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Block 1 - Fundamental Principles > Pharmacology > Flashcards

Pharmacology Flashcards

0
Q

What are three important aspects of drug absorption?

A
  1. Lag time
  2. Extent of absorption (bioavailability)
  3. Rate of absorption
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1
Q

What are the four main pharmacokinetic principles and what does each determine?

A
  1. Volume of distribution - loading dose
  2. Clearance - maintenance dose
  3. Half-life - time to (and from) steady state
  4. Bioavailability - determines correct non-IV dose
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2
Q

Why is there a linear relationship in first order drug elimination?

A

Because most drugs are designed to work at low concentrations and enzymes that eliminate poisons are fairly non-specific and thus have a high km.

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3
Q

What determines and is described by ke on a log plot?

A

The slope of the decay line.

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4
Q

What two phases of serum concentration decay are seen with IV administration?

A

Rapid phase = distribution phase (into tissues)

Slower phase = elimination

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5
Q

What’s the definition of bioavailability?

A

The fractional amount of a given dose of drug that gets into the blood. Represented by F.

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6
Q

What does F of a drug depend on if it is administered orally?

A

The amount absorbed and the amount metabolized by first-pass metabolism through the liver.

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7
Q

What could alter a drug’s bioavailability?

A
  • Liver function (for those undergoing first pass)
  • Changes in gastric acidification
  • If food is competing for transport, binding the drug, inhibiting an enzyme, etc.
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8
Q

What is Vd?

A

A ratio of how much drug led to what concentration. Empirical parameter that may or may not describe the body space into which the drug can diffuse. Directly represents only the concentration in blood.

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9
Q

What can affect Vd?

A

Disease states

Amount of body fat that can act as a sink

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10
Q

What is the definition of clearance?

A

The conceptual amount of blood or other fluid from which all drug is removed per unit time.

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11
Q

What is the half life of a drug a function of?

A

Both clearance and volume of distribution.

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12
Q

What are the four things drug behavior is dependent on and which can you choose?

A
  1. Formulation - you can choose
  2. Route - you can choose
  3. Patient
  4. Drug
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13
Q

Where will weak acids be absorbed best?

A

In the intestine.
They are uncharged in acidic environments and thus absorbed well in the stomach but the time spent and surface area of the intestines makes up for this.

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14
Q

What is the first pass effect?

A

Drugs absorbed in the GI tract enter portal system and are delivered to liver before entering systemic circulation.

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15
Q

What two things is lag time for absorption dependent on?

A

Product formulation and gastric emptying

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16
Q

What two things does the mAgnitude of the first pass effect depend on?

A

Liver blood flow and capacity of liver to metabolize drug

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17
Q

What are the 3 main types of drug metabolism?

A
  1. Cytochrome p450s - predominant phase 1 enzymes, mostly oxidative, anything that is a substrate is also an inhibitor, wide range of substrates, inducible
  2. Glucoronide synthesis - er system, wide range of substrates, inducible, products more hydrophilic
  3. Non microsomal enzymes - usually not induced but can be competitively inhibited
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18
Q

Why does the rate of drug loss increase almost linearly with drug concentration?

A

Because most enzymes of drug metabolism have very high metabolism and are not near saturation at therapeutic concentrations.

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19
Q

What are the three main enzymes that can get rid of a poison?

A

Oxidases
Hydrolases
Conjugating enzymes

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20
Q

What is the main difference in elimination of drugs obeying zero order kinetics?

A

The eliminations pathways get saturated so clearance decreases and half life increases with increasing drug concentration.

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21
Q

Why ate some drugs designed to be absorbed through the oral mucosa?

A

To avoid the first pass effect.

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22
Q

What does a significant lag time usually reflect?

A

Uptake of the drug at the initial site of application.

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23
Q

What is the protein binder for weak hydrophobic acids and for weak bases?

A

Albumin and alpha glycoprotein

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24
Q

What are the three ways you should think about distribution of a drug in the body?

A

From the blood
To tissue sites of action
From tissue depots (fat, etc.)

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25
Q

What are four determinants of a drug’s capacity to be filtered by the glomeruli?

A

Protein binding
Molecular size and charge
Glomerular integrity (damage can allow protein bound molecules to be filtered
Number of nephrons

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26
Q

Where can weak acids and bases be passively reabsorbed in the kidney?

A

The collecting duct

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27
Q

What are the two major determinants of passive transport in the kidney?

A

Urinary ph and flow rate

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28
Q

When should you draw blood to get an accurate serum concentration when a drug has a long distribution phase?

A

Just prior to the next dose

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29
Q

Which receptors are located in the nucleus or translocated there after binding?

A

Receptors for lipid soluble, membrane permeable molecules

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30
Q

What does the occupancy model of drug receptor interactions state?

A

Magnitude of effect is proportional to concentration of drug receptor complex (ex. 50% of receptors filled yields 50% max effect)

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31
Q

What are the two ways to define Kd?

A
  1. Ratio of reverse and forward rate constants

2. Concentration of free drug at which 50% of receptors are bound

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32
Q

What limits K1?

A

The rates of diffusion of the molecules involved

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33
Q

What is the difference between potency and efficacy?

A

Potency is concentration of drug necessary to produce a given effect - related to affinity of drug for receptor. Efficacy is magnitude of effect that can be produced by a drug - reflected in plateau of dose response curve. Efficacy is more useful because you can overcome potency by giving more drug.

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34
Q

How might you get rid of a non competitive antagonist?

A

Dilute it

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35
Q

What do full agonists, partial agonists, and inverse agonists do to the active inactive equilibrium of receptors?

A

Full - shifts fully to active
Partial - shifts partially to active (can still be more or less potent than full)
Inverse - greater affinity for inactive

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36
Q

How many different alpha beta and gamma gpcr subunits are there?

A

Roughly 20, 5, 12

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37
Q

Why does GTP replace GDP so readily when the G protein encounters and activated receptor?

A

Because it is abundant in the cytoplasm

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38
Q

What is the rate limiting step in signal transduction through GPCRs?

A

Dissociation of GDP from alpha subunit

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39
Q

What are three actions of protein kinase A?

A

Activates phosphorylase kinase
Inhibits glycogen synthase
Activates triglyceride lipase

METABOLIC EFFECTS

40
Q

What is protein kinase A’s effect on the heart?

A

Phosphorylates voltage sensitive calcium channels causing influx - positive inotropic effect (lengthens action potentials) and positive chronotropic effect (increases heart rate)

41
Q

What are three non metabolic effects of the PKA pathway? Which G protein does it use?

A

Relaxation of smooth muscle (targets myosin light chain kinase)
Stimulation of secretion
Steroidogenesis

Gs

42
Q

What are four effects of inhibiting adenylyl cyclase? Which G protein does this pathway use?

A

Opens potassium channels and closes calcium channels
Inhibition of secretion
Hyper polarization
Negative inotropy and chronotropy

Gi/o

43
Q

What three things does the DAG system do? Which G protein does it use?

A

Calcium causes tension in smooth muscle
Smooth muscle contraction
Secretion

Gq

44
Q

What does cholera toxin do to G proteins?

A

Modifies alpha subunit so it cannot inactivate itself

45
Q

What does pertussis toxin do to G proteins?

A

Prevents if from being activated

46
Q

What are the basics of ligand regulated ion channels?

A

Channel activation results in change of membrane potential or ionic composition
Include nicotinic cholinergic receptor and channels regulated by GABA, glutamate, aspartate and glycine
Built for speed

47
Q

What are the basics of receptor protein kinases?

A

Used for growth factors
Mostly tyrosine kinases
Slow

48
Q

What are the basics of receptor guanylyl cyclases?

A

Extra cellular peptide binding domain and intracellular guanylyl cyclase domain
Receptors for NO

49
Q

What are the basics of cytotoxic transcription factor receptors?

A

Ligand binding, DNA binding, and regulatory domains

Large number of orphan receptors

50
Q

What is desensitization of receptors and how does it happen?

A
  • follows continued stimulation
  • homologous affects only responses elicited by stimulated receptor
  • heterozygous affects responses of other receptors with same mechanisms of action
  • receptor phosphorylation, relocalization, or alteration in rates of synthesis or degradation
51
Q

What do GRKs do?

A

Phosphorylate and inactivate active conformation of gpcr causing homologous desensitization

52
Q

What is beta arrestin?

A

Phosphorylated gpcr has greater affinity for it, blocks interaction with G protein and promotes receptor endocytosis to cause desensitization

53
Q

When does super-sensitivity of a receptor occur?

A

Following chronic reduction in level of receptor stimulation

54
Q

What are ED50, LD50, and the therapeutic index?

A

Dose necessary to either cause effect or death in 50% of tested
Index is ratio of LD to ED, higher number indicates safer drug

55
Q

What are the three types of adverse reactions to drugs?

A

Toxic effects
Allergic effects
Idiosyncratic effects (toxic effects that occur infrequently and are sometimes due to genetic differences)

56
Q

What is the rate limiting step in prostaglandin and leukotriene production?

A

Production of arachidonic acid by phospholipase A2

Products synthesized upon demand and not stored and released

57
Q

What structural components does biological activity of PGs require and what determines which type it is?

A

C1 carboxyl group
C13 double bond
C15 hydroxyl group
Cyclopentane ring (substituents on it determine type)

58
Q

What enzyme catalyzes the first two steps in conversion of arachidonic acid to pg or thromboxane? Is it a drug target?

A

Cyclooxygenase

Yes - inhibited by NSAIDs

59
Q

What is the difference between cox1 and cox2?

A

Cox1 - expressed in most cells of body constitutively, protects stomach from gastric acid and mediates production of TXA2 in platelets
Cox2 - protects renal and cardiac blood flow, induced in monocytes and fibroblasts during inflammation - shunts arachidonic acid down cyclooxygenase pathway, induction blocked by corticosteroids

60
Q

What promotes the synthesis of leukotrienes?

A

White cell stimulation

61
Q

What is a difference between cyclooxygenase and 5-lipoxygenase?

A

5 not stored in tissues but is found in neutrophils, eosinophils, monocytes, macrophages, and mast cells

62
Q

What are the four different things produced by the cyclooxygenase pathway and what enzyme during synthesis leads to each?

A

PGE2 - isomerase
PGF2alpha - reductase
PGI2 - prostacyclin synthase
TXA2 - thromboxane synthase

63
Q

What are the effect of PGs on blood pressure? What do they do to the heart?

A

PGE2 and PGI2 vasodilate coronary arteries and decrease BP, also maintain patency of ductus arteriosis before birth, TXA2 does the opposite

64
Q

What do PGs do to platelets?

A

TXA2 promotes aggregation

PGI2 inhibit aggregation

65
Q

What do PGs do to the kidneys?

A

PGI2 and PGE2 cause local vasodilation, natriuresis, diuresis, and release of renin (to support blood pressure long term)

66
Q

Which PGs dilate bronchioles and which constrict them?

A

PGE2 and PGI2 dilate

PGF2alpha and TXA2 constrict

67
Q

What are PGs effects on the GI system?

A

PGI2 and PGE2 inhibit gastric acid and pepsin secretion from parietal cells
PGE2 and PGF2alpha increase GI motility

68
Q

What do PGs do to the reproductive system?

A

All cause contractions in pregnant uterus

PGE2 relaxes non pregnant uterus, PGF2alpha contracts it and causes lysis of corpus luteum

69
Q

How is each pg degraded?

A

TXA2 - degraded in lung
PGI2 - evades metabolism in the lung
PGE2 and PGF2 metabolized in lung

70
Q

Which two PGs are physiological antagonists?

A

PGI2 and TXA2
Aspirin affects anti aggregation effects of PGI2 from endothelial cells less than pro aggregation effects of TXA2 from from platelets –> anti aggregation

71
Q

What is a dietary effect on arachidonic acid metabolism?

A

Omega 3 fatty acids reduce TXA2 potency and thus aggregation

72
Q

What are three prospects for drugs in pg system?

A

PGI2 analogs as renal vasodilators
TXA2 antagonists for anti thrombotic effect
TXA2 receptor antagonists and PGE analogs for treatment of asthma

73
Q

What are the mechanisms of action of NSAIDs?

A

Inhibit cox enzymes

74
Q

What are the therapeutic uses of NSAIDs?

A

Analgesic - reduce mild to moderate pain peripherally, especially if inflammation is involved
Antipyretic - PGE2 results in increased body temp set point
Anti-inflammatory - higher doses required
Anti platelet - cox1 inhibition blocks TXA2

75
Q

What is the difference between fever and hyperthermia?

A

Fever - produced by pyrogen infectious process, IL1 IL6 and TNF involved, regulated rise in temp - set point is just increased
Hyperthermia - no pyrogen, not regulated by PGs, antipyretic has no effect

76
Q

What are the pharmacokinetic aspects of NSAIDs?

A

Highly bound to plasma proteins

Most metabolized by hepatic transformation and urinary excretion

77
Q

What is the toxicity of NSAIDs?

A

Acute - usually overdose
Chronic - ulcer, GI bleeding, renal failure, possible risk of thrombosis with cox2 selective agents, headache, tinnitus, rash
Late pregnancy - premature closing of ductus arteriosus

78
Q

What is an example of a salicylate and what is its mechanism of action?

A

Aspirin(ASA) - irreversibly acetylates cyclooxygenase - most other NSAIDs are competitive antagonists

79
Q

What are the therapeutic uses of salicylates?

A

Analgesia
Antipyretic
Anti-inflammatory - same doses as for other purposes
Anti platelet - low doses effective
Cancer prophylaxis - colon cancer
Reduced risk of Alzheimer’s in patients taking for over 5 years

80
Q

What are the kinetics of salicylates?

A

Non linear, zero order

Several days to a week may be required to reach steady state

81
Q

What are the toxic or adverse effects of aspirin?

A

Overdose rarely fatal
Acute and chronic intoxication (more likely in children)
Risk of GI bleeding - avoid use in patients with ulcers
Inhibit platelet aggregation and prolong bleeding - avoid use in patients taking anticoagulants or with clotting disorders

82
Q

What are the signs and symptoms of acute ASA intoxication?

A 
Vomiting
Hyperventilation 
Tinnitus
Confusion
CNS effects
Dehydration 
Respiratory alkalosis is protective
83
Q

What are the signs and symptoms of chronic ASA intoxication?

A

Mild hyperthermia - don’t mistake for fever!

Same as with acute but more serious CNS effects (altered mental status and convulsions)

84
Q

What is the management of acute ASA intoxication?

A
  1. Aggressive fluid therapy with isotonic sodium bicarbonate - want to get urine ph up to 7.5 so it’s higher than plasma - this will trap ASA in the urine to increase renal clearance
  2. Gastric lavage
  3. Hemodialysis (but only 10% is unbound)
  4. Lower body temp with water
  5. Respirator to avoid acidosis
85
Q

What is Reye’s syndrome?

A

Viral illnesses with fever treated with aspirin occasionally produced fatal hepatic necrosis - use acetaminophen in children

86
Q

What can aspirin intolerance cause?

A

Cross sensitivity to most other NSAIDs

Hypersensitivity to aspirin is contraindication of use of any NSAIDs!

87
Q

How are the uses of acetaminophen different than salicylates?

A

Not useful as anti inflammatory or anti platelet

88
Q

What is the toxicity of acetaminophen?

A

Liver damage from acute intoxication (especially in alcoholics)
-managed by symptomatic and acetylcysteine - can substitute for glutathione in the liver
Analgesic neuropathy - worse when NSAIDs in combination

89
Q

What can act synergistically when used with NSAIDs?

A

Opioids

90
Q

What is the difference between NSAIDs and DMARDs in treatment of RA?

A

NSAIDs can provide symptomatic relief but don’t actually slow the cartilage or bone destruction
DMARDs have no analgesic or antipyretic activity

91
Q

What is the current standard of care for moderate to severe RA?

A

Methotrexate with or without prednisone
Then one of the TNF or cofactor targeters)
Methotrexate failures can get leflunomide

92
Q

What is the major category of drugs used to treat migraines?

A

Triptans - serotonin 5-HT 1B/1D agonists - cause vasoconstriction of cerebral vessels

93
Q

What classes are used to treat acute migraines as opposed to prophylaxis?

A

Analgesics
Antiemetics (ondansetron)
Triptans

94
Q

What four classes of drugs are used for prophylaxis of migraines?

A

Beta blockers
Antidepressants (amitriptyline)
Calcium channel blockers (verapamil)
Anti seizure drugs (topiramate) or vasoconstrictors (methysergide)

95
Q

What are the four classes of drugs used for immunosuppression?

A

Glucocorticoids
Calcineurin inhibitors
Antiproliferative/antimetabolic drugs
Biological immunosuppressants

96
Q

What does the glucocorticoid receptor do after it is bound?

A

Migrates into nucleus to activate ant inflammatory genes including IkappaB that inhibits NFkappaB
Binds to AP1 to inhibit transcription of pro inflammatory genes

97
Q

What is the “typical” protocol for immunosuppression in transplantation?

A

Induction - deplete T cells with anti il2 receptor antibodies
Maintenance - calcineurin inhibitor + glucocorticoid + anti proliferative drug (usually mycophenolate)

Block 1 - Fundamental Principles (6 decks)

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