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Pharmacology (Dustin, Ben) > A3: Pharmacokinetics, pt. 1 > Flashcards

A3: Pharmacokinetics, pt. 1 Flashcards

1
Q

What is pharmacokinetics?

Its 4 main parts?

A

the study of how the body affects administered substances through the following processes…

Absorption, Distribution, Metabolism, Excretion

(ADME)

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2
Q

What important characteristics of a drug regimen can be determined by studying the drug’s pharmacokinetics?

4 things

A
  1. route of administration
  2. dose
  3. frequency of admin.
  4. duration of treatment

RDFD

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3
Q

What are the 4 main membrane transport mechanisms for drug absorption?

A
  1. Aqueous Diffusion
  2. Lipid Diffusion
  3. Carrier-Mediated Transport
  4. Endo- / Exocytosis
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4
Q

What kind of molecules tend to undergo aqueous diffusion?

(And through what spaces do these molecules diffuse?)

A

molecules that are small (< 0.4 nm) and ionized

(Diffuse through pores in the epithelial membrane and endothelial layers)

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5
Q

What are the determinants of lipid diffusion?

A
  1. concentration gradient
  2. “lipid/aqueous partition coefficient” of drug
  3. membrane characteristics
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6
Q

What general kind of molecules are lipid soluble?

(What is one exception to this?)

A

Non-ionised and uncharged molecules

(Aminogylcosides are an exception… apparently they are lipid-insoluble even in non-ionised form)

Ionised molecules have weak lipid solubility

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7
Q

What are the 2 general types of carrier-mediated transport?

And the general characteristics of CMT? (3)

A

Facilitated diffusion and active transport are…

  1. Selective
  2. Saturable
  3. Inhibitable - # of carrier molecules can be changed, i.e. by protein synth inhibition
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8
Q

What kind of molecules undergo carrier-mediated transport?

(examples? 3)

A

large endogenous molecules, non-lipid soluble molecules and xenobiotics

  1. peptides + AAs
  2. glucose
  3. L-DOPA
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9
Q

What are 2 important transporter “superfamilies”, their general function and driving force?

A
  1. ATP-binding cassette (ABC) - functions mostly in efflux using ATP; (7 families)
  2. Solute Carriers (SLC) - mostly influx (some efflux) using ion gradients; (48 families)
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10
Q

What is the general role of ABC transporters?

3 examples of them?

A

Excretion of drug into urine, bile, intesting and drug resistance of tumors to chemo

  1. Multidrug Resistance Protein (MDR), AKA P-glycoprotein
  2. Multidrug resistance-associated Protein (MRP)
  3. BCRP, breast cancer resistance protein
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11
Q

What are 4 sites of action of MDR / P-glycoprotein and its function at these sites?

(extra: examples of drugs blocked by it)

A
  1. Intestinal Epithelium - reverse transport toward lumen; e.g. with cyclosporin
  2. BBB - on endothelial cells; keeps drug in blood, away from CNS (ex: loperamide can’t cross)
  3. Placenta - blocks entry of drug to fetus
  4. Testis - same
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12
Q

Name several examples (5) of drugs / foods that inhibit P-glycoprotein and thus increase absorption of drugs in the intestine.

A
  1. clarithromycin
  2. verapamil (Ca channel blocker)
  3. ritonavir (HIV protease inhibitor)
  4. grapefruit
  5. nicardipin (Ca channel blocker)
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13
Q

What is the primary function of the “solute carrier” (SLC) superfamily of transporters?

2 examples of sub-families?

A

Uptake (“influx”) of small molecules into cells

Includes organic anion transporters (OAT, OATP) and organic cation transporters (OCT)

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14
Q

As an example of how one cell has multiple types of transporters acting in pharmacokinetics…

how do these 2 carrier superfamilies facilitate hepatocyte function?

A
  • influx transporters (SLCs) facilitate drug entry into hepatocyte + its metabolism
  • efflux transporters (ABC) facilitate polar glucuronide-derivative excretion to bile
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15
Q

What kind of drugs / biomolecules undergo endocytosis and exocytosis?

A
  • endo - large molecules such as iron/B12 complexed w/ proteins or anti-cancer drugs bound to mAbs
  • exo - NT release from vesicles, HA etc. from mast cell granules
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16
Q

Considering that non-ionized forms of drugs are more lipid soluble…

what physical/chemical characteristic of an absorption site determines how well a drug is absorbed there + how can this be calculated?

A

pH of body compartment determines ionization of a drug

  • Henderson-Hasselbach equation can be used to determine how much of a drug is ionized in a certain compartment’s pH (pKa of drug taken from reference source)
17
Q

In the case of salicylates (i.e. aspirin, a weak acid), what does this pH dependence of ionization tell us about…

…where aspirin is best absorbed?

…why aspirin damages gastric mucosa?

…how to increase the urinary excretion of aspirin (or a diff. drug that is a weak base)?

A
  • Aspirin is best absorbed in the acidity of the stomach (luminal pH = 1.4, aspirin pKa = 4.4), where asprin is 1000x more non-ionized
  • In mucosal cells, cytoplasmic pH = 7.4 makes aspirin 1000x more ionized + thus aspirin is “trapped” in gastric cells once absorbed
  • Increasing urine pH will ionize weak acids + incr. excretion, decreasing urine pH ionizes weak bases + incr. their excretion
  • Srry for long card… you can plug numbers into the eqn. or just believe me / the lecture slides
18
Q

How does this “pH partitioning” affect the concentration of drugs in the CNS?

(Think of a weak acid drug first, and a weak base drug would be the opposite)

A
  • Increasing plasma pH (i.e. with NaHCO3) would extract weak acidic drugs from CNS to plasma (more of the drug would be ionised in plasma)
  • Reducing plasma pH (as in acidosis) would concentrate the drug in the CNS (b/c in plasma it would be non-ionized and thus diffusable)
19
Q

Besides pH / ionization, what other factors influence absorption? (4)

(This list will be without pH obviously, but be sure to always include it when talking about absorption factors)

A
  1. Blood flow to absorption site - intestines receive more bloodflow than stomach; shock decr. cutaneous flow + thus subcut. absorption)
  2. Total surface area - intestinal villi -> high abs.
  3. Contact time - diarrhea speeds intestinal transit, decr. absorption
  4. P-glycoprotein - decreases absorption via efflux
20
Q

What are the 3 basic groups of routes of administration?

(Didn’t want 1 card for all ROAs so this is an overview, more detail on each group later)

A
  1. Enteral / Oral - includes sublingual, enteric-coated + extended release
  2. Parenteral - IV/IM/SC injections
  3. Other - inhalation, topical, etc.
21
Q

What are the types of oral / enteral administration?

(essentially 3, with more detail to 1 of them)

A
  1. Oral - as in swallowed, can be extended-release, enteric-coated to prevent gastric breakdown, etc.
    • weak acids absorb in stomach; weak bases in SI
  2. Sublingual - rapid, bypasses portal circulation
  3. Buccal - similar to sublingual
22
Q

What are several important considerations for oral administration of swallowed (not sublingual/buccal) medications concerning their absorbability?

(extra stuff from slides, with drug examples etc.)

(5 items… kinda long)

A
  1. GI motility and splanchnic blood flow affect absorption
  2. Particle size / formulation - absorption varies depending on drug vehicle (ex: buffered vs. non-buffered aspirin; chloramphenical, digoxin, ampicillin)
  3. Physico-Chemical factors - tetracyclines chelate Ca++ and neither the drug nor Ca will absorb
  4. Carrier Mediated Transport - important for L-DOPA and fluoruracil
  5. P-glycoprotein efflux
23
Q

What are the 3 main types of parenteral administration?

What are the advantages (3)?

A

Intravenous (IV), Intramuscular (IM) and Subcutaneous (SM)

  1. Absorbability - for non-orally absorbable drugs / pts who can not swallow
  2. Bioavailabity - most direct; no gastric / hepatic breakdown
  3. Dose control - most precise route
24
Q

What are the advantages and disadvantages of IV administration?

A
  1. Bolus vs. infusion - rate control
  2. Rapid dilution - drugs which may otherwise irritate tissues rapidly diluted in blood
  3. Rapid effects
  4. Difficult to reverse - i.e. can’t use charcoal, etc.
  5. Infection
  6. May preciptate blood constituents / hemolyse
25
Q

What types of drug vehicles are used for IM / SC injections?

What are the advantages?

Disadvantages?

A
  • Aqueous solutions or depot preparations
  • Slow, sustained absorption
  • Minimal hemolysis/thrombosis risk
  • Tissue irritation - certain drugs can not be used
26
Q

Aside from oral and parenteral administration…

what are the other routes of administration?

A
  1. Inhalation - asthma / anesthetics
  2. Nasal - ADH, decongestants, corticosteroids
  3. Intrathecal - into CSF (penicillin, opioids)
  4. Topical - antifungal creams, etc.
  5. Transdermal - sustained delivery patches
  6. Rectal - partial portal circ. bypass, local action
  7. Eye Drops - parasympathomimetics for glauc.
27
Q

What are some (4) examples of unique administration techniques / vehicles?

A
  1. Prodrugs - metabolized to active molecule (L-DOPA, cyclophosphamide, zidovudine)
  2. Ab-Drug Conjugate - Ab targets tumor antigen
  3. Liposome - spherical lipid layer w/ drug inside
  4. Coated Implant - IUD, coronary stent
28
Q

What is volume of distribution (Vd) in pharmacokinetics?

A
  • the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is found in the plasma
  • Vd = amount of drug in body / [drugplasma]
  • ex: 100 mg of a drug is injected and then found to be at 5 mg/l in the plasma; with 4 L total plasma, the other 80 mg must be distributed elsewhere and if we assume that 80 mg is at the same concentration as in plasma, then the Vd is the volume of plasma (4 L) plus the 16 other liters needed to contain 80 mg at 5 mg/l … so Vd = 20 L total
29
Q

What is the use for Vd in pharmacokinetics?

What does a Vd of below 5 L indicate? And one higher than that?

A
  • comparison of the distribution of a drug with the volumes of fluid compartments of the body, to determine where it distributes generally
  • Vd < 5 L means drug distributes only in blood; a larger Vd means it may distribute also in the interstitial fluid (Vd ~ 14L) or total body water (Vd ~ 42L)
30
Q

In studying drug distribution pharmacokinetics…

how can the body compartments be divided by their relative perfusion?

A
  1. Central compartments - good blood supply; plasma, brain, liver, lung, kidney, heart
  2. Peripheral - poor blood supply; fat, skin, muscle
  3. Deep - very poor blood supply; bone, cartilage, joint
31
Q

What types of molecules tend to accumulate in…

total body water? extracellular fluid? blood/plasma? fat? bone?

(examples?)

A
  • TBW - small, water soluble molecules (ethanol, phenytoin, diazepam)
  • ECF - bigger water solubles (gentamycine, tubocurare)
  • blood - large / protein-bound molecules (heparin, insulin, warfarin)
  • fat - highly lipid-soluble (DDT, thiopental)
  • bone - ions (lead, fluoride, tetracyclines)
32
Q

What is the effect of volume of distribution (Vd) on half-life?

A
  • Elimination depends on drug delivery to liver/kidneys via blood
  • A drug with high Vd has a low plasma concentration + thus is not well-delivered to these organs for elimination
33
Q

Through what kind of interactions do plasma proteins bind drugs in the blood?

How many of what kind of molecules can be bound by albumin? What kind of binding takes place + what is the result of this? (Extra: specific drugs involved)

A
  • ionic, van der waals + hydrogen bonding
  • One albumin can bind two acidic molecules
  • Albumin-drug binding is non-specific and thus competitive
    • (NSAIDs displace warfarin; sulfonamides displace bilirubin)
34
Q

How does plasma protein binding affect pharmacokinetics AND -dynamics?

What are the factors affecting the amount of bound drug?

A

Bound drugs are not pharmacologically active + may be metabolized / excreted more slowly.

1) drug concentration, 2) binding affinity and 3) protein concentration affect drug-plasma protein binding.

35
Q

What 3 mechanisms account for the selectivity of the BBB?

A
  1. Functional barrier - tightly-associated endothelial cells w/o slits (allows only non-ionized/lipophilics across)
  2. Efflux pumps - p-glycoprotein pumps out some molecules that would otherwise pass (i.e. loperamide)
  3. Special uptake mechanisms - to transport some ionized endogenous substances in
36
Q

What 3 mechanisms account for selectivity of the placenta / fetus regarding which molecules can pass / enter?

A
  1. Plasma pH - plasma is more acidic in fetus, leading to retention of bases (more base will be in ionized form in fetus)
  2. Tight Endothelium - excludes hydrophilic molecules > 1 KDa
  3. P-glycoprotein
37
Q

What is bioavailability? (from slide)

[How is it determined? (from book)]

A
  • The fraction of unchanged drug which reaches the systemic circulation after administration
    • differs by ROA (IV 100%, IM 75-100%, Oral >5 but <100%, Rectal >30 but <100%, transdermal 80-100%)
  • Determined by comparing the “area under curve” (AUC) of a plasma conc. vs. time graph when administered by the route in question vs. AUC when administered IV
38
Q

What 4 factors influence bioavailability?

(from Lippincott)

A
  1. First Pass Metabolism - hepatic alteration of the drug between its site of absorption and entry into systemic circ.
  2. Solubility - very hydrophilic drugs can’t cross membranes; very lipophilic drugs are insoluble in body fluids + don’t gain access to cell surfaces; mostly lipophilic but partly water soluble drugs are best absorbed
  3. Chemical Stability - drugs degraded by gastric HCl or intestinal enzymes not absorbed well
  4. Drug Formulation/Vehicle - particle size, salt form, crystal polymorphism, enteric coating, binders/dispersing agents (“excipients”)
39
Q

What is first pass metabolism?

Where does it occur? … Give some examples of drugs affected in each location.

A
  • Metabolism of a drug after oral administration before it can reach systemic circulation. Can occur in…
  • Liver - morphine, meperidine, verapamil, propranolol, lidocaine (w/ toxic intermed.)
  • Intestinal Wall - clonazepam + midazolam
  • Stomach - penicillin
  • Digestive Enzymes - polypeptides

Pharmacology (Dustin, Ben) (17 decks)

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