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Pharmacology > First Pass Miss Exam 1 > Flashcards

First Pass Miss Exam 1 Flashcards

1
Q

What is the mechanism by which a Jak kinase carries signal downstream and give one receptor example?

A

Jak kinases will bind and phosphorylate STAT receptors, which dimerize and regulate transcription of target genes

I.e. growth hormone

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2
Q

What are the molecular mechanisms underlying desensitization and resensitization?

A

Desensitization - phosphorylation of GPCR via GPCR kinases when activated allows binding of Beta-arrestin, which diminishes the receptor’s ability to interact with Gs subunit, terminating the response.

Resensitization - GPCR activation is terminated, disallowing further GPCR kinase activation, and phosphatases will subsequently cause removal of Beta-arrestin

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3
Q

What are the functions of Beta-arrestin?

A
  1. Blocks Gs binding
  2. Accelerated endocytosis of receptors, which allows quicker resensitization via phosphatases. However, endocytosis also means that cells may be degraded by the lysosome more readily.
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4
Q

What is the certain safety factor vs therapeutic index?

A

Therapeutic index = LD50/ED50 (based on animal studies)

Certain safety factor = TD1/ED99

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5
Q

What is tachyphylaxis?

A

When responsiveness diminishes rapidly after administration of a drug -> rapid tolerization

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6
Q

What relays in electrons to CYP in microsomal CYPs?

A

the NADPH-cytochrome P450 oxidoreductase (utilizes a flavin group to do single electron transfers) - also known as P450 reductase

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7
Q

What is the mechanism of action of CYP450s?

A
  1. RH drug binds to CYP with its heme iron in Fe+3 state.
  2. First electron is provided by P450 reductase, reducing the iron to +2.
  3. Molecular oxygen binds, and second electron is donated to oxygen by P450 reductase or cytochrome b5 (giving it a -1 charge).
  4. One oxygen gains the second electron from Fe+2 as well as two protons, forming water (the reduction). The other oxygen is incorporated into the substrate as ROH (oxygen is reduced here as well, but the substrate is oxidized).

Two electrons come from NADPH to form water, two electrons come from the substrate to oxidize molecular oxygen into the organic compound

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8
Q

List two major groups of enzymes that carry out hydrolysis reactions?

A
  1. Carboxylesterases -> as in the hydrolysis of novocaine

2. Epoxide hydrolases -> including microsomal and soluble

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9
Q

How do epoxide hydrolases function and why are they important?

A

Trans-addition of water to epoxides to form alcohols

Important for detoxifying electrophilic epoxides which can bind proteins and nucleic acids and cause toxicity. They will break up epoxides formed by CYP450s so they are expressed in the same cells to detoxify them

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10
Q

What co-factor is required for sulfonation reaction, and what is one substrate which cannot be used?

A

PAPS - 3-PhosphoAdenosine-5’PhosphoSulfate

Sulfate cannot be attached to a carboxylic acid

Usually attaches to alcohols, phenols, and nitrogens via sulfotransferases (SULTS)

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11
Q

What are the two types of reactions which occur for amino acid conjugation?

A
  1. Conjugation of carboxylic acid to glycine, glutamate, or taurine via intermediate activation with CoA
  2. Conjugation of aromatic hydroxylamine via aminoacyl tRNA synthetase. Literally add via carboxylic acid and it looks like a peptide bond of a protein.
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12
Q

What is the debrisoquine polymorphism example?

A

Dr. Robert Smith was developing an anti-hypertensive drug. Took a dose of it, and had orthostatic hypertension for several days. Was found to have a CYP2D6 mutation which made him metabolically deficient in drug processing -> drug product found in his urine even days later.

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13
Q

What two sites for SNPs show the largest association with human variants in disease?

A
  1. Intronic - due to splice site changes

2. Intergenic - due to altered interaction with chromatin, topoisomerases, or DNA replication

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14
Q

What is the acetylation polymorphism and what is the major gene affected?

A

NAT2 is primarily affected

“Fast” acetylation is dominant, individual must have two “slow” alleles to see an affect. Large ethnic variability, with altered response to many chemicals including caffeine and 4-aminobiphenyl (bladder carcinogen) and sulfa drugs (hemolytic anemia)

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15
Q

What is enterohepatic cycling? What drug can inhibit this?

A

Excretion of drugs in the bile, and reabsorption from the intestine into the body

Drug: cholestyramine, a nonspecific adsorbent
Also ezetimibe, lowers LDL cholesterol by reducing enterohepatic cycling

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16
Q

What is the steady state equation?

A

input = output

f(D/T) = (C_ss)(CL) 
concentration/time = (concentration/volume)(volume/time)

Where C_ss = Concentration at steady state

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17
Q

Why is clearance useful?

A

The clearance multipled by the plasma concentration of the drug will predict the rate of elimination (the output)

This is why Css*CL = steady state elimination,

Because CL = Rate of elimination / C (concentration of drug in plasma)

Furthermore, CL = Vd * Ke
CL has units volume / time

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18
Q

If a drug has a very high distribution, will the required dose be high or low?

A

High distribution = high dose (lower effective concentrations at any place, due to large Vd)

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19
Q

What is the formula for a loading dose?

A

Loading dose = Css * Vd

Css = desired plasma concentration at steady state 
Vd = Volume of distribution, a property of the drug
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20
Q

How is Pb poisoning diagnosed?

A

Hematological abnormalities typically:

Blood lead concentration >0.5 mg/mL
Elevated free erythrocyte protoporphyrin test (FEP)

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21
Q

What causes Severe gingivitis, discolored gums, and metallic taste in mouth. (stomatitis)?

A

Mercury poisoning

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22
Q

Why are these compounds elevated in lead poisoning?

A

Lead inhibits several SH-containing enzymes of heme biosynthesis, causing anemia by inhibiting hemoglobin synthesis (microcytic anemia).

Major enzyme blocked: Ferrochelatase -> build up of protoporphyrin 9

Secondary: delta-ALA dehydratase, and co-PPR oxidase

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23
Q

What is trivalent vs pentavalent arsenic?

A

Trivalent - inhibits pyruvate dehydrogenase via lipoamide

pentavalent - uncoupler of oxidative phosphorylation

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24
Q

More water soluble derivatives have been made which have less adverse effects: DMSA (succinate) and DMPS (propane sulfonate)

A

How have the toxicities of dimercaprol been overcome?

these include tachycardia, hypertension, and nausea/vom

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25
Q

More water soluble derivatives have been made which have less adverse effects: DMSA (succinate) and DMPS (propane sulfonate)

A

How have the toxicities of dimercaprol been overcome?

these include tachycardia, hypertension, and nausea/vom

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26
Q

What is the primary side effect of all chelators except maybe dimercaprol?

A

nephrotoxicity

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27
Q

How is HCN poisoning diagnosed?

A
  1. By abruptness of onset of symptoms (within seconds of inhalation)
  2. Almond odor on breath
  3. Ataxia, convulsions, coma, nausea, vomiting

Can be from insecticides, inhalation of fumes from burning nitrogen-containing compounds, or fruit seeds

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28
Q

What does Rhodanese do?

A

Detoxifies CN- in vivo to SCN- (thiocyanate)

It is a thiosulfate sulfurtransferase

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29
Q

What is responsible for methanol toxicity? What do they cause?

A

The biproducts of oxidation are:

Formaldehyde - blindness -> damage retinal cells

Formic acid - Acidosis, cardiotoxic (cardiac depression)

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30
Q

How is ethylene glycol toxic? What is the treatment?

A

Metabolized by alcohol dehydrogenase (like methanol).

Forms:

  1. Oxalate - produces crystals which cause kidney damage
  2. Formic acid - causes acidosis like methanol

Treatment is same as methanol poisoning, with option for hemodialysis

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31
Q

What are some examples of chlorinated hydrocarbon insecticides and what is their mechanism of action of toxicity?

A

DDT, chlordane, lindane

Interfere with the inactivation of sodium channel, thus causing repetitive firing in response to a single stimulus -> CNS stimulation and effects

-> these bioaccumulate in adipose tissue due to their high lipid solubility, unlike organophosphates

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32
Q

What is the mechanism of action of carbamate insecticides and how do they differ from organophosphorous compounds?

A

They inhibit acetylcholinesterase via carbamoylation of esteric site of enzyme. However, this is more reversible than organophosphorous (which phosphorylate the active site irreversibly)

Carbamates thus have a shorter duration of action and are less toxic.

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33
Q

What is the major drug interaction of concern with tobacco use?

A

Induces some drug-metabolizing enzymes, thus decreasing the effectiveness of some drugs like TCA, acetaminophen, benzodiazepines, cimetidine, oral contraceptives, estrogens, insulin, propanolol, and theophylline

  • > caffeine tends to block
  • > alcohol tends to induce
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34
Q

How does fluoroacetate toxicity work?

A

Lethal synthesis - similar structure to acetate and is made into fluoracetyl-CoA in the mitochondria, then forms fluorocitrate which will block aconitase -> citrate accumulates and mitochondrial energy is destroyed

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35
Q

What are the biogenic amines and their functional groups?

A
  1. Dopamine
  2. Norepinephrine
  3. Epinephrine
    (all three made from tyrosine, have catechol group)
  4. histamine - imidazole - from histidine
  5. serotonin - indole - from tryptophan
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36
Q

What produces the slow EPSP via acetylcholine and what is the mechanism?

A

Muscarinic Ach receptor activation -> stimulates PLC to hydrolyze PIP2 to IP3 and DAG

Decrease in PIP2 causes the closure of M-type delayed rectifier K+ channel -> depolarizes the neuron

IPSP is due to G-protein-gated K+ channel activation in heart via M2 receptor

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37
Q

How does the acetylcholinesterase enzyme work? How does this relate to ACh inhibitors?

A

Enzyme is negatively charged to attract ACh, then uses a serine to do an Acyl transfer reaction. The intermediate is an acetyl group covalently attached to serine. The structure is ultimately resolved via hydrolysis (this step is blocked via acetylcholinesterase inhibitors which remain covalently bound)

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38
Q

What are the presynaptic receptors of skeletal muscle?

A

Nicotinic -> increasing tetanus

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39
Q

What are the reversible anticholinesterases which act by slow removal from the enzyme?

A

Physostigmine (tertiary), neostigmine (quaternary), rivastigmine (tertiary), pyridostigmine (quaternary)

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40
Q

What are the reversible competitive inhibitor anticholinesterases?

A

Edrophonium, tacrine, donepezil, galantamine

41
Q

What are the irreversible anticholinesterases (require enzymatic turnover)?

A

Echothiophate
Sarin - nerve gas
Malathion, parathion - organophosphate insecticides

42
Q

What is the MoA of Pilocarpine, amine type, and what is it used for?

A

Tertiary amine which is a muscarinic AGONIST

Used for causing miosis of the eye -> allows easier drainage of Canal of Schlemm to reduce IOP

1st line: emergency therapy of acute glaucoma
2nd line: chronic glaucoma (beta blocker better)

Also: used to treat dry mouth in cancer patients or those with Sjogren’s syndrome (increases salivation and sweating) -> along with civemiline

Think of Pile of Carpine

43
Q

How do low vs high levels of muscarinic agonists affect the heart rate and why?

A

Low levels - reflex tachycardia due to drop in blood pressure from stimulation of M3 receptors on vascular system

High levels - directly stimulate cardiac post-synaptic M2 receptors to cause a cardiac depression

44
Q

When is propantheline used? Is it tertiary or quaternary?

A

Quaternary amine. Muscarinic antagonist, kind of the opposite of bethanechol -> Spasmolytic agent

Used in treating spasms (hypermotility) of GI tract, biliary tract, and urinary bladder

45
Q

What is the structure of tolterodine, and what is it used for?

A

Tertiary amine metabolized by CYP2D6. It’s basically the same as oxybutynin (CYP3A4).

Muscarinic antagonist, used for the treatment of urinary urgency.

Think of the turtle receiving the drink from the ox butler

46
Q

What are the reversible anti-muscarinic compounds (competitive antagonists)?

A

Atropine, tropicamide, ipratropium, tiotropium, scopolamine, tolterodine (urinary urgency), oxybutynin, benztropine, propantheline (GI hypermotility)

47
Q

How can acetylcholine be used diagnostically?

A

Can be injected into coronary arteries in patients with vasospastic angina pectoris -> will cause spasm only in diseased vessels

48
Q

What two agents are used to treat COPD, and how do the differ? Are they tertiary or quaternary?

A

Quaternary amines which are inhaled, they are muscarinic antagonists

Ipratropium and tiotropium

Tiotropium has a longer half-life, and less M2-antagonist activity (good because it allows ACh to bind presynaptic receptor, limiting release)

49
Q

What are the clinic uses of atropine? When is it contraindicated?

A
  1. Treatment of organophosphate poisoning
  2. Long-term dilation of eye
  3. Infant colic -> causes constipation
  4. Relief of AV block (like isoproterenol)

Contraindicated in patients with glaucoma due to increased ICP

50
Q

What is cisatracurium and why is it much more attractive of an option than d-TC?

A

Competitive nAChR antagonist, but only has mild hypotensive actions (less histamine release and ganglion blockade).

Much more attractive: spontaneously broken down with short half-life and thus safely used in patients with hepatic and renal failure

Does however have a breakdown product which causes seizures (CNS active)

51
Q

Why should succinylcholine not be used in children and what is its main side effect?

A

May have an undiagnosed muscular dystrophy which upregulates nACh receptors, which can lead to an oversized response

  • > main side effect is increase in blood potassium due to significant depolarization
  • > also avoid in patients with extensive burns, trauma, people with K+ sparing diuretics or digitalis, or people with renal failure due to cardiac arrest risk
52
Q

What is pancuronium used for? In what way is it cross-reactive?

A

It is a nAChR competitive antagonist, with some M2 cross-reactivity (causes tachycardia)

Used in lethal injection, eliminated in the kidney (like d-TC)

53
Q

Give three muscle relaxants based on their mechanism of action: 1. inhibit Ca+2 release via SR. 2. GABA-B agonist. 3. Alpha-2 agonist, centrally.

A
  1. Dantrolene
  2. Baclofen
  3. Tizanidine (think of Sketchy “to christine” letter in reclining chair)
54
Q

What is the MoA of Riluzole and what is it used for?

A

Inhibits glutamate signaling -> limited antispasmodic activity (baclofen better), but it does:

Prolong life in ALS patients

55
Q

What is the name of the spasmolytic most frequently given as an anti-spasmodic by everyone? Mechanism of action unknown, but is definitely anti-muscarinic and sedative

A

Cyclobenzaprine

56
Q

What is the primary indication for Dantrolene?

A

UMN spastic paralysis, maligant hyperthermia (muscle spasms in anesthesia)

57
Q

What is the mechanism of action of Mecamylamine? Is it a tertiary or quaternary amine?

A

Works via competitive antagonism of nAChR’s in postganglionic cell dendrites

It is actually a SECONDARY amine -> only one

  • > causes orthostatic hypotension
  • > only used to keep blood pressure down in neurosurgery
58
Q

What causes the EPSP and IPSP for muscarinic receptors?

A

EPSP - M1 receptors

IPSP - M2 receptors

59
Q

How is physostigmine metabolized and what is it used for? Is it tertiary or quaternary?

A

Tertiary amine - metabolized by ester hydrolysis in plasma

  1. Miotic treatment of glaucoma
  2. Treatment of atropine poisoning - Reversal of toxic CNS and peripheral effects of muscarinic antagonists (but can cause seizures itself)
60
Q

What is the first drug shown to slow rate of deterioration of Alzheimer’s, and what is its mechanism of action?

A

Memantine - competitive antagonist of glutamate receptors

Same as riluzole for ALS, muscle relaxant

61
Q

What is Malathion used for? Why?

A

M is for Mosquito -> Mosquito control and killing head lice (slowly detoxified in humans, vs Parathion which is not)

62
Q

Why is edrophonium selective for the NMJ?

A

It is also a direct agonist of nAChR (like neostigmine), so will not produce too high acetylcholine levels at other receptors at the doses used therapeutically

63
Q

What are the three most common causes organophosphate death?

A
  1. Hypotension - due bradycardia and drop in peripheral resistance (elevated levels of ACh, even though you will have more sympathetic action due to ganglionic effects)
  2. Difficulty breathing due to bronchial constriction and increased secretions in pulmonary tree + paralysis of respiratory muscles from phase 1 blockade
  3. CNS depression due to Phase 1 blockade causes abolishment of respiration and coma
64
Q

What are the two systems involved in baroreceptor blood pressure response?

A
  1. Vasomotor sensor - from baroreceptors present in aortic arch and carotid sinus (SANS control of BP)
  2. Renal sensors in JG cells - via renin system
    (RAA control of BP)
65
Q

How do the three subclasses of agonists differ with respect to their effect given prior treatment of reserpine?

A

Direct acting - unaffected or increased by prior treatment (upregulation of receptors for agonist to bind)
Indirect acting - completely blocked due to loss of NT packaging in vesicles which leads to their breakdown via MAO
Mixed acting - Reduction in activity (due to two components)

66
Q

Where are MAO and COMT present? Why is this relevant?

A

COMT - postsynaptic cleft

MAO - intraneuronally, and high concentration in liver

Both MAO and COMT are present on the gut wall -> relevant because catecholamines are rapidly inactivated when taken orally = poor oral bioavailability. Must be given parenterally or topically

67
Q

What will the effect of norepinephrine be on the heart?

A

Due to increased BP, there will be a reflex bradycardia mediated by baroreceptors and vagal activity -> can cause tachycardia if atropine is pre-administered

->Beta1 positive inotropic effect will still remain, however

68
Q

What are the uses of dopamine vs norepinephrine?

What is dobutamine and when is it typically used?

A

Dopamine - cardiogenic / septic shock, increases blood pressure but keeps blood flowing to kidneys
Also hypotension in congestive heart failure

Norepinephrine - hypovolemic shock - increases blood pressure (similar to phenylephrine, which is alpha-1 only, still cause reflex bradycardia)

Dobutamine - Do is not for dopamine. you’re thinking of Fenoldopam. Synthetic catecholamine - selective beta1 agonist

Typically used in acute heart failure to increase cardiac output -> does not significantly elevate oxygen demands either! (think of do a bugling shirt person cranking up the heart)

69
Q

When is epinephrine contraindicated?

A

When beta-blockers are used, can cause hypertensive crisis

May also cause cerebral hemorrhage or cardiac arrhythmias

70
Q

What is the mechanism of action of fenoldopam and what is its indication?

A

Binds peripheral D1 receptors, used in severe hypertension to keep blood flow to coronary arteries, kidneys, and mesenteric arteries

71
Q

What are the inhaled nasal decongestant agonists?

A

Oxymetazoline - non-selective alpha (also used to decrease eye redness)
Phenylephrine - alpha1 only

Pseudoephedrine /ephedrine is mixed action agonist which is used as a nasal decongestant

72
Q

What two drugs interact with MAOI to cause hypertensive crisis?

A
  1. Amphetamine

2. Tyramine

73
Q

Give three clinical uses of phentolamine?

A
  1. Short-term management of pheochromocytoma
  2. Prevention of dermal necrosis at norepinephrine injection site
  3. Treatment of hypertensive crisis from clonidine withdrawal or tyramine-foods + MAOI+ cocaine
74
Q

give the selective agonists for alpha1 alpha2 beta1 beta2?

A

alpha1 - phenylephrine
alpha2 - clonidine
beta1 - dobutamine
beta2 - SABAS and LABAs

75
Q

Give the selective antagonists alpha1 alpha2 beta1

A

alpha1 - prazosin, tamsulosin (alpha-1-a blocker, allowing bladder relaxation in BPH), doxazosin, terazosin (okay for hypertension because they do not block alpha2 and thus cause less reflex tachycardia)

alpha-2 - yohimibe

beta1 - ABEAM - adenolol bismolol esmolol acebutolol, metoprolol

76
Q

Why does propanolol initially cause peripheral vasoconstriction?

A
  1. Blocks the beta-2 mediated vasodilation in skeletal muscles
  2. Reduction in cardiac output leads to decreased blood pressure and subsequent peripheral vasoconstriction

This goes away with long-term use and TPR will drop, causing a general drop in BP

77
Q

What happens to the lipid profiles of patients on propanolol and why?

A

Beta-3 receptors are also blocked, so patient’s lipids get messed up. LDL goes up, HDL goes down, and triglycerides go up

-> much less pronounced effect with selective B1-antagonists like metoprolol

78
Q

What drugs interfere with beta blockers like propanolol’s metabolism?

A

SSRI’s and cimetidine

79
Q

Why is metoprolol preferable to propanolol in long-term hypertension management?

A

Does not interfere with pulmonary function (usable in asthma and COPD), peripheral resistance, and carbohydrate metabolism (all beta-2 mediated)

80
Q

First-line treatment for chronic heart failure?

A

Metoprolol, bisprolol, carvediol (some alpha-1 activity and anti-remodelling activity)

81
Q

When are pindolol and acebutolol used?

A

Patients with hypertension and underlying bradycardia

->decreased metabolic effects and reduction in cardiac output, acebutolol is most selective (B1 blocker only)

82
Q

What are labetalol / carvediol and when are they used?

A

nonselective beta-antagonists with alpha1 blocking effect -> not associated with reflex peripheral vasoconstriction like propanolol
Labetalol - pregnancy-induced hypertension
Carvediol - heart failure

83
Q

What is nadolol?

A

A long-term nonselective beta blocker

84
Q

How do many therapeutic compounds stimulate histamine release?

A

Cause the dissociation of histamine from heparin-bound complex inside the granules (includes tubocurarine and radiocontrast dies)

Compound 48/80 and polymyxin B are ionophores which stimulate the release via Calcium influx

Cromolyn sodium inhibits calcium influx to stop release

85
Q

Where are H2 receptors found? What’s their mechanism?

A

Gastric mucosa (parietal cells), cardiac muscle cells, “mast cells”

Gs -> increase cAMP

Remember H1 causes vasodilation and is Gq

86
Q

What is the side effect of concern with PPIs?

A

stops anti-platelet drug effectiveness and causes increased cardiovascular risk

87
Q

What are the drug targets of tacrolimus and cyclosporin A?

A

Tacrolimus - FK-binding proteins

Cyclosporin A - cyclophilins

88
Q

What are the calcineurin inhibitors and how do they work in general?

A
  1. Tacrolimus
  2. Cyclosporin A

They work by having their protein - drug complex bind and inhibit calcineurin, a phosphatase which is required to activate NF-AT. NF-AT is responsible for increasing translation of IL-2 and other cytokines for T-cell proliferation.

89
Q

What is the non-calcineurin-inhibiting immunophilin and how does it work?

A

Sirolimus (rapamycin) - binds FKBP12 (similar to tacrolimus) but rather inhibits mTOR (mammalian target of rapamycin), a protein responsible for downstream signalling of IL-2. This will keep the cell arrested at G1 phase.

90
Q

What does leflunomide do? Mycophenolate?

A

Leflunomide - inhibits de novo pyrimidine synthesis via inhibition of dihydroorotate dehydrogenase

Mycophenolate - inhibits de novo purine synthesis via inhibition of inosine monophosphate dehydrogenase

91
Q

Why can we not used cyclophosphamide with tricyclic antidepressants?

A

TCA’s will decrease bladder emptying, leading to prolonged bladder exposure to “acrolein”, the toxic metabolite of cyclophosphamide

92
Q

What drug should cyclophosphamide never be used with?

A

Succinylcholine because it reduces pseudocholinesterase activity

93
Q

Why is hydroxychloroquine useful in rheumatoid arthritis and what particular patient populations should use it?

A

Useful in pregnant patients since methotrexate, leflunomide and cyclophosphamide are all teratogens

DO NOT USE in G-6-P DH Deficiency

It is a basic drug that accumulates in lysosomes of immune cells and phagocytes (like amoeba and protozoans) and inhibits chemotaxis, phagocytosis, and superoxide production of PMNs.

94
Q

How does abatacept work? When is it used?

A

Binds CD80 / CD86 on APCs to prevent T-cell activation via CD28

Used when anti-TNF agents are not working

95
Q

How does Rituximab work? When is it used?

A

Binds to B-cell receptor CD20 and causes apoptosis. This is expressed from the pre-B cell stage

Used when anti-TNF agents are not working

96
Q

Why is Ciclesonide juicy?

A

It is activated by two enzymes that are only expressed in upper and lower airway epithelium limiting adverse effects

-> it is the last corticosteroid other than budesonide and fluticasone for the treatment of asthma

97
Q

What are the long-acting Beta-2 agonists of consequence?

A

Formoterol
Salmeterol
Olodaterol

98
Q

Why is Ciclesonide juicy?

A

It is activated by two enzymes that are only expressed in upper and lower airway epithelium limiting adverse effects

-> it is the last corticosteroid other than budesonide and fluticasone for the treatment of asthma

99
Q

What are the long-acting Beta-2 agonists of consequence?

A

Formoterol
Salmeterol
Olodaterol

Pharmacology (54 decks)

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