the maximal effect o fa drug (the higher the Emax of a drug, the greater efficacy it’s said to have)

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12
Q

full agonist

A

generates the maximal observed effect (elicits full biological response)

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13
Q

partial agonist

A

generates a fractional effective (its maximal response is less that the possible biological Emax)

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14
Q

inverse agonist

A

inhibits receptor baseline activity, leading to an overall decrease in activity

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15
Q

tyrosine kinase receptors, TKRs

A
  • transmembrane
  • ligand binding triggers dimerization, they auto-phosphorylate (usually at crit Tyr residues) and become activated, able to phosphorylate internal systems
  • drugs that inhib or stim their activation will influence downstream signaling mechanisms
  • common in immune systems
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16
Q

drug effect equation

A

Emax x [drug]
E = ———————-
[drug] + EC50

or
Emax
E = ———————-
1 + (EC50/[drug])

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17
Q

orthosteric binding site

A

the active site that binds and agonist

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18
Q

competitive antagonists

A

suromountable

  • do not affect Emax (with a high enough conc of agonist, you can eventually elicit the response) but do shift the EC50 right (as you need a higher conc of the agonist than usual to generate the response)
  • compete for the same orthosteric binding site as the agonist

(reduce potency but not efficacy)

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19
Q

non-competitive antagontists

A

non-surmountabe
do not generally affect EC50, but do drop Emax (no matter how much agonist you add, you never reach the maximal response)
-bind to an alternate, allosteric site, and can therefore not be out-competed by the agonist

(reduce agonist efficacy but not necessarily potency)

-binding can prevent activation of the agonist bound receptor, but might also lead to a change in the shape of the binding site which could reduce agonist potency

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20
Q

irreversible competitive antagonism

A

-reduce efficacy by binding irreversibly to the orthosteric site (usually bind forming a covalent or chemical bond)

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21
Q

allosteric potentiation

A

-drugs that bind an allosteric site and thereby enhance the receptor response to an agonist (increase efficacy, potency, or both)
one example of positive allosteric modulators are benzos, which increase the activity of GABA signaling at its A receptors to compensate for the receptors lost during tolerance

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22
Q

allosteric binding site

A

binding to a receptor site other than the orthosteric (active, agonist binding) site

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23
Q

receptor reserve

A

as you take more and more receptors out of the system, it can compensate to an extent by enhancing the response of those remaining to generate the full biological response (there is a reserve of receptors that aren’t all needed to elicit the maximal response)
-eventually though, too many are taken out to compensate, leading to a drop off in efficacy

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24
Q

considerations of oral dosing

A
  • first pass metabolism (will enough of the drug in its current form make it where it needs to? what are the metabolites and their effects)
  • solubility (can it be absorbed into the gut cells?)
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25
Q

distribution

A
  • how a drug/substance is partitioned into different body compartments after it’s absorbed
  • can greatly influence the drug’s effective concentration and lifetime in the body
  • drugs that are highly bound to plasma proteins can have long lifetimes in the plasma even if only a small free conc is acting on target tissue
  • highly lipophilic drugs can cross plasma membranes and accumulate in more highly profuse tissues, creating a bodily reserve of the drug
  • poorly lipid soluble drugs can distribute through the extracellular fluid
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26
Q

first pass metabolism

A
  • occurs in the hepatic circulation (drugs must make it through the liver before they can get into the bloodstream)
  • being a major site of metabolism, it can strongly influence the bioavailability of many drugs
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27
Q

hepatic portal circulation

A
  • a major processing-related consideration for orally administered drugs
  • the hepatic portal vein brings all the drugs absorbed from the intestine to the liver before entering the systemic circulation, which can lead to significant processing or breakdown of the drugs
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28
Q

volume of distribution

A

= total amount of drug in the body / [drug]

  • provides relative comparison of how well drugs are distributed into the body (the higher the volume of distribution, the better distributed the drug)
    ex. drugs restricted to the plasma will have very low volumes of distribution, but if there’s a huge amount of drug in the body compared to the amount circulating the plasma, then the volume of distribution would be high
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29
Q

single compartment distribution

A
  • the drug is contained within a single compartment (ex. a drug that is delivered into and primarily contained within the bloodstream)
  • if an elimination pathway is present, the concentration of that drug would decrease with exponential decay kinetics (rate of elimination depends on drug conc)
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30
Q

multiple compartment distribution

A
  • after administration, the drug is distributed into multiple compartments
  • if an elimination pathway is present, the drug concentration in the blood will determine the rate of elimination, but the reservoir of drug in the tissues will keep replenishing the plasma conc, prolonging its lifetime in the body
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31
Q

biotransformation (phase 1, 2)

A

phase 1-mixed function oxidase system (CYP family enzymes in the liver) generates oxidative modifications of drugs (hydroxylation, dehydrogenation, etc)
phase 2-conjugation of parent compound or phase 1 products with larger polar adducts to make them more prone to excretion

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32
Q

drug effect equation

A

Emax x [drug]
E = ———————-
[drug] + EC50

or
Emax
E = ———————-
1 + (EC50/[drug])

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33
Q

binding equation

A

Bmax x [drug]
B = ———————-
[drug] + Kd

where Bmax = max number of receptors in the system, Kd = dissociation constant (conc at which 50% of the receptors are occupied; refers to potency of direct binding of a drug to a receptor)

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34
Q

therapeutic window

A

concentration range over which the drugs is effective
-too little will have no effect while too much can have an adverse effect, so it’s important for the dosing regimen to keep the drug conc w/in this window

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35
Q

routes of admin: important considerations

A
  1. convenience (is it easy to take? oral is ideal, but IV or other routes may be necessary)
  2. bioavailabilty (different drugs may be absorbed with different efficiency in the gut, and may also be degraded more or less rapidly by first-pass metabolism)
  3. processing (hepatic portal vein brings drugs absorbed from the gut to the liver before they can enter the systemic circulation, which can impart significant processing of breakdown)
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36
Q

extraction ratio

A

clearance by liver/blood flow

  • highest possible is therefore 1
  • higher extraction ratios indicate higher degree of processing by liver, meaning that lots of what was taken up by the git will be eliminated by first pass metabolism, resulting in lower bioavailabilty
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37
Q

relative risk reduction (RRR)

A

1 - (event rate in treatment group / event rate in control group)
-can be misleading as it doesn’t convey the magnitude of the baseline risk or capture the difference between large reductions in things that occur frequently vs infrequently (doesn’t convey the rarity of the disease you might be protected against on the larger scale)

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38
Q

absolute risk reduction (ARR)

A

= event rate in control - event rate in treatment group

  • describes absolute number of cases that are prevented by taking a drug, rather than a percentage relative to the baseline
  • more descriptive way to report the benefit of taking a drug for the broad population
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39
Q

number needed to treat (NNT)

A

= 1 / ARR

  • gives a sense of the population-level benefit of a drug by calculating how many people need to take the drug in order to protect one person from the event that you’re looking to prevent
  • low NNTs are good; an NNT near 1 means that just about everybody taking the drug will receive the desired effect
  • high NNT is bad, bc it means most ppl won’t benefit, and may only be exposed to possible harms
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40
Q

number needed to harm (NNH)

A

low NNH is bad, high NNH is good

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41
Q

the case of terfenadine

A

terfenadine has a t-butyl group; liver metabolism replaces one of the methyl groups with a carboxylic acid, converting it the an active antihistamine form call fexofenadine, the substance that was actually acting at the receptors to produce the effect

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42
Q

primary routes of drug excretion

A
  1. bile/feces
    - biotransformed drugs from the liver are incorporated into bile the secreted into the gall bladder and gut; large polar adduct modifications make them polar and prevent them from being reabsorbed in the digestive tract
  2. urine
    - drug passes through glomerular filtration or is actively secreted into the renal tube, then excreted in the urine
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43
Q

drug excretion

A
  • elimination is typically described by a half-life, meaning the enzymes and systems mediating elimination are not saturated; the rate of elimination therefore depends on the concentration of the drug and can be described by an exponential decay equation
  • in some cases though, the elimination capacity can be limited in the effective dose of the drug is much higher that the affinity or ability of a key enzyme involved in the elimination; this is capacity-limited elimination, and the rate proceeds at a fixed conc/unit of time (ex. ethanol, which rapidly saturates the system)
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44
Q

clinical trials

A

controlled human studies to assess dosage, admin, safety, efficacy
phase 1 - small scale (dozens of subjects); testing for tolerable dosing ranges, bioavailability, excretion
phase 2 - intermediate scale (100s of subjects) testing for efficacy and monitoring for safety in greater number of patients
phase 3 large scale, randomized, double-blinded trial, compared against placebo or currently accepted standard

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45
Q

therapeutic index

A

= TD50/ED50

  • ratio of the median toxic dose and effective dose
  • tells how big of a safety window you have between doses that are effective and doses that are harmful (the lower the number, the more risk is associated with the drug, bc the toxic dose will be were close to the effective dose)
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46
Q

NSAIDS

A

non-steroidal anti-inflammatories

  • advil (ibuprofen), tylenol (acetaminphen), voltaren (doclfenac), aleve (naproxen)
  • provide symptomatic relief from pain and swelling, used to treat low/mod intensity pain and fever
  • all anti-inflammatory (except aceaminophen)
  • not much evidence to suggests any one is particularly better than another (v little clinical difference)
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47
Q

peripheral pain and inflammation

A

when the skin surface is compromised, cells release a signal that is transduced to a pain response picked up by nociceptors (specialized neurons that respond to noxious chemical, mechanical or thermal stimuli)

  • this triggers a depolarization that sends pain signals to the spinal cord and brain
  • during pain, CGRP (calcitione gene related peptide) and substance P (peptide) are released; they interact to cause vasodilation (which makes the vessels leak fluid that causes swelling) and histamine release (P)
  • prostaglandins (PGs) also hypersensitize nocis to subsequent stimuli released from injury or inflammation, leading to direct and indirect effects on blood vessels

-NSAIDS largely prevent PG formation, causing decrease in noci sensitization and decrease in vasodilation, reducing swelling, itching, redness

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48
Q

prostaglandin synthesis

A
  • PGs are lipid-derived signaling molecules
  • phospholipase enzymes are activated by damage and immune signaling to cleave out these very specific lipids from the membrane; sometimes this results in the release of arachidonic acid (C20)
  • the C20 is converted to PGH2 by cyclooxygenase enzymes (COX 1 and 2)
  • PGH2 is a PG parent molecule and depending on the enzymes in the cell, can be converted to all kinds of different products by PG synthases (or by thromboxane synthase to give thromboxane A2)
  • the dominant PG formed when PGE synthases act on PGH2 is PGE2, which causes inflammation and is also involved in other normal physiological processes
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49
Q

COX1

A
  • housekeeping enzyme that’s constitutively expressed in most tissues (including platelets); does things the cell tissue needs to thrive and be successful (not specialized)
  • may also be involved in vasoconstriction
  • produces tonic lvls of PGs involved in secretion of protective gastic mucous (PGE2) in the gut that protects stomach cells from being eaten away by the acid
  • promotes platelet aggregation and constriction of blood vessels through production of thromboxane A2
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50
Q

COX2 enzyme

A

most active after mechanical/chemical/thermal damage or bacterial/viral infection as it’s induced in inflammatory cells when those are activated by other signaling molecules

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51
Q

NSAID/COX interactions

A
  • most traditional NSDAIDs inhibit both COX 1 and 2
  • it’s beleived that most anti-inflammatory effects are brought about via COX2 inhibition
  • also believed that some of the unwanted side effects (such as gastric concerns) are caused by COX1 inhibition
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52
Q

aspirin

A
  • ppl noticed that if you chewed willow bark, it helped alleviate mild to mod pain (turns out this was due to salicylic acid, a nat occurring chemical with analgesic properties)
  • since chewing bark is Not Fun (also v bitter) and since the salicylic acid cause intestinal bleeding and inflammation, it was reacted with acetic anhydride to produce acetylalicylic acid (aspirin) which causes far fewer GI probelms
53
Q

NSAID structures

A
  • most are weak acids with a carboxyl group
  • they’re hydrohpobic which allows them entrance to enzyme active site
  • modification of the original salicylic acid gave rise to 4 new classes (salicylate class (to which aspirin belongs), propionic class (naproxen), aminophenol class (acetaminophen) and acetic acid class (diclofenac))
54
Q

Aspirin and COX

A
  • aspirin works a bit different than other NSAIDs at COX enzymes
  • NSAIDs are hypho and wriggle into the lipophilic channels of the enzyme to the active site, where the long chain arachadonic acid would sit to be transformed into PGH2
  • aspirin is special, because the acetyl group can covalently modify Ser529 (COX1) or 516 (COX2) which blocks arachidonic acid from getting in and becoming a PG (other NSAIDs are just competitive inhibitors as opposed to being irreversibly bound)
  • this means a new protein needs to be synthesized to recover function (which can take a hot second)
55
Q

NSAID antipyretic (fever-reducing) effect

A
  • during infection, bacterial endotoxins trigger the release of signaling molecules (interleukins (ILs), which travel thr the blood to the brain) from immune cells
  • IL1 specifically induces COX2 in the CNS, leading to increased PGE2 synth; binding of this PG to its receptors in the hypothalamus (where body temp is regulated) increases body temp (thought to fight off infection) and cause vasoconstriction (which decreases heat loss and prevents sweating)
  • NSAIDs inhibit COX2 and therefore decrease all describes above, reducing fever
  • interesting, studies show that NSAIDs only affect body temp if IL1 is involved and COX2 is being stimulated (they won’t affect body temp in a healthy individual)
56
Q

NSAID headache analgesia

A
  • may be from reducing production of PGs involved in cerebral vasculature vasodilation, which seems to be involved in some types of headaches (it might drigger the release of chemical signals that ultimately result in migraine pain)
  • headache might also be from dilated blood vessels near the skull that are forced to impinge upon brain tissue, giving rise to an inflammatory reaction; some of those nerve endings are also releasing calcitone gene related peptide (CGRP) which causes further dilation
  • NSAIDS might be preventing the initial vasodilation, and are most effective when used to nip a headache in the bud (esp for migraine)
  • effective in tension headaches, though mechanism is unclear (related to nociceptor sensitization?)
57
Q

NSAIDs: unwanted effects

A
  • main problem is adverse GI effects due to inhibition of COX1, which leads to decreased synthesis of PGE2; without the protective mucous, stomach acid eats away at te cells in the stomach to the point where blood vessels are being exposed
  • side effects might include blood in stool/vomit, gastric pain, diarrhea, bloating, gastric bleeding, ulceration
  • ibuprofen and acetominophen typically have the lowest reporting of complaints
  • push for drugs that can selectively inhibit COX2 and avoid all this
58
Q

COX1 vs 2 inhibition

A

COX2 active site is significantly larger; need a drug that will fit in COX2 but be too big for the COX1 site; enter the coxibs

  • usually also contains a sulfur group that imparts further specificity for COX2 site
  • unfortunately still produced some gastric side effects, and may also increase risk of cardiovascular events (myocardial infarction, stroke, vascular death) bc COX2 forms molecules (sucha s PGI2) that play important roles in blood pressure, inhibit formation of clots (thrombosis) and arterial plaque
  • this lead to many coxibs being withdrawn from the market
59
Q

acetaminophen-induced hepatotoxicity

A
  • toxic doses (10-15g) of acetaminophen can cause fatal hepatotixicity and tylenol is the leading cause of N american liver failure
  • CYP2E1 in liver metabolizes it to N-acetyl-p-benzoquinone imine (NAPQI) which is a very toxic metabolite
  • normally, glutathione binds to them to make them non-toxic, but if you take more than the recommended dose, you run out of glutathione to conjugate and inactivate it
  • alcoholics can be very sensitive to acetaminophen effects bc their CYP2E1 expression is upregulated, leading to surplus NAPQI production
  • medical treatment is to admin N-acetyl cysteine, a glutathione precursor that is only one AA away
60
Q

the aspirin rebrand

A

while initially marketed as a painkiller, it has recently been rebranded as stroke protective (prevents clot formation by inhibiting thromboxane A2 products in platelets)

  • no evidence tho that it helps for ppl with not preexisting risk for thrombotic events
  • duration of action doesn’t depend on half life in plasma (which is only 15 min) because it has irreversible effects on COX activity
61
Q

salicylism

A

collection of symptoms resulting from chronic OD of aspirin
-include tinnitus (due to constriction of blood vessels in auditory vasculature and effect on cochlear hair cells), vertigo, nausea, vomiting

62
Q

notes on acetaminophen

A
  • unsual NSAID bc it has excellent analgesic and antipyretic properties via CNS PG synthesis inhibition, but weak anti-inflammatory properties
  • indeed, has only weak effects on COX1 and 2, leading to fewer gastric and platelet side effects
  • true mechanism of action may be mediated by COX3 in the CNS (an alternate splice product of the COX1 gene)
  • plama half life is 2-4 hours with therapeutic doses, and 4-8 with toxic ones
63
Q

why do we cough?

A
  • irritants activate receptors in the airway (larynx, trachea, bronchi), stimulating afferent limb vagal nerves which synapse at the cough centre in the medulla oblongata
  • this then sends signals via efferent limb motor nerves to the laryngeal and respiratory muscles to stimulate coughing
64
Q

mucinex

A
  • active ingredient is guaifenesin, an expectorant (like mucokinetics, should increase ability to get rid of stimuli)
  • ancient remedy, obtained from plants
  • used to anesthetize animals, esp horses
  • muscle relaxant effects in humans
  • mech of action on cough unclear; no effect on cough reflex nerves, but seems to have multiple indirect effects on mucous properties, may change type of muscin molecules in airway mucous
65
Q

gauifenesin and the gastro-pulmonary reflex

A
  • parasym reflex mediated via Ach release that activates muscarinic M3 receptors on globlet and serous cells in airways; causes glandular exocytosis of less viscous mucous in airways (the mucous secreted is more watery and easy to clear)
  • this reflex is activated by irritation of gastric vagus nerve receptors in gastric mucosa (which are triggered by guaifenesin when swallowed, either causing vomiting or Ach release)
66
Q

guaifenesin and mucous properties

A
  • MUC5AC is a major type of mucin found in airway mucous; it’s overproduced in infection and is very sticky
  • guaifenesin activates muscarinic receptors leading to Ach release from the vagal nerve that changes the secretion, rate of transport, and viscosity of the mucous (in a dose related response, the MUC5AC production is decreased and the mucous becomes less sticky, making it easier to transport out of airways)
67
Q

opioid and opioid-like cough suppressants

A

(dextromethorphan, codeine)

  • still uncertain how drugs act in the cough centre (a collection of specialized neurons) to modify the cough reflex
  • suppression of cough can occur via activation of opioid receptors involved in analgesia and resp depression, but there are also high lvls of excitatory Glu receptors there, suggesting other NTs play a role
  • unclear how everything works together, but just abt every opioid gives clinical suppression of cough even at doses that aren’t clinically analgesic
68
Q

DXM

A
  • dextromethorphan, an opioid-like cough suppressant
  • doesn’t act at opioid receptors (know this bc op antag naloxone doesn’t oppose DXM effects) but DXM and its metabolite DXO suppress cough via blockade of NMDA Glu receptors (make sense, since we know irritants can stim Glu release in the cough centre, activating cough receptors)
  • DXO is more potent, which can be problematic due to indv diffs in CYP2D6 enzymes leading to huge variabil in response/sensitivity
  • no strong evidence of any effect beyond placebo on cough tho
69
Q

codeine

A
  • an opioid and cough suppressant
  • converted to morphine in brain and liver by CYP2D6 enzymes (removal of methyl group), which allows it to act at mu-opioid receptors in brain stem to suppress cough
  • due to genetic variation in CYP2D6, some indv will be extremely sensitive to codeine while others will be resistant (insufficient conversion for analgesic or cough suppressant effects)
  • at high doses, gives rise to same symptoms as morphine (sedation, nausea, constipation)
70
Q

dangers of cough remedies

A
  • high CYP2D6 lvls lead to increased production of metabolites (DXO, morphine)
  • DXM can be addictive and lead to psychosis (risk increases with production of DXO) due to NMDAR blockade (same mech as PCP and ket)
  • DXM inhibits clearance of release 5HT from synaptic cleft, leading to 5HT syndrome (causing potentially life threatening cardiovasc and nerve issues)
  • morphine from codeine can depress respiration at high doses and lead to addiction via mu opioid receptors
  • codeine linked to deaths, esp of children and ppl with high CYP2D6 activity
  • mixed evidence whether they work beyond placebo effect for cough
71
Q

nasal congestion

A
  • nasal cavities are full of blood vessels; viral infections give release of signaling molecules such as bradykinin, which triggers vasodilation of large veins in the epithelium;, sometimes swelling to such a degree that the airways are physically obstructed
  • the endothelial cells also pull apart and the swollen vessels leak fluid, contributing to mucous volume
72
Q

mechanisms to increase nasal blood vessel diameter

A
  • the blood vessel has a layer of smooth muscle that can exist in a relaxed or constricted state (big vs tight diameter), depending upon action of myosin and actin
  • to manipulate contractility, we want those muscles to squeeze together and decrease diameter; adrenergic adrenaline and NA receptors are targeted by a variety of drugs to do so
73
Q

alpha 1 adrenergic receptors (in the context of cough and cold)

A 
Gq coupled (activates phopholipase C to hydrolyze specific membrane lipids, increasing conc of IP3 and DAG)
-net result is vasoconstriction, hence targeting a1 receptors is useful to combat nasal congestion
74
Q

alpha 2 adrenergic receptors (in the context of cough and cold)

A 
Gi coupled (inhibit adenylate cyclase, leading to decreased cAMP production) 
-has vasoconstrictive effect, but we don't mess with this type of receptor for OTC cold meds bc it has other effects that are bad
75
Q

beta type adrenergic receptors (in the context of cough and cold)

A
  • Gs coupled (stimulate adenylate cyclase to produce more cAMP)
  • overall vasodilation effect, which doesn’t help at all for curing colds
76
Q

mechanism of action at a1 adrenergic receptors

A
  • vasoconstriction is a calcium dependent process
  • binding of the drug to a1 causes an exchange of GDP with GTP, allowing the now activated G protein to dissociate and interaction with PLC
  • PLC then targets PIP2, a minor component of the lipid bilayer, cleaving it into IP3 and DAG
  • DAG remains in the bilayer and activate protein kinase C (which has a minor effect on smooth muscle contraction)
  • more importantly, IP3 binds to receptors on the endoplasmic reticulum, causing calcium release; this binds to calmodulin protein to form an active complex
  • the Ca-calmodulin complex binds myosin light chain kinase, which phosphorylates myosin, leading to smooth muscle contraction and therefore vasoconstriction
77
Q

adrenergic a1 receptor agonists

A
  • all bear resemblance to NA (makes sense since we’re hijacking its system)
  • pseudoephedrin and phnylephrine (both oral), xylometazoline (topical (thr the nose))
  • NA has 2 phenyl OHs; removal of one or both allows more to escape the liver, increasing bioavailability and duration of action; complete absence prevents more CNS penetration
  • pseudoeph specifically is resistant to metab by MAO
  • all relatively selective for a1 receptors (which is good, bc it allows us to focus on vasoconstriction and avoid adrenergic interactions involved in cardiovasc issues)
78
Q

concerns with a1 adrenergic receptor agonists

A
  • a1 receptors are found on vasculature throughout the body and vasoconstriction leads to high BP; this makes it extremely dangerous for indv who already have high BP (hypertension)
  • pseudoephedrine can be converted to meth; companies have moved towards phenylephrine, but it’s less clinically effect bc the oral admin leaves it with low bioavailability and extensive liver metabolism (also has shorter half life)
  • extended use of topical decongestants (>5 days) results in rebound congestion as the body tries to compensate for the presence of the agonist
79
Q

mucinex: mechanism of action

A
  • made of mucin proteins, other proteins, water
  • submucosal glands, globlet and clara cells secrete mucous, which hydrates and traps irritants; cilia move it to the throat to be coughed out
  • acting via Ach in the parasymp NS, guafenesin decreases mucin production, makes less sticky mucous, and leads to greater mucocilary clearance
  • only works when swallowed (needs to make it to stomach)
80
Q

histamine

A
  • local hormone in the periphery (chemical messenger that conveys signal from one cell to another) and NT in CNS
  • present in high conc in tissues exposed to environment (lings, skin, GI tract), a well as enterochromaffin cells in the stomach, histaminergic neurons, and mast/basophil cells (these relase histamine after mechanical damage, or during immune and inflammatory reactions)
81
Q

clinically useful H1 antihistamines

A
  • oppose the actions of histamine at specific target receptors
  • inverse agonists (binding drops receptor activity below a basal level)
  • first gen (ex diphenhydramine (benadryl)) were good at relieving allergies, but were neutral at phsyiol pH so could cross the BBB, interfering with Hist neurons and causing sedation
  • the 2nd gens had a negative charge at physiol pH, which made it harder for them to cross the BBB; there are also ATP driven transporters called P-glycoprotein that pump them out of brain capillary endothelial cells (greatly reduced drowsiness)
82
Q

histamine receptors

A
  • 4 types (H1-4), all 7 TM, GPCRs
  • most therapeutically useful agents act selectively at H1 and/or H2 (ex antihistamines are selective for H1 and H2, but may still bind to similar non-histamine receptors from the superfamily of 7TM GCPRs, such as the a1 adrenergics
83
Q

H1 histamine receptors

A
  • Gq coupled; effector is PLc, and 2nd messengers are increased IP3, DAG (which leads to smooth muscle constriction via receptors in the airways and gut) and NO (nitric oxide, which creates vasodilation in the vascular endothelium (cells that line the fine blood vessels in the vasculature))
  • vasodilation causes endothelial cells to pull apart and allow fluid to leak out, causing the characteristic swelling and inflammation of an allergic reaction
84
Q

tissue specific responses to H1 receptors

A

-primary afferent nerve terminals are depolarized by his binding, which can cause itching
-his causes endothelial cells to contract, allowing fluid and protein to leak out of postcapillary venules (fine blood vessels that collect and return blood from capillaries to veins, and are present in high number in the skin) ((this is edema, swelling, the wheal))
-the post capillary venules are dilated by his (this results in redness as more red blood cells can get into each unit of that region); this also results in a drop in BP (as the blood rushes to and even leak out of these vessels), which contributes to anaphylactic shock
the effects can be counteracted with adrenaline or analogues (which is why epi-pens contain epinephrine)

85
Q

how do antihistamines interfere with allergic and inflammatory processes?

A
  • allergies are typically related to IgE antibody production
  • the first time you’re exposed to an allergen, it will bind to the receptor on a B immune cell
  • this cell can then convert to a plasma cell, a factory hat makes copies of the receptor that first bound the allergen, called antibodies
  • IgEs float freely through the body or bind to mast cells, and can be activated by subsequent exposure to the allergen
  • if you never encounter the allergen again, nothing happens, but if you do and it binds a receptor on the mast cells, it can cross-link two receptors to trigger His release from dense granules w/in the cell, producing allergy symptoms
  • antihistamines oppose this by preventing the release histamine from acting on its receptors to produce symptoms
86
Q

1st generation H1 antihistamine structure

A

-all H1 agonsits contain a substituted ethylamine backbone including one tertiary amino group and either an N, a C, or a C-o bonded to two aryl ring substituents

87
Q

2nd generation H1 antihistamine structure

A
  • all have a carboxyl group, which becomes negatively charged at physiological pH, which prevents CNS penetration as well as selectivity for H1
  • these drugs also often have the rings joined
88
Q

why are 2nd gen antihistamines more selective than 1st gen?

A
  • the binding pocket of H1 receptors is hydrophobic and similar in nature to the binding pockets of other GPCRs
  • 1st gens will bind in the pocket, but fit just as well into similar pockets in other receptors
  • x-ray crystallography shows a strong positive spot at the entrance to the H1 pocket; when the H dissociates from the carboxyl on 2nd gens, it produced a negative charge that binds quite strongly here to give selectivity
89
Q

adverse effect of H1 antihistamines

A

1st gen:
-drowsiness, fatigue and sedation from blockade of CNS receptors
-disruptionof heart rhythm from interactions with noradrenergic cardiac receptors
-inappropriate vasodilation leading to orthostatic hypotension and dizziness via anti alpha-adrenergic effects (muscarinic, seratongergic and adrenergic blocks)
-as dose and therefore effects at other receptors increase, can die from CNS and cardiac toxicity
-in terms of abuse, some report feelings of hallucinations and high
2nd gen:
-minimal CNS effects, minimal vasodilation
-no fatalities or serious consequences reported as a result of overdose, and no reports of drug abuse
-screened for cardiotoxicity and not approved when detected

90
Q

antihistamines as sleep aids

A
  • most common is diphenhydramine (a 1st gen anti)
  • in the CNS, histamine is involved in circadian rhythm, arousal, and sleep
  • all his releasing neurons originate from the tuberomammillary nucleus in the brain and project to areas involved in wakefulness (cerebral cortex, ventral tegmentum)
  • H1 blockage in these areas decreases wakefulness, and non-specific blockades of other receptors adds to sleep-inducing effects
  • also present in cough/cold preparations for nighttime use
91
Q

what is heartburn?

A
  • burning pain in chest that usually occurs after eating (esp with certain foods/drinks (spicy, fatty, wine, coffee))
  • cause by mvmt of gastric juices up the esophagus and often into into the mouth (gastroesphogeal reflux disease, GERD)
  • normally, the sphincter should close off to prevent this, but sometimes it doesn’t work
  • the acid causes blistering, burning pain in the chest, and lying down makes it worse bc it straightens out the junction btw the esophagus and stomach, allowing the acid to flow more easily
92
Q

methods to prevent heartburn

A
  • avoiding certain foods
  • using a physical barrier to prevent acid from entering the esophagus
  • neutralizing the acid with a simple chemical reaction
  • decrease acid production
93
Q

Gaviscon

A
  • tablets that foam up when chewed, contain seaweed cell wall components called alginates (natural plysaccharide polymers, sugar residues in long chains with a common repeat of 2 M (mannuronic acid) then 2G (glucuronic acid))
  • in contact with acids, form a low-density viscous gel that, with the help of release CO2 bubbles from the NaHCO3, will float on top of the food and acid, creating a physical barrier to the esophagus
94
Q

metal-containing antacids

A
  • directly neutralize stomach HCl
  • most are AlOH or MgOH
  • Mg causes influx of fluid to the GI tract which usually triggers peristalsis (diarrhea), while Al can cause constipation; they’re often combined to cancel each other out
  • form no CO2, so no belching or bloating
  • reaction with HCl can be slow, so relief isn’t immediate
95
Q

issues with metal containing antacids

A

Al:
-can bind phosphates released from food, which may lead to excess fecal elimination via formation of insoluble Al-phosphates in the GI tract
-P is important for ATP and phosphorylation, and in healthy ppl the liver already eliminates a lot of phosphates, leading to hyposphatemia (weakness, lethargy, anorexia) (note tho that this could be helpful for ppl with kidney failure, who can’t process P well and end up with blood concs that are way too high)
Mg:
-should be avoided by patients with chronic kidney disease, as they may have trouble eliminating Mg which can lead to hypermagnesemia (interference with Ca channels that affects contractility of heart muscle, respiratory depression, lowered BP)

96
Q

ENO and TUMS

A

ENO:
-NaHCO3 antacid; reacts HCl to form CO2, water, salt
-bc they’re a rich source of sodium, ppl on Na-reduced diets should avoid as increased sodium can increase BP
-fast acting, but the CO2 generated can cause bloating/distention and belching
TUMS:
-CaCO3 antacids, react with HCl to give CaCl and CO2
-slower than ENO, and also forms CO2
-sufficient Ca for use as a supplement in prevention of osteoporosis
-overuse in healthy individuals can lead to constipation and the increase blood Ca levels can cause CNS issues (seizures) and kidney overload failure
-both can also escape the stomach in their unreacted forms

97
Q

can antacids affect blood acidity?

A

NaHCO3 antacids (ex ENO) are called systemic antacids bc the fraction that doesn’t react with stomach acid can escape the GI tract and enter the general circulation

  • at high doses, the pH of the blood can be raised, resulting in systemic alkalosis (reducing the function of sensitive enzymes, transporters, etc) which can lead to tremors, resp depression, coma
  • the Na can also result in Na overload, causing fluid retention, hypertension (increased BP), congestive heart failure, renal failure
98
Q

H2 receptors and stomach acid production

A
  • he stomach lining has parietal cells which are the source of the H+ used to make acid (they pump into into the stomach lumen); when activated by histamine release from enterochromaffin-like cells (ECLs) in the stomach, H2 receptors induce increased acid secretion via increase of cAMP levels (this has a positive effect on the proton K+/H+ ATPase pump driving H+ into the stomach)
  • h2 selective antihistamines such as xantac prevent this (but note that they onl block part of the H+ pump pathway, as muscarinic M3 Ach GI receptors and gastrin (a hormone) can also act on ECLs to boost H+ release)
99
Q

the story behind H2 receptor antsgonists

A
  • the first clinically successful one was cimetidine, which was marketed as tagamet and bore no structural resemblance to the H1 antagonists
  • this led to the development of ranitidine (zantac), which was developed using rational drug design (that is, they looked at the receptor and deliberately made something that would bind nicely there); it had fewer side effects and better pharmacokinetics
100
Q

clinical aspects of H2 antagonists

A
  • major for healing of gastric and duodenal ulcers, treatment of GERD and prevention of stress-related ulcers
  • even without feeding, the drugs suppressed resting lvls of stomach acid (bc it’s constitutively generated)
  • suppressed 24 hr acid secretion by 70%
  • cimetidine in particular can be problematic as it inhibits CYP enzymes, which may be necessary if you’re taking other drugs that need to be metabolized
  • they’re really selective for H2, so few if any other receptor-mediated side effects, which is why they’re available OTC
101
Q

antidiarrheal agents

A
  • ex immdium
  • diarrhea is typically characterized by excess gastrointestinal motility (increased fluid)
  • throughout the gut tissue, there are mu opioid receptors involved in regulating the mvmt of gut muscle and fluid secretion; when exposed to agonists, they inhibit peristalsis and fluid buildup by preventing neurotransmission in the plexi
  • this leads to a different muscular tone (muscle tend to remain in more excited, rigid state, so you stop squeezing food through the intestines)
102
Q

loperamide

A
  • an antidiarrheal opioid, the active ingredient in immodium
  • an opioid receptor antagonist that acts in the GI tract and inhibits enteric nerve activity, propulsive motor activity (muscular squeezing of food through the guts), an ion/fluid secretion (allowing the body to absorb more water)
  • note that ppl who die from cholera die bc of dehydration (too much water is being expelled via diarrhea)
103
Q

can you get high on immodium?

A
  • while loperamide is an agonist at the same receptors to which abused opioids act, it cannot cross the BBB very easily, and is also actively pumped out by the same P-glycoproteins that pump out 2nd gen H1 antihistamines and extensively metabolized by the liver
  • at high doses, can result in fatal cardiotoxicity, but very little evidence that it would ever get you high (you’d need SO much to overwhelm the P-glycoproteins)
104
Q

laxatives

A

4 basic groups:

  • osmotic (ex polyethylene glycol; large, poorly absorbed water molecules; cannot cross bilayers, causing water to flow into the bowels to equillibrate conc; the osmotic pressure and fluid volume alone cause distension, triggering peristalsis to flush everything out)
  • bulk-forming (ex psyllium (metamucil), powdered seeds containing hemicellulose that absorb water and expand to gelatinous masses, increasing bulk softening stool, and stimulating peristalsis)
  • wetting agents (ex mineral oil; lube everything up for easy passage, allow stool to absorb water)
  • stimulants (ex senna; local irritants whose metabolites stim PGE2 synth with induction of COX2 in the gut (which should decrease aquaporins in gut cells, allowing for less water to be removed from the gut and increasing export0
105
Q

blood pressure

A
  • blood in the circulatory system is under pressure in order to distribute it throughout the system; the is generated by beating of the heart and resistance of the circulatory system
  • BP changes during the cardiac cycle; the peak of ventricular contraction is called systolic pressure and the minimum during ventricular relaxation is called diastolic pressure
  • pressure increases with a beat then drops back down; this cycle repeats ~1/sec in adult humans
  • blood pressure is categorized as normal, prehypertension, or stage 1 and 2 divisions of hypertension (as BP increases)
106
Q

blood pressure consequences

A
  • elevated BP is the most common cardiovascular disease
  • hypertension increase the risk a variety of other diseases, including renal failure, coronary disease, heart failure, stroke, dementia
  • incidence of diseases increases with age and severity of hypertension
107
Q

blood pressure risks

A
  • in most cases, increased BP is associated with a higher hazard ratio for cadiovascular outcomes; in virtually every age group, the likelihood of suffering a given cardiovascular outcome also increases with the severity of hypertension
  • the likelihood for any one specific outcome is still pretty low, but the total likelihood of experiencing any cardiovascular event greatly increases with hypertension, and even more so in older people
108
Q

targets for blood pressure regulation

A
  • moment to moment BP is defined as cardiac output (how much blood the heart is pumping) multiplied by peripheral vascular resistance (the higher the resistance, the harder you need to pump and therefore the higher the BP)
  • in the heart, BP decreases as force/frequency of pumping decreases
  • resistance vessels (parts of the body where the vessels are most contstricted and act as a choke point against which the heart is pumping)
  • RAAS (a multi organ system involving the kidneys, adrenal gland, and vasculature, that regulates vasodilation, blood volume, peripheral resistance)
109
Q

fluid regulation in the kidney

A

-the distal renal tubule filters blood, reabsorbs ions and water, and generates urine

110
Q

thiazide diuretics

A

EX. bendroflumethiazide
-inhibit NaCl reabsorption in the distal convoluted tubule by blocking a Na/Cl co-transporter (NCC)
-reabsorption of Na is the main driver of water reabsorption in the kidney, so if you prevent sodium from being taken up, you’ll redice blood volume (more of the water is sent out in the urine)
(note also that these drugs often have a direct vasodilatory effect, which reduced peripheral resistance too, though that’s not their primary mechanism of action)

111
Q

B1 adrenergic receptors and BP

A
  • subset of adrenergic GPCRs activated by extracellular binding of catecholamines (adrenaline, NA)
  • in the heart, B1 receptors are the primary adrenergic receptors, and are responsible for acceleration of heart rate and increased force of pumping during fight/flight response
  • the Gs signaling cascade causes PKA to target voltage gated L-type Ca channels (increasing intracell Ca during a heartbeat), ryanodine receptors (which increase Ca release from intracell stores during a heartbeat) and SERCA pumps (which clean up Ca by taking it up into ER stores during termination of heartbeat)
112
Q

B2 adrenergic receptors and BP

A
  • predominant adrenergic receptors in the longs and some vasculature
  • cause bronchioles to dilate and enhance perfusion of skeletal muscle during flight/flight response
  • in vasc/bronchiolar smooth muscle, key arget of PKA is myosin light chain kinase, a protein that, when phosphorylated by PKA, causes smoorh muscles to relax by dilating bronchioles and vessels
  • the dilated airways allow more O2 to circulate
113
Q

beta blockers

A
  • used to reduce BP; anti-hypertensive primarily because they lead to a decrease in cardiac output (but also reduction of sympathetic activity and inhibition of renin secretion)
  • mostly inotropic effect (influence cardiac contractility)
  • some b blockers (ex carvedilol) have non-specific inhibition of a receptors too, which leads to peripheral vasodilation
114
Q

harms of b-blockers

A

due to role of b2 receptors in bronchial smooth muscle, a side effect of non-specific b blockers in bronchospasm
-for patients prone to asthma or respiratory issues, this can cause contractility that decreases airway capacity and exacerbates the condition

115
Q

alpha adrenergic receptors and BP

A

-a blockers aren’t commonly used for hypertension bc they have lots of other issues and cause orthostatic hypertension
-receptors are most common in the periphery, and stimulation by adrenaline triggers vasoconstriction in tissues where you want lots of blood flow for a fight/flight response
(this works via a Gq cascade, that activates PLC to trigger IPC3 signal to the ER to release Ca; the Ca binds to regulatory calmodulin protein to turn on the myosin light chain kinase, leading to increased contractile force)
-inhibition of these a1 receptors would then cause vasodilation (this drops BP, but blood will pool when you stand up, making you feel faint/dizzy)

116
Q

inhibition of adrenergic receptors (BP)

A
  • two broad categories of antagonists; alpha blockers (which aren’t widely used for treatment of hypertension) and beta blockers
  • a prototypical B1 selective blocker is atenolol
  • a non-selective b blocker is propranolol (targets b1 and b2)
  • there are also some drugs such as carvedilo which target both alpha and beta adrenergic receptors
117
Q

RAAS

A

renin angiotensin aldosterone system
-powerful, multiorgan regulatory system that control blood volume, salt
balance, and BP
-targetted by several classes of drugs, including ARBs (angiotensin receptor blockers) and ACEis (angiotensin converting enzyme inhibitors)
important components:
-renin (enzyme secreted by kidney that processes angiotensinogen, a prohormone, to angiotensin I (ATI)
-ACE (enzyme that converts ATI to ATII)
-ATII (powerful vasoconstrictive peptide that causes vascular smooth muscle control and aldosterone release in the adrenal cortex)
-aldosterone (steroid hormone whose main target tissue in the distal convoluted tubule in the kidney; promotes reabsorption of Na and H2O (preserving blood volume and increasing BP))

118
Q

ATII hormone mechanism

A
  • when ATII binds to GqPCRs in vascular smooth muscle, g alpha and beta dissociate to activate PLC, which breaks off the PIP2 head group, IP3, and leave the acyl backbone DAG in the membrane
  • IP3 signal triggers Ca release from the ER; the Ca binds to calmodulin and this complex activates cycling of myosin light chain kinase to allow smooth muscle tensing and vasoconstriction
  • in the adrenal cortex, those Ca signals trigger release of aldosterone, a highly lipophilic signaling molecule that can diffuse through membranes
119
Q

aldosterone hormone action

A
  • aldosterone is a steroid hormone that promotes reabsorption of Na and H20 in the kidney, preserving blood volume and increasing BP
  • binding to it’s receptor causes dimerization and migration to the DNA, when it upregulates key transcriptional targets (Na/K pump, epithelial Na channel, and Na/Cl symporter) in the nephron and distal convoluted tubule
  • all of the targets contribute to Na reabsorption
    (note: thiazide diuretics directly bind to those targets to impede Na reuptake, while drugs that target RAAS have indirect effect via gene expression)
120
Q

ACE inhibitors

A

PROTOTYPE: captopril

  • inhibits enzymatic cleavage of angiotensin I to angiontensin II, reducing the generation of all downstream RAAS effects relating to ATII and aldosterone signaling
  • common side effect is dry cought, due to bradykinin-mediated bronchoconstriction
121
Q

AT1 blockers or ARBs

A

(angiotensin II receptor blockers)
PROTOTYPE: losartan
-have vasodilatory effect
-inhibit the powerful vasoconstrictive effects of ATII mediated by thr AT1 receptors
-widely used class of drugs, and often better tolerated than ACE inhibitors

122
Q

aldosterone antagonists

A

PROTOTYPE: spirnolactone

  • competitive antagonist of the aldosterone receptor; acts right at the end of the cascade, preventing effects in distal convoluted tubule from aldosterone binding to its receptor and inducing transcriptional upregulation of proteins involved in increased Na reabsorption
  • by reducing reabsorption of Na and water, there’s a diuretic effect (more urine is excreted), decreasing BP and volume
123
Q

lipid transport in the body

A
  • mediated by lipoprotein complexes (HDL-high density, small size; LDL-low density, big size; VLDL-very low density)
  • lipoproteins are packages of lipids (TAGs, cholesterol) surrounded by a phospholipid layer with embedded apolipoproteins
  • must be a good balance of HDL and LDL; too much (V)LDL or too little HDL, are risk factors for serious diseases
124
Q

risk of lipid imbalance

A
  • high levels of total cholesterol, esp LDL-C, are linked to adverse cardiovascular effects via the formation of atherosclerotic plaques
  • these form in the blood vessels and if they rupture or lead to clotting, they occlude vessels in the heart or brain, leading to death
  • the ideal lvls of cholesterol in a healthy individual are low on LDL and high on HDL
125
Q

atherosclerosis

A
  • atherosclerotic plates are fatty deposits that form over time as cholesterol accumulates in the plaque, and can occlude blood vessels
  • macrophages take up cholesterol and differentiate in foam cells that invade the endothelial wall of a blood vessel, forming a deposit that grows and grows
  • when LDL interacts with its ApoE receptor, the foam cells take it up, leading to cholesterol accumulation
  • that cholesterol can then be re-packaged into HDL to re-enter circulation and be carried away from the plaque (lots of LDL in the blood will bias towards uptake, and if HDL is low, macrophages aren’t doing a good job of shipping cholesterol away from the plaque)
  • these plaques usually evolve to be stable and mature and are generally inert as they’re isolated by a fibrous cap of smooth muscle and connective tissue, but thinning/rupture can expose pre-thrombotic factors that lead to clot formation and total vessel occlusion
126
Q

VLDL and LDL formation

A
  • (V)LDL formation is primarily regulated in the liver
  • statins target the intrinsic pathway, which synthesizes cholesterol for packaging (the extrinsic path takes up cholesterol from blood and diet by macrophage LDLR and repackages, or sends to capillary endothelium for breakdown into fatty acids)
  • both intrinsic and extrinsic cholesterol enter a pool and are packaged together with apolipoproteins and TAGs for circulation
127
Q

statin mechanism

A
  • statins target the intrinsic pathway for cholesterol synthesis
  • in the RDS, acetyl CoA, the upstream precursor, is converted to mevalonate by HMG-CoA reductase, a transmembrane protein that resides primarily in the ER membrane
  • statins are competitive inhibitors of this enzyme; this decreases the synthesis of cholesterol
  • steroid receptors in the liver cell sense it isn’t generating much cholesterol so it increases expression of LDL receptors, which will scavenge fro and take up more LDL from the blood, reducing circulating levels (which is what we want!)
128
Q

statins

A

PROTOTYPE: atorvastatin (lipitor)

  • statins are high extraction drugs (nicely absorbed by the liver for first-pass metabolism processing)
  • in this case, this isn’t a bad thing, given that the liver is actually the primary target organ
  • some are administered as prodrugs (like lovastatin) while others are given in their active form
  • usually taken before bed as most cholesterol synthesis takes place during sleep
129
Q

fribrates

A

PROTOTYPE: fenofibrate

  • class of drugs used to treat dyslipidemias
  • thought to target and activate a family of receptors called PPARs (peroxisome proliferator-activated receptors), specifically of type alpha, that are intracellular receptors
  • these act as transcriptional factors (when bound to endogenous ligand, migrate to nucleus and heterodimerize with retinoic acid receptors) and can enhance the expression of lipoprotein lipase, an enzyme embedded on the endothelium that will take up chylomicrons (V/LDL) and convert to fatty acids for fuel
  • also reported to increase LDL uptake and reduce VLDL production in the liver
  • not as effective as statins

PMCOL 200 (9 decks)

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