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pharmacology > PHAR 300 final > Flashcards

PHAR 300 final Flashcards

1
Q

Pharmacology

A

The study of all compounds that interact with the body and includes knowledge of the interactions between these compounds and body constituents at any level of organization.

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2
Q

What is a drug?

A

Any chemical substance that affects a living system.

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3
Q

Risk-benefit evaluation

A

There is no such thing as a drug with no side effect, therefore if the benefit outweighs the risk, it can be used.

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4
Q

Pharmacogenomics

A

Understanding genetic differences among people and how these genetic differences influence one’s response to a drug.
→ an understanding of pharmacology + genetic differences in a population allows healthcare professionals to develop effective and safe drugs that can be tailored to one’s personal genetic makeup.

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5
Q

Proteomics

A

The study of proteomes

→ proteome: entire complement of proteins that is or can be expressed by a cell, tissue, or organism

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6
Q

Current sources of drugs

A
  1. Plants
  2. Synthetic production
  3. Biological methods
  4. Mono-clonal antibodies
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7
Q

Drug names

A
  1. Chemical name (N-(4-Hydroxyphenyl)acetamide)
  2. Generic name (Acetaminophen)
  3. Trade name (Tylenol)
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8
Q

Pharmacodynamics

A

What the DRUG does to the body
→ looking at drug receptors & immune system
→ looking at biological effects of the drug

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9
Q

Pharmacokinetics

A

What the BODY does to the drug

→ ADME

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10
Q

Therapeutics

A

Using drugs to prevent diseases

→ indications vs. contraindications

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11
Q

Methods of administration

A
  1. Oral (enteral)
  2. Injection (parenteral)
  3. Inhalation
  4. Topical (skin/mucosa)
  5. Sublingual
  6. Rectal
  7. Other
    → enclosed in liposome, implants, transdermal
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12
Q

Modified-release tablet

A
  • For oral administration *

Used to adjust the time it takes to be absorbed for drugs that are quickly absorbed by the body and that have a shorter lifespan

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13
Q

First-pass effect

A
  • AKA liver inactivation *

Phenomenon where the drug concentration is reduced before reaching the systemic circulation due to partial inactivation by the liver.

→ no first-pass effect with parenteral + sublingual methods
→ variable with rectal administration

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14
Q

Bioavailability

A

Amount of the drug available to get into the circulation after getting through the liver.

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15
Q

Different injection methods

A
  1. Subcutaneous
  2. Intravenous
    → fastest!!
  3. Intramuscular
  4. Other (cerebrospinal fluid to bypass BBB, catheter…)
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16
Q

Administration routes & Peak drug concentrations in blood

A
  1. Intravenous → rapid rise + rapid decline as it reaches the target
  2. Oral → slower rise (takes time to be absorbed by GI tract) + lower peak concentration (first-pass effect)
  3. Rectal → slow absorption + lower peak level
  • NTC L2 F3 *
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17
Q

Selectivity of drugs

A
  1. Selective effect → mostly targets one area

2. Generalized effect → acts on all systems (on the cell, in the cell, non-specific mechanisms)

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18
Q

Endogenous binding sites

A
  1. Antagonists BLOCK the the endogenous ligand from binding

2. Agonists MIMIC the natural ligand and bind the endogenous binding site

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19
Q

Allosteric binding sites

A

A different site from the endogenous binding site, which will alter the response at the endogenous binding site upon activation by the binding of a modulator

  1. Allosteric activators INCREASE response at a different site
  2. Allosteric inhibitors DECREASE response at a different site
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20
Q

Transmembrane signalling mechanisms

A

Involve the recognition and binding of an extracellular signal by an integral membrane receptor protein and the generation of intracellular signals by one or more effector proteins.

→ EX: receptor-activated enzyme, receptor-activated TK, receptor-activated ion channel, GPCR

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21
Q

Cellular receptors

A
  1. Ion channels
  2. GPCR
  3. RTK
  4. NPR
  5. Intracellular receptor
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22
Q

Ion channels

A
  • found all over the body
  • transmembrane-spanning proteins
  • 3 conformations: open, closed, inactive
  • types: voltage or ligand controlled
  • drug affinity depends on:
    1. membrane potential
    2. channel cycling frequency
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23
Q

G-Protein Coupled Receptor (GPCR)

A
  • receptor spanning the plasma membrane 7 times
  • acts as an “on/off” switch for cell signalling
  • general process:
    1. signal binds GPCR
    2. GPCR exchanges GTP for GDP
    3. Dissociation of alpha & beta-gamma subunits
    4. Activation of effector protein by detached alpha subunit
    5. production of secondary messenger
    6. downstream signalling
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24
Q

GPCR: Muscarinic receptors

A
  1. ACh binds GPCR
  2. GPCR activates K+ channel
  3. K+ exits the cell
  4. Hyperpolarization of cell
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25
Q

GPCR: Epinephrine receptor

A
  1. Epinephrine binds GPCR
  2. cAMP released as second messenger
  3. leads to release of glucose
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26
Q

Receptor turnover

A

Receptors are dynamic

  1. internalization & recycling
  2. changing number of receptors at the plasma membrane
  3. degradation through fusion with lysosome
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27
Q

Receptor tyrosine kinase (RTK)

A
  • General process:
    1. ligand binds to receptor
    2. RTK dimerizes (activated)
    3. phosphorylation of Tyr residues
    4. activation of related protein
    5. downstream signalling
  • typical agonists = insulin, GF
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28
Q

Natriuretic peptide receptor (NPR)

A
  • peptide receptor

- activate cellular responses in kidney + heart

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29
Q

Intracellular receptors

A
  • alter gene expression + protein synthesis
  • receptor = ligand binding domain + DNA-binding domain
  • response time may differ depending on receptor type
    ion channel → GPCR → enzymes → DNA-linked
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30
Q

Dose-response curve

A

x axis: [drug] in log scale
y axis: response in % max

→ ED-50 (effective dose) = drug dose required to produce an effect on 50% of population
→ potency based on amount of drug needed to get ED-50 (the further to the left, the more potent the drug)
→ threshold = point where you start to see an effect of the drug (smallest dose to get a response)
→ ceiling dose = point at which the effects of the drug level off (plateau)

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31
Q

Receptor occupancy

A
  • typically WAY LESS than 100% → no need to occupy all available receptors to get 100% response
  • this is due to spare receptors used as a fail-safe mechanism
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32
Q

Drug affinity

A
  • drugs differ in affinity for receptor binding site

- the lower a drug’s affinity, the more drug is required to get the same effect as a more potent drug

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33
Q

Efficacy

A

The proportion of receptors forced into their active conformation when occupied by a particular by a particular drug and give the DESIRED response.

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34
Q

Agonists

A

Lock & key model

  1. Full agonist
    → binds its receptor and leads to a large response
    → high efficacy
  2. Partial agonist
    → binds its receptor but only leads to a small response in the cell
    → low efficacy
    → allows blockage of full agonists (not the same as giving antagonist)
    → commonly used for withdrawal
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35
Q

Antagonists

A

Drugs that simply block the receptor and get in the way of its endogenous agonist.

  1. Competitive antagonist
    → binds to same site as agonist
    → shift the DR curve to the RIGHT
  2. Non-competitive antagonist
    → binds to a different site than the agonist (allosteric modulation)
    → its effect cannot be overcome with an increased dose of agonist
    → lowers DR curve peak
  3. Irreversible antagonist
    → binds to receptor irreversibly (longer effect)
    → decreases number of available receptors
    → causes an increase in receptor turnover
  4. Reversible antagonist
    → binds to the receptor reversibly
    → avoids toxicity
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36
Q

Potentiation

A

Potentiation is an interaction between two or more drugs resulting in a pharmacologic response greater than the sum of individual responses to each drug.

→ agonist + allosteric activator will cause peak to go DOWN and curve to shift to the LEFT
→ less natural ligand needed for a certain response

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37
Q

Quantification of side effects

A
  • ED-50: dose of drug required to produce a therapeutic effect in 50% of population
  • TD-50: dose of drug required to produce a toxic effect in 50% of population
  • LD-50: dose of drug required to produce a lethal effect in 50% of population
    (→ determined in animals only and usually only LD-10)
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38
Q

Therapeutic index (TI)

A

The ratio of toxic to therapeutic effect → LD50/ED50 or TD50/ED50

  • the larger the TI, the safer the drug

(distance between the toxic/lethal dose and the therapeutic dose)

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39
Q

Therapeutic window

A

The dose range within which most people get therapeutic effects without getting side effects.

→ the larger the therapeutic window, the safer the drug

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40
Q

Safety factor

A

The ratio of the highest exposure that does not induce toxicity to the exposure that exerts efficacy → TD1/ED99

→ the larger the safety factor, the safer the drug

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41
Q

DR outliers

A
  1. Benefit outliers

2. Toxicity outliers

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42
Q

(L)ADME

A
  1. Liberation
  2. Absorption
    → enteral route: stomach, SI, liver, capillaries
  3. Distribution
  4. Metabolism
  5. Excretion
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43
Q

Weak acids vs Weak bases

A
  1. weak acid
    → a weak acid in a more acidic environment is in its unionized form (lipid soluble)
    → some drug absorbed in stomach
    → regular antacid use may affect the rate of absorption of weak acid drugs
  2. weak base
    → able to easily diffuse through membrane in SI where the environment is more basic
    →
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44
Q

One compartment model

A

Drug is distributed evenly throughout the body

→ FALSE!

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45
Q

Two compartment model

A

A drug is more concentrated in organs with more blood flow and eventually gets distributed equally in all the body after a long time.

→ the rate of blood flow varies with respect to the different organs
→ highest blood flow to brain + heart + liver + kidney

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46
Q

Three compartment model

A

Drug goes to the brain first, then muscles, then adipose tissue, and is distributed unequally

→ FALSE!

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47
Q

Distribution to the brain → BBB

A
  • Blood brain barrier (BBB) used for protection
  • fat-soluble drugs cross the BBB readily
  • tight-junctions present for protection
  • active transport mainly needed to cross BBB
  • drug is eliminated from the brain by CSF → not much metabolism in the brain
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48
Q

Defective BBB

A
  1. underdeveloped in newborns
  2. people with infections
  3. no barrier between the CSF and brain
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49
Q

Placenta

A
  • NOT an effective barrier to drugs

- drugs can concentrate in the fetus

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50
Q

Volume of distribution

A

As drugs enter into the blood, it will over time go from the central volume of distribution to the peripheral volume of distribution to reach an equilibrium

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51
Q

Apparent volume of distribution

A

Amount of drug in body (mg) / [Drug] in plasma (mg/L)

→ low AVD: most of the drug is bound to plasma proteins
→ high AVD: most of the drug is distributed to tissues
→ knowing the AVD of a drug + [drug] in the plasma for a required effect, one can determine the LOADING dose
→ AVD variations due to:
- drug properties
- protein binding
- tissue binding

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52
Q

Metabolism

A
  • involves the alteration of the chemical structure of the drug by an enzyme
  • conversion of drug to (usually) less active/inactive metabolites
    → as [parent drug] in the blood decreases, [metabolite] will increase
    → typically converted to a more water-soluble form
  • occurs mainly in the liver
53
Q

Prodrug

A

Inactive/less active form of a drug to promote absorption, which will then be converted to a more active form following absorption

54
Q

Liver

A
  • metabolizes all exogenous compounds
  • vital for synthesis of essential proteins + inactivation of compounds
  • liver damage = cirrhosis
  • Blood pathway:
    1. portal vein carries blood from intestine to liver
    2. hepatic artery carries oxygenated blood from heart to liver
    3. blood from portal vein and hepatic artery mix and flow into sinusoids
    4. hepatocytes exchange blood with sinusoids
    5. drugs move from sinusoids to hepatocytes to be metabolized
    6. blood flows back to systemic circulation
55
Q

Drug metabolism: Phase I

A

Oxidation/Reduction/Hydrolysis

  • renders the drug biologically inactive + water-soluble
    (may also transform it into an inactive form + not water-soluble)
  • catalyzed by CYP450 enzymes
56
Q

Xenobiotics

A

Substances that are foreign or exogenous to a system; present in what we inhale and in plants.

57
Q

Cytochrome P450 (CYP450)

A
  • mainly found in smooth ER of hepatocytes
  • drugs often have specific enzymes to break them down (though one enzyme can break down more than one drug)
  • differential function:
    1. liver → drug metabolism
    2. brain → compound breakdown required for brain function
  • human CYP450 families:
    1. CYP1
    2. CYP2
    3. CYP3
  • in the liver:
    → relative importance not related to relative quantity
    → important for drug metabolism = CYP2C, CYP2D6, CYP3A
  • in the intestinal epithelium:
    → also contains enzymes to metabolize drugs
    → may also perform first-pass
58
Q

Cytochrome nomenclature

A

EX: CYP2C19*8

  1. Cytochrome P450: CYP
  2. Family (1-17): 2
  3. Sub-family (letter): C
  4. Enzyme or gene (number): 19
  5. Allele: *8
59
Q

CYP450: Liver

A
  • relative importance not related to relative quantity

- important for drug metabolism = CYP2C, CYP2D6, CYP3A

60
Q

Individuality of drug effects

A

Individual variability in activity levels of CYP450s due to:

  1. Genetic factors
    → polymorphic distribution (PM vs. EM vs. URM)
    → enzyme polymorphism (wt vs. wt/+ vs. +/+)
  2. Environmental factors
    → drug therapy, alcohol, cigarettes, nutrition, infection, occupational exposure
  3. Impairment of drug elimination
    → kidney, liver, heart, renal, GI diseases
  4. Age
    → young + elderly
61
Q

Case study: CYP450 variations

A
  • individual variations of CYP2D6 exist
  • important for metabolizing codeine to morphine, beta-blockers, tricyclic antidepressants
  • absent in on population pool & hyperactive in another
  • codeine by itself has no effect
  • metabolism to morphine by CYP2D6 gives relief of pain

→ people deficient in CYP2D6 will need an alternative drug or will need to be given morphine directly

62
Q

Drug metabolism enzymes: inhibition/induction

A
  1. induction
    → high exposure to drugs stimulates the synthesis of drug-metabolizing enzymes to increase the speed of metabolism
    → protection mechanism
    → EX: CYP3A4 induces increase clearance + decreased blood level [ ]
  2. inhibition
    → opposite of induction
    → may lead to rapid overdose of a drug since it cannot be broken down
    → EX: CYP3A4 inhibitors reduce clearance + increase blood level [ ]
63
Q

Drug metabolism: Phase II

A

Conjugation

  • coupling of drug molecule to an endogenous substituent group in order to increase water solubility
  • leads to enhanced renal elimination
  • catalyzed by transferases
    → transfer of a conjugate onto the metabolite from phase I to render it water
    soluble for excretion
  • watch out for toxic metabolites !!
64
Q

Excretion

A

Removal of drug from body

  • mainly done by nephrons in kidney
  • water-soluble compounds easily excreted by kidneys
65
Q

Kidney function

A
  1. filtration
  2. secretion
  3. reabsorption
  • Bowman’s capsule → drug bound to albumin is too big to be filtered, but equilibrium allows for some free drug to always be excreted
66
Q

Drug elimination methods

A
  1. exhalation
  2. saliva secretion
  3. sweat secretion
  4. renal clearance
    → renal drug clearance = filtration + secretion - reabsorption
  5. hepatic clearance

→ total clearance (CL) = CL ren + CL hep + CL other

67
Q

Drug elimination time course

A
  • distribution + elimination phase
    → straight line of elimination allows us to calculate 1/2 life
    → T1/2 = time it take to eliminate half the drug
    → after 4 half-lives (94% eliminated), the drug is essentially ineffective
68
Q

Reaction rates

A 
1. zero order kinetics
→ constant amount of drug eliminated
→ due to saturation of enzymes
→ takes longer to eliminate drug
2. first order kinetics
→ constant fraction per unit time
→ no saturation

** when overdose, first order can switch to zero order due to high [drug] saturating enzymes

69
Q

Dosing schedules

A
  • want to remain in therapeutic window

- steady state achieved after 4 1/2 lives & dose-independent

70
Q

Toxins in plant life

A

fungi → mycotoxins

plants → phytotoxins

71
Q

Daffodils

A
  • poisons: galantamine + lycorine + calcium oxalate crystals

→ galantamine = competitive inhibitor of acetylcholinesterase

72
Q

Atropine

A

cholinergic blocker acting on PSNS

73
Q

Lily of the valley

A
  • poisons: lycorine + glycosides

→ glycosides affect cardiac system

74
Q

Oleander

A
  • poison: glycosides
75
Q

Castor oil beans

A
  • poison: ricin

→ 2 moieties which will (1) disrupt protein synthesis + (2) bind toxin to cell surfacee

76
Q

Biomagnification

A

Accumulation of a chemical by an organism from water and food exposure that results in a concentration that is greater than would have resulted from water exposure only and thus greater than expected from equilibrium

77
Q

Toxicity thresholds

A
  1. No-Observed-Adverse-Effect Level (NOAEL)
    → highest data point at which you see no observed adverse effects of the substance
    → anything below this point is safe
  2. Lowest-Observed-Adverse-Effect Level (LOAEL)
    → lowest data point at which you see an adverse effect of the substance
    → anything above this point is harmful
  • anything in between is unknown
78
Q

Hormesis

A

Change in the effect of a drug when you move from low to moderate dose
→ EX: vitamins (downward parabola)
→ EX: antibacterial drugs (upward parabola)

79
Q

Observational studies of humans

A
  1. Cohort study
    → monitoring two groups (exposed + not exposed)
    → prospective (compare future exposure) & retrospective (compare previous exposure)
  2. Case control study
    → compare those with disease vs. those without
    → always retrospective
  3. Cross-sectional study
    → collect data on defined population and determine similarities
80
Q

Observational studies quantification

A
  1. Odds ratio
    → risk of disease in exposed group vs non-exposed group
    → ratio of two odds
  2. Standard Mortality Rate (SMR)
    → relative risk of death in exposed group vs non-exposed group
  3. Relative risk
    → relative risk of disease in exposed group vs non-exposed group
    → ratio of two probabilities
81
Q

Epidemiological studies variations

A

Causes include:

1. Selection bias
→ study group is not representative of the population
2. Information bias
→ misclassification 
3. Confounding factors
→ factor that wasn't accounted for
82
Q

Lead contamination

A
  • main targets: CV system, nervous system, kidneys
  • developmental toxicity in children
  • pharmacodynamic effect: blocks Ca2+ signalling and NMDARs, effect on mGLURs, mito and gene transcription
  • accumulates in bones (may eventually mobilize!)
  • historically found in paint, pipes, gasoline, pellets
83
Q

Mercury poisoning

A
  • methylated mercury = highly toxic
  • bioaccumulates
  • demonstrates “Grasshopper effect”
    → transported from warmer to colder regions of the Earth, particularly to the North
84
Q

Pesticides & Insecticides

A
  • mechanisms of action: inhibit cell division, protein and carotenoid synthesis, and photosynthesis
  • different insecticides:
    1. organochlorines
    → act on VG Na+ channels by making the channel stay open longer, causing hyper-excitability
    → bioaccumulation
    → EX: DDT, lindane
    2. pyrethroids
    → act on VG Na+ channels by making the channel stay open longer
    3. organophosphates
    → block the breakdown of ACh by blocking acetylcholinesterase, which can lead to respiratory failure
    → EX: malathion
85
Q

Drug Discovery: Chronic diseases

A
  • Alzheimer’s
  • Parkinson’s
  • Arthritis
    1. rheumatoid arthritis (autoimmune)
    2. osteoarthritis (wear&tear)
86
Q

Drug Discover: Government vs. Industry

A
  • government funding: basic research > translational research > clinical research
  • PhRMA funding: clinical research > translational research > basic research
87
Q

Gene therapy

A

An experimental technique that uses genes to treat or prevent disease.

→ a viral vector carrying a new gene gets into the cell and then inserted into the nucleus, where it will encode a protein that is missing in a particular disease
→ EX: cystic fibrosis

88
Q

Strategies for drug development

A
  1. Microarray technology
    → complementary DNA techniques
  2. Functional genomics
  3. Molecular biology
89
Q

Angiogenesis

A

Formation of new blood vessels around a tumor

90
Q

Combinatorial chemistry

A

How you go about finding what ligands bind to your target.

  • compound library → lead compounds (!) → pre-clinical testing → lead optimization (!)
  • combinatorial chemistry allows us to quickly develop and synthesize thousands of compounds
  • combinatorial chemistry affects lead compound discovery + lead optimization
  • high-throughput screening used
  • done in vitro
  • possibility of eliminating drugs that will certainly not work ahead of time (use mammalian cells, microbes if antiviral, P450 enzymes, cell-based assays, cell-free assays)
91
Q

High-Throughput Screening (HTS)

A

Basic requirements:

  1. suitable compound libraries
  2. assay method configured for automation
  3. robotics workstation
  4. computerized system capable of handling the data
92
Q

Automated ligand identification system

A

Method to identify potential ligands

→ combining target protein in vitro with a mixture of potential ligands
→ wash solution, such that only ligand+protein is left
→ release bound compounds and run through MS to identify the ligand

93
Q

HTS: What cannot be evaluated in humans?

A
  1. bioavailability
  2. pharmacokinetics
  3. toxicity
  4. mutagenicity
  5. specificity
94
Q

Bioinformatics

A

The algorithmic generation of understanding from vast amounts of biological data.

95
Q

Computational chemistry

A

Calculations to tell us what sense we can make from what we obtained from combinatorial chemistry

  • EX: HIV & HIV protease inhibitor
  • EX: Ibrutinib blocks an enzyme that is over-expressed in malignant B cells
  • EX: Statins decrease the production of endogenous cholesterol and release of cholesterol from the liver
  • EX: PCSK9 inhibitors → PCSK9 is involved in LDL receptors, thus PCSK9 inhibitors increase receptor recycling to increase LDL clearance
96
Q

Monoclonal Antibodies (MAb)

A
  • Strategies:
    1. chimeric antibodies (mouse variable region + human constant region)
    2. primatized antibodies (chimeric with primate-derived variable region)
    3. humanized antibodies (all human except for antigen recognition site)
    4. transgenic mouse antibodies (fully humanized)
  • Success stories
    → rheumatoid arthritis
    → crohn’s disease
    → B cell malignancies (cancer)
    → breast cancers (ABs against HER2)
    → osteoporosis (ABs against osteoclasts)
    → colorectal cancer
97
Q

Tumor Necrosis Factor (TNF) inhibition

A
  • Adalimumab → autoimmune diseases

- Infliximab → rheumatoid arthritis

98
Q

Preclinical studies

A

Animal studies need to be conducted

  • Ames test used to look for mutants
  • DNA repair genes and luciferase test in yeast
  • teratogen studies
  • ADMET !!
  • reasonable 1/2 life + cost + known TW
99
Q

Clinical Trial Phases

A 
1. Phase I : human safety
→ pharmacokinetics observed
→ small group of volunteers
2. Phase II : expanded state
→ experimented with people who have the disease
→ larger group of patients
→ monitor side effects
3. Phase III : efficacy & safety
→ very large group of patients
→ monitor side effects for long-term use
4. Phase IV : post-approval surveillance
→ detect very rare side effects
→ study effectiveness in general population
→ optimize drug use
→ observe effects on young, elderly and pregnant women
→ consider drug interactions 
→ record patient compliance
→ if a serious risk is discovered, use BLACK BOX WARNING
100
Q

Clinical Trials: Special Cases

A
  • 3 classes of trials:
    1. Class 1: very fast
    2. Class 2: fast
    3. Class 3: normal
  • orphan drugs
    → rare drugs / designed for limited number of people
    → company will typically use money on it
    → may get subsidized by gov.
101
Q

Recent drug discovery: Immunotherapy for cancer

A
  • checkpoint inhibitor drugs
  • PDL1 on tumor cell will bind to PD1 receptor on T-cell, leading to inhibition of its attack on the abnormal cell
  • strategy: block receptors on T-cells so they can no longer be activated by the ligands on the tumor cell → T-cell now recognizes tumor as invader
  • drug: Pembrolizumab
102
Q

Recent drug discover: Melanoma treatment

A
  • combination with MAb allows for higher survival rates
103
Q

Recent drug discovery: chronic lymphocytic leukemia

A
  • too much B cell proliferation → Btk enzyme (which facilitates B cell production) is blocked!
  • drug: Ibrutinib
    → selective for B cells
    → highly potent
    → more successful in treatment-naive people
104
Q

Cancer therapy

A
  • strategies:
    1. making an Ab that could deliver a toxic compound to the tumor cell in order to kill it
      → EX: lymphoma
    2. knowing an abnormality in a tumor cell and targeting it with an Ab, making it unable to grow
      → EX: herceptin (subtype of breast cancer that over-expresses HER2)
105
Q

Other drugs

A
  • Neprilysin blockers to avoid breakdown of peptides necessary for lowering blood sugar and promoting sodium excretion
  • Sofosbuvir → blocks RNA production of HCV
  • mRNA and adenovirus vector vaccines for COVID19
106
Q

Designing clinical trials

A
  1. parallel design
  2. crossover

→ must always be double blind + randomized !!

107
Q

Nature study

A

Identical doses of pain relief medications given to patients in two different circumstances:

  1. hidden application
  2. open application → much stronger response
108
Q

Classification of drug interactions

A
  1. Additivity
  2. Antagonism
  3. Potentiation
  4. Synergism
109
Q

CYP2D6

A

metabolizes Codeine, Beta-blockers, tricyclic antiDepressants (CBD)

110
Q

ADR: Drug interactions

A
  1. Propranolol (reduces hepatic blood flow) + morphine
  2. Grapefruit (CYP3A4 inhibitor) + most drugs
  3. MAO inhibitors + tyramine-containing foods (wine, cheese, pickled foods)
  4. Penicillin + probenecid → reduced penicillin elimination
  5. tricyclic antidepressants + antihistamines → atropine-like effects (additive effect)
  6. aspirin + warfarin → bleeding (additive effect)
  7. herbal remedies + anticoagulants (additive effect)
  8. penicillin + aminoglycosides → positive effect! (avoids bacterial resistance through synergism)
111
Q

Beneficial vs harmful drug interactions tricks

A
  • synergism → PABO
  • additivity → QAAM
  • antagonism → ONCP & WV
112
Q

CYP2A6

A
  • metabolizes nicotine to cotinine (less active metabolite)

- may activate some procarcinogens

113
Q

Nicotine Addiction Treatments

A
  1. replacement therapy
  2. bupropion → blocks nicotinic receptors on dopaminergic receptors
  3. varenicline → partial agonist
  4. topiramate → inhibit dopamine release following nicotine
  5. CYP2A6 inhibition
114
Q

Ethanol pharmacodynamics

A
  • inhibits excitation → glutamate (NMDA) receptor
  • potentiates inhibition → GABA A (pre/post) + glycine receptors (post)
  • lowers release of serotonin + ACh → behavioural issues
  • facilitates release of dopamine + opiate neuropeptides → addictive properties
  • blocks vg Ca2+ channels
115
Q

Alcohol: two-step metabolism

A
  1. ethanol → (alcohol dehydrogenase) → acetaldehyde
  2. acetaldehyde → (acetaldehyde dehydrogenase) → acetate
  • metabolized by CYP2E1
  • acetaldehyde dehydrogenase blocked by DISULFIRAM
116
Q

Cocaine pharmacodynamics

A 
1. Reuptake pumps at synapse (decreased reuptake) → reward pathway + SNS activated together
    → dopamine
    → serotonin
    → noradrenaline 
2. Ion channels at axons
     → blocks vg Na+ channels
     → blocks NSS family
117
Q

Cocaine metabolism

A
  • metabolized by hCE1

- cocaine + alcohol metabolized to cocaethylene

118
Q

Amphetamines & derivatives

A
  • increase dopamine and NA release + block reuptake
  • act both pre/post
  • derivatives:
    1. methamphetamine
      → block MAO
    2. MDMA (ecstacy)
      → block MAO
      → big effect on serotonergic neurons + 5HT
    3. ephedrine
119
Q

Caffeine pharmacodynamics

A
  • competitive antagonist of adenosine receptors (inhibitors) → decreased inhibition
  • rapid tolerance
120
Q

Cannabinoid pharmacodynamics

A

Retrograde signalling system

  1. AEA/2-AG naturally synthesized in post-synaptic neuron and act pre-synaptically at CB1R
  2. THC & its derivatives act on CB1R also
  3. activation of CB1R on pre-synaptic terminal decreases Ca2+ intake
  4. hyperpolarization of cell → decreased release of neurotransmitters
  5. less stimulation of post-synaptic neurotransmitter receptor
121
Q

Schizophrenia

A
  • elevated dopamine levels in the brain

- drugs: chlorpromazine (blocks the inhibitory D2 receptor), but not selective

122
Q

Depression

A

Types of antidepressants:

  1. MAOIs
    → MOA (found in pre + synaptic cleft) breakdown neurotransmitters
    → increase levels of NA + 5-HT at synaptic cleft + post
  2. tricyclic antidepressants
    → interfere with neurotransmitter reuptake by blocking NA + 5-HT reuptake transporter
    → increase levels of NA + 5-HT
    → many side effects (vascular system, GI, sedation) due to non-specificity
  3. SSRIs (Prozac!)
    → specifically interfere with 5-HT reuptake by blocking 5-HT reuptake transporter
    → increase levels of 5-HT
  4. Atypical NA + 5-HT reuptake inhibitors
123
Q

Anxiety & Benzodiazepine pharmacodynamics

A
  • act on GABA A receptors by increasing its activity
    → binding of BDZ facilitates GABA neurotransmitters to open Cl- channels, thus leading to hyperpolarization and an inhibitory effect
  • affects frequency of opening, no direct effect
  • shift DR curve to the LEFT
  • drugs: diazepam (valium), chlordiazepoxide (librium)
  • other drug: zolpidem (does not act on BDZ)
124
Q

Barbiturate pharmacodynamics

A
  • increase duration of channel opening → direct effect (more dangerous)
  • increase in dose can be lethal
  • not as selective
125
Q

Benzodiazepine antagonist & agonist

A
  1. benzodiazepine antagonist
    - used when someone is heavily sedated
    - shift DR curve to the RIGHT
    - EX: flumazenil
  2. beta-carboline
    - inverse agonist
    - increases anxiety
    - shift DR curve to the RIGHT
  3. benzodiazepine agonists
    - increased GABA effect
126
Q

Benzodiazepine metabolism

A

metabolized by CYP3A + CYP2C19

127
Q

Opioid drugs

A
  1. buprenorphine → weak agonist
  2. methadone → weak agonist
  3. naltrexone → antagonist
  4. naloxone → antagonist
  5. pentazocine → agonist-antagonist
128
Q

Opioid analgesia pharmacodynamics

A
  1. decrease pain signal
    → pre-synaptic: block Ca2+, such that there is less transmitter release
    → post-synaptic: increase K+, such that hyperpolarization causes less firing
  2. increase inhibition
    → decrease GABA release onto descending pathway
129
Q

Codeine metabolism

A
  • metabolized by CYP2D6

pharmacology (1 decks)

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