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Neuropharmacology > Chapter 1: Pharmacokinetics and Pharmacodynamics > Flashcards

Chapter 1: Pharmacokinetics and Pharmacodynamics Flashcards

1
Q

Pharmacokinetics vs Pharmacodynamics

A

Pharmacokinetics- how substances are distributed through the body
Pharmacodynamics- interactions of the substance with a receptor

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2
Q

Pharmacology

A

the scientific study of actions of drugs and their effects on a living organism

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3
Q

Neuropharmacology
Psychopharmacology
Neuropsychopharmacology

A

Neuropharmacology- drug induced changes in nervous system function
Psychopharmacology- drug-induced changes in mood, thinking, and behavior
Neuropsychopharmacology- drug- induced changes in the nervous system that influence behavior

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4
Q

Drug Action

A
  • specific molecular change
  • drug binds to its target (receptor)
  • can be very distant from ultimate effect
  • occur at many different target sites
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5
Q

Drug Effect

A
  • more widespread/ systemic change
  • eg. in physiology or behavior
  • Therapeutic effects
    - desirable effects of a drug
  • Side effects
    - undesirable: annoying, distressing, dangerous
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6
Q

Specific Drug Effects vs Nonspecific Drug Effects

A

Specific Drug Effects
- result from interactions between a drug and it’s target (pharmacodynamics)

Nonspecific Drug Effects

     - may affect outcome of drug use
     - can't be explained by drug-receptor interactions
     - include mood, expectations, perceptions, attitudes
     - ex. different moods when drunk, placebo effect
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7
Q

Pharmacokinetics

A
  • what body does to drug
  • mechanisms involved in delivering a drug to its target, where it can have a pharmacological effect
    - Administration- routes of administration
    - Absorption and Distribution- pass through variety of cell membranes and enter blood plasma
    - Elimination
    - Metabolism- inactivation
    - Excretion- liver metabolites are excreted/ unaltered forms are excreted
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8
Q

Bioavailability- […]

depends on several factors:

  - (...) into the blood by route of administration
          - affected by (...)
  - drug (...) to target sites
           - (...)
  - (...)/ clearance mechanisms
           - for a drug to be (...) it must be (...) or (...)
A

Bioavailability- is the amount of drug in the blood that is free to act on a specific target

depends on several factors:

  - absorption into the blood by route of administration
          - affected by lipid solubility, ionization, selective barriers
  - drug distribution to target sites
           - plasma proteins, depot binding (inactive storage site)
  - elimination/ clearance mechanisms
           - for a drug to be bioactive it must be unchanged (not metabolized) or active metabolite
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9
Q

Pharmacokinetic factors determine bioavailability

A
  1. Drug Administration- oral, intravenous, intraperitoneal, subcutaneous, intramuscular, inhalation
  2. Absorption and Distribution- membranes of oral cavity, gastrointestinal tract, peritoneum, skin, muscles, lungs
  3. Binding
    - Target site: neuron receptor
    - inactive storage depots: bone and fat
  4. Inactivation- liver, stomach, intestine, kidney, blood plasma, brain
  5. Excretion- intestines, kidneys, lungs, sweat glands

Excretion products: feces, urine, water vapor, sweat, saliva

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10
Q

Time Course of Plasma Concentration

A

*picture on phone

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11
Q

Absorption

A

movement of the drug from site of administration to the blood circulation

     - oral delivery requires absorption through the GI tract
     - drugs must survive this "first-pass" metabolism (toxins go through portal vein to liver where they're altered by enzymes before passing through heart for circulation) in active form
     - once in the blood, a drug can reach its active site or bind to inactive sites in blood (eg albumin) muscle or fat
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12
Q

4 common routes of administration

A

Oral injection: tablet, capsule, liquid
Injection: intramuscular, intravenous, subcutaneous
- may not go through first pass metabolism
Inhalation: smoking, inhalers, nebulizers
Through mucous membranes: sublingual, intranasal, rectal suppository, transdermal

Route of administration affects drug half-life and bioavailability

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13
Q

Absorption: lipid solubility

A
  • cell membranes are comprised of phospholipid bilayers
  • substances must be lipid-soluble to pass through the membranes by passive diffusion
  • movement down a concentration gradient
    - higher concentration gradient= faster movement

Membrane lipid bilayer:

    - Phosphate head group
               - carry ionic charge
               - polar, hydrophilic
     - 2 fatty acid tails
                - do not carry charge
                - non-polar, hydrophobic
                - impedes ability of substances to cross membrane
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14
Q

Absorption: ionization

A
  • most psychoactive drugs are weak acids or weak bases that are ionized in water
    - passive diffusion ceases when drug is 50% ionized and 50% unionized
    - highly charged molecules don’t absorb easily in GI tract
  • ionization depends on pH of solution and pKa of molecule
    - example. aspirin
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15
Q

Absorption: transport across membranes

A
  • Blood- Brain Barrier: supplies O2, glucose, AA; gets rid of CO2, and other waste
    - reduces diffusion of ionized molecules
  • Placental Barrier
    - acute toxicity
    - teratogenic effects (some depend on timing of exposure)
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16
Q

Distribution

A

once absorbed, a drug is distributed throughout the body via the circulatory system

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17
Q

The amount of drug at a target is a fraction of the total dose administered

A

Drug depots

    - aka silent receptors
    - plasma proteins ( eg albumin), muscle and fat
    - affects its administration and elimination
               - reduces bioavailability
    - determines the duration and intensity of the drug effect; including side-effects
    - non- selective binding; drug displacement

Depot binding

     - binding of drugs to inactive sites
     - delays onset, lowers intensity (once a month injection rather than daily dose)
     - contributes to drug interactions due to non- selective binding/ drug displacement
     - slows metabolism, prolongs duration
     - can terminate drug action
     - reduces drug concentration at active sites so only free, unbound drugs can pass through membrane
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18
Q

Elimination

A

process by which the body removes drug

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19
Q

Psychoactive drugs are commonly metabolized […] and excreted by the […]

A

Psychoactive drugs are commonly metabolized liver and excreted by the kidney

  • rates of elimination depend on drug concentration in the blood, and on the blood flow into the metabolizing organ
    - First-order kinetics- exponentially cleared from body; unsaturated enzymes
    - Half- life (t1/2)- amount of time to clear 50% of drug (most drugs of clearance of 6 half-lifes)
    - determines steady state plasma levels- desired blood concentration of drug when absorption/ distribution= metabolism/ excretion
  • clearance rate is an important factor when considering dosing schedule (time interval between doses)
  • Some drugs are cleared on zero-order kinetics- drug cleared at constant rate regardless of concentration; enzyme saturation (ex ethyl alcohol)
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20
Q

Extended Release

A

lower peak concentration, but much longer duration

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21
Q

The liver […] the drug

A

The liver inactivates the drug

  • The active substance is converted to an inactive substance (metabolite) by
    - microsomal liver enzymes (CYP450 family) that chemically modify the drug

2 types of modifications: makes molecules more soluble

      - type 1 (nonsynthetic, nonconjugate): oxidation (most common), reduction, hydrolysis
      - type 2 (synthetic, conjugate): glucuronide, sulfate, methyl groups

type 2 modifications cause molecules become bulkier

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22
Q

The kidney […] the drug

A

The kidney excrete the drug

  • The kidneys filter the metabolites from blood, to be excreted in urine
  • has an easier time getting bulkier, more soluble molecules out
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23
Q

Drug elimination is affected by the amount and activity of liver enzymes

A

Enzyme Inhibition- some drugs directly inhibit liver enzymes

    - metabolism decreases
    - drug levels go up

Enzyme Induction- increased enzyme levels following chronic use
- can affect other drugs modified by some enzyme

Drug Competition occurs when drugs share metabolic system

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24
Q

Patient- related factors affecting drug elimination

A

Genetics
Gender
Age
Liver disease

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25
Q

Pharamcodynamics

A

interactions between the drug and it’s target (receptor)
- mechanisms of drug action

  • Concentration- response relationships
  • Receptor affinity
  • Drug potency and efficacy
26
Q

Agonists vs Antagonists

A

Receptor Agonists- binds to particular receptor protein
- Drugs that mimic the effect of the endogenous transmitter

Receptor Antagonists- block active ligand from binding to receptor
- drugs that block the effect of the endogenous transmitter

Partial Agonists- less efficient than agonist, but better than antagonist

        - drugs that cannot produce the full agonist response
        - agonist at low concs, but antagonist at high concs

Inverse Agonists- bind to receptor, but have the opposite effect of agonist

27
Q

Receptor

A
  • protein in neural membrane/ inside neuron
  • protein molecules that are initial sites of action
  • has at least 1 binding site for substance
  • receptor selectively binds endogenous ligand like NT

Function:

  • produce longer lasting changes
  • when ligand bind the receptor, signal relayed inside neuron
  • magnitude of response is determined by receptor occupancy (bound with drug) and rate of unbinding (dissociation)
28
Q

Ligand- Receptor Interaction

A
  • dynamic and reversible
  • in constant state of binding (association) and dissociation (breaking away)
  • initiates series of intracellular effects
  • follows the law of mass action
29
Q

Ligand

A

any molecule that binds to receptor with some selectivity

30
Q

Dose- response curve

A

extent of biological/ behavioral effect produced from certain drug concentration

31
Q

Law of Mass Action

A
  • rate of chemical reaction is proportional to product of masses of reacting substances
  • amount of LR* formed depends on how much product of reactants there are
  • ligand combines with receptor to form an activated ligand- receptor complex
  • at equilibrium, the rate of LR* formation is equal to the rate of L+R dissociation
  • the concentration of L determines the biological effect
  • magnitude is determined by ligand concentration (and available receptors)

learn the formula

32
Q

Potency

A

amount of drug necessary to produce specific effect

33
Q

Receptor occupancy depends on […] of the receptor for ligand

A

Receptor occupancy depends on affinity of the receptor for ligand

L-R interaction can be described by affinity or dissociation constants

formulas

  • units of Kd are M (mols)
  • lower Kd represents higher affinity
34
Q

Total number of receptors is [Rt]

A

[Rt]= bound receptors [LR*] + free (unbound) receptors [R]

understand the two formulas

35
Q

Radioligand

A
  • ligand that has been labeled with radioactive element
  • incubated with a tissue preparation that contains the binding sites of interest
  • amount of radioligand bound to tissue is measured using scintillation/ gamma counter
  • Total binding increases with higher concentration of radioligand [L]
36
Q

Total Binding

A
  • includes specific and non-specific binding
    - Specific: high-affinity, few binding sites
    - Non- Specific: low-affinity; many binding sites
  • want to look at specific binding
  • to determine non-specific, an excess (very high concentration) of unlabeled ligand is added
  • excess unlabeled (“cold”) ligand outcompetes (“hot”) radioligand for specific binding sites

**Receptor binding is specific, high-affinity, and saturable

37
Q 
Binding Criteria:
1.
2.
3.
4.
A
  1. Specificity
  2. Saturability
  3. Reversibility and high affinity
  4. Biological relevance
38
Q

Autoradiography

A

can help look at distribution of receptors their affinity in certain brain tissue

39
Q

[…] are used to determine Bmax

A

Equilibrium Binding Curve are used to determine Bmax

  • specific binding is determined for several concentrations of radioligand [L]
  • at very high concentrations of [L], all specific binding sites are occupied with radioligand

** equilibrium binding curves show saturability of specific binding at many [L]

40
Q

Saturation Curve

A

can measure total number of binding sites and receptor affinity

looks at Kd and Bmax

41
Q

Concentration- Response Relationship

A
  • describes ligand- receptor interaction
    - depicts the magnitude of drug effects at progressively larger doses
  • The response can be:
    - pharmacological (receptor binding)
    - biochemical (receptor activation)
    - physiological (neural activity)
    - behavioral (whole animal)
42
Q

Semi- logarithmic saturation curve

A

x- axis: log [L]

Bmax: same for any particular receptor population

43
Q

Receptor Affinity

A

how tightly the receptor holds onto the drug

- lock and key mechanism

44
Q

Drug Potency

A

the amount (concentration) of drug necessary to produce a desired level of effect

  • high potency is correlated to high affinity
45
Q

Drug Efficacy

A

the maximum response produced by a drug

46
Q

Therapeutic Index

A

TI= TD50 (toxic effect)/ ED50 (therapeutic effect)

47
Q

Competitive antagonists

A

“compete” with the agonist for binding to agonist binding site

  • high affinity for the agonist binding site, but no efficacy
  • shifts dose- response curve to right
  • can eventually outcompete antagonist
48
Q

Noncompetitive antagonists

A

bind to site different from agonist binding site

  • negative allosteric modulation
  • agonists can’t overcome inhibition
49
Q

Partial agonist

A

low efficacy
agonist at low concentrations
antagonist at high concentration

50
Q

Physiological antagonism
Additive effects
Potentiation

A

look at picture

Potentiation- bigger response than if just added together

51
Q

Drug Tolerance

A

diminished response to drug administrations after multiple exposures

52
Q

Cross Tolerance

A

tolerance to one drug can diminish effects of second drug

53
Q

Characteristics of Tolerance

1.
2.
3.
4.
5.
A

Characteristics of Tolerance

  1. Reversible
  2. Dependent on dose, frequency, and environment
  3. May occur rapidly, after long time, or never
  4. Not all drug effects have same degree of tolerance
  5. Different mechanisms show different forms of tolerance
54
Q

Acute Tolerance

A

develop during single administration

55
Q

Metabolic Tolerance

A
  • drug disposition tolerance

- repeated use of drug reduced amount of the drug available at the target tissue

56
Q

Pharmacodynamic Tolerance

A

changes in nerve cell function compensate for continued present of the drug

57
Q

Behavioral Tolerance

A
  • context- specific tolerance

- tolerance is not apparent or is reduced in a novel environment

58
Q

State- Dependent Learning

A
  • tasks learned in the presence of a psychoactive drug may subsequently be performed better in the drugged than the non-drugged state
  • conversely, learning acquired in the non-drugged state may be more available
59
Q

Sensitization

A
  • reverse tolerance
  • enhancement of drug effects after repeated administration of the same dose
  • can persist over long periods of abstinence
60
Q

Therapeutic Drug Monitoring

A

blood samples taken after drug administration to determine plasma levels of drug
- detects changes in pharmacodynamics

61
Q

Pharmacogenetics

A

study of genetic basis of variability in drug response among individuals

Neuropharmacology (15 decks)

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