Chapter 1: Basic Principles Flashcards

1
Q

What is Pharmacology?

A

Study of chemical interactions with living systems
-Medical Pharmacology: Substances used to prevent, diagnose, and treat disease

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2
Q

What is Toxicology?

A

Study of undesirable effects of chemicals on livings systems
-Toxins: Organic from living things
- Poisons: Inorganic from nonliving

Paracelsus: Father of toxicology
-Any compound can become poisonous if excessive amounts were taken in

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3
Q

History of Pharmacology

A

-First Recorded physician- Imhotep
-Still use traditional Chinese Medicine: Use of plants and animals (ex. Rhino horn used for fertility, Bear bile- Covid)
-People confused Rod of Asclepius and Caduceus
-Material Medica: First textbook of pharmacology
-Want Controlled Drug trials
>Avoid anecdotal evidence (Imermectin for COVID)

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4
Q

Pharmacodynamics

A

Effect of drug on the body (Why are we taking it?)

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5
Q

Pharmacokinetics

A

Effect of body on drug (ADME)

A: Absorption- Move across a barrier
D: Distribution- Where is the drug going to end up
M: Metabolism- Activate vs. Inactivate
E: Elimination- How do we get rid of it?

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6
Q

What is an agonist?

A

Molecule that binds to a receptor site that elicits a response similar to endogenous ligand
-Degree of response may differ from endogenous ligand

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7
Q

What is an antagonist?

A

Block endogenous ligand from binding to the receptor site
-Does not elicit a response

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8
Q

Allosteric Site

A

Molecule binds at a site away from orthosteric site, but still on same protein
Causes a conformational change change of the orthosteric site
-Activator vs Inhibitor

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9
Q

Orthosteric Site

A

Drug binds to the same site as the endogenous ligand

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10
Q

Bond Strength

A
  1. Covalent Bond Strongest (50-150 kcal/mol)
  2. Ionic (5-10)
  3. Hydrogen Bond (2-5)
    -Van der Waals Forces
  4. Hydrophobic: Not really bonds- just trying to stay away from water (0.5-1)
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11
Q

Bond Strength Relationship with Specificity

A

Inverse Relationship
-Strong bond=Less Specific

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12
Q

What is a racemic mixture?

A

Combination of R:S Isomers
-R:S isomers interact differently with receptor site so can cause different responses/side effects

-Sterioisomeres

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13
Q

Partial Agonist

A

Effect is much weaker than full agonist
- Absence of Full Agonist- Agonist
- Presence of Full Agonist- Antagonist
>Why? Competing for same receptor sites

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14
Q

Inverse Agonist

A

Agonist that favors (greater affinity) the INACTIVE form of receptor; suppresses response
- Acts as an antagonist b/c binds to inactive receptor so less active receptors available
-To have this; need to have constituent activity at the site with endogenous ligands still acting on site
>If site doesn’t have activity, then inverse agonist can’t occur

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15
Q

Competitive Antagonist/Inhibitor

A

Bind to same site so inhibits response by competition

Surmountable: Increase Agonist concentration and will achieve same Emax/response
-Increase EC50 or ED50 (move EC50 to the right on log dose vs response curve)

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16
Q

Non-Competitive Antagonist/ Allosteric Inhibitor

A

Binds to a different site causing a change to orthosteric site
-Receptor was a square, but now a circle so agonist
unable to bind

Insurmountable: No increase in agonist concentration will elicit same response
- Emax: Decreases
- EC50: Stays the same (i.e changing the scale)

17
Q

Irreversible Inhibitor

A

Binds to the same site, but unable to break connection
ex) covalent bond forms so inhibitor it does’t leave

Can be competitive or noncompetitive

Insurmountable: No increase in agonist
concentration will elicit same response because it is decreasing the amount of available sites
- Emax: Decreases
- EC50: Stays the same (i.e changing the scale)

18
Q

Beta 1 Receptor

A

Think Heart
-Agonist: increases heart rate
>Direct: Epi, Norepinephrine
>Indirect (mimic): Cocaine, Amphetamine (Blocks reuptake in synapse so epi stay longer)
-Partial: consider them anatagonist
>Pindolol, Acebutolol
-Antagonist: Keep same/constituent activity ~70 BPM
>Propanolol, Atenolol
-Inverse: further decrease constituent activity (decrease HR)
>Carvedilol, Nadolol

19
Q

Duration of Drug Action Scenarios

A
  1. Only act as long as drug binds receptor
    - tightly bound=longer duration; vice versa
  2. Long term downstream effects last until downstream effectors go away
    -Elicits a downstream effect: Cascade
    -Covalent bonds- receptor degraded (lysosome)
  3. Desensitization- Constantly being signaled; response will shut down (GPCRs)
20
Q

Good vs. Bad Receptor

A

Good:
- Selective: Only bind 1 ligand so not competing with other ligands
- Alteration: Changes shape/conformation that elicits cascade
Bad:
- Non-regulatory molecules that bind drugs with no detectable change in function
> Drug Carriers: Good for carrying stuff around body

21
Q

Drug Carriers

A

Plasma Proteins (Albumin):
- Free drugs cross borders; bound drugs don’t
- Decreased levels based on nutrition, liver funct.
- Other drugs may displace (kick) one another off
Types:
- Albumin: Binds mostly to acidic (release H+)
- alpha-acid glycoprotein: Binds mostly basic (release OH-)
- Lipoprotein: neutral drugs (cholesterol)

22
Q

What is potency?

A

Concentration of drug (EC50/ED50)required to produce 50% of maximal effect
- Sedation vs. very drowsy
- More potent: reaches EC50/ED50 with less drug dose

23
Q

Maximal Efficacy

A

-Greatest possible responses drug can deliver
- Emax higher
- Ex) Cardiac output increase comparing diff ionotropes
-Must also take into account drug toxicity

24
Q

Median Effective Dose (ED50)

A

Drug dose when 50% of population elicits the response we want

25
Median Toxic Dose (TD50)
Dose of drug when 50% of population begin to elicit negative side effects
26
Median Lethal Dose (LD50)
Dose of Drug when 50% of population dies
27
Therapeutic Index
Establishes margin of safety of drug Calculation: TD50/ED50 -Larger number/Wider margin means drug is safer -Smaller number/Narrow margin: Probably should closely monitor patient (Digoxin)
28
Bmax & Kd
Bmax: 100% of target receptors bounds Kd: Drug concentration that binds 50% of target receptors
29
Emax vs. EC50
Emax: Maximal drug response/effect EC50: Concentration of drug that results in 50% response/effect Ex) Pain scale
30
Variations in Drug Response
1. Drug-Drug Interactions -Ex) Phenytoin & Carbamazepine 2. Individual patient responses vary -Idiosyncratic -Unusual: genetics (pharmacogenomics); hyporeact vs. hyperreact 3. Tolerance: response changes over course Ex) Morphine -Tachyphylaxis: Quick tolerance (nitric oxide) 4.Chemical Antagonist: interacts directly with the drug being antagonized to remove or prevent it from binding with its receptor site 5. Physiology Antagonism
31
Causes of Variation
1. Alteration in conc of drug that actually reaches the receptor (Pharmacokinetics- ADME) -Age, weight, sex, disease state 2. Variation in conc of endogenous receptor ligand Ex) Differing amount of epi circulating in body in diff people so B-blocker dose needed may be diff 3.Alteration in # or function of receptors -Less receptors to begin w/ or receptor # decreasing 4. Changes in components of response downstream to receptor - Post receptor process: use up messenger more quickly - Largest & most important cause of variation -Body has natural ability to compensate
32
Physiologic Antagonism
Two different receptors causing a squelching of the intended response Ex) -Beta: Sympathetic response -Muscarinic: Parasympathetic response
33
Henderson Hasselbach Equation
PH= PKA + LOG (A-)/(HA) -log function so 1x, 10x, 100x, 1000x PH > PKA: Favors Unprotonated PH < PKA: Favors Protonated
34
Acidic Drugs
Release H+ into solution Protonated form is uncharged Unprotonated form is charged “Trapping” in urine OD with weak acid give NaHCO3 (Bicarb) -Want to alkalinize urine
35
Basic Drugs
Absorbs H+ from solution Protonated: Charged Unprotonated: Uncharged “Trapping” Drug in Urine OD with weak base give Ascorbic acid (Vit. C) -Want to acidify urine
36
Agonist mimic (indirect agonist)
Effects downstream inhibitors Ex) usually blocks enzyme down the cascade -Cocaine, amphetamine act like beta agonist but aren’t really effecting same receptor
37
Understand Log dose vs. Response Curve
A: agonist alone A+B: Competitive inhibitor A+C: Allosteric/Noncompetitive Activator A+D: Noncompetitive Inhibitor