A3: Pharmacokinetics, pt. 1

Question 1

What is pharmacokinetics?

Its 4 main parts?

Answer 1

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

Absorption, Distribution, Metabolism, Excretion

(ADME)

Question 2

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

4 things

Answer 2

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

RDFD

Question 3

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

Answer 3

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

Question 4

What kind of molecules tend to undergo aqueous diffusion?

(And through what spaces do these molecules diffuse?)

Answer 4

molecules that are small (< 0.4 nm) and ionized

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

Question 5

What are the determinants of lipid diffusion?

Answer 5

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

Question 6

What general kind of molecules are lipid soluble?

(What is one exception to this?)

Answer 6

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

Question 7

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

And the general characteristics of CMT? (3)

Answer 7

Facilitated diffusion and active transport are…

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

Question 8

What kind of molecules undergo carrier-mediated transport?

(examples? 3)

Answer 8

large endogenous molecules, non-lipid soluble molecules and xenobiotics

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

Question 9

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

Answer 9

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)

Question 10

What is the general role of ABC transporters?

3 examples of them?

Answer 10

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

Question 11

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

(extra: examples of drugs blocked by it)

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

2 examples of sub-families?

Answer 13

Uptake (“influx”) of small molecules into cells

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

Question 14

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

how do these 2 carrier superfamilies facilitate hepatocyte function?

Answer 14

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

Question 15

What kind of drugs / biomolecules undergo endocytosis and exocytosis?

Answer 15

• 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

Question 16

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?

Answer 16

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)

Question 17

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)?

Answer 17

• 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

Question 18

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)

Answer 18

• 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)

Question 19

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)

Answer 19

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

Question 20

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)

Answer 20

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

Question 21

What are the types of oral / enteral administration?

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

Answer 21

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

Question 22

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)

Answer 22

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

Question 23

What are the 3 main types of parenteral administration?

What are the advantages (3)?

Answer 23

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

Question 24

What are the advantages and disadvantages of IV administration?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

Aside from oral and parenteral administration... what are the other routes of administration?

Answer 26

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.

Question 27

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

Answer 27

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

Question 28

What is **volume of distribution** (**Vd**) in pharmacokinetics?

Answer 28

* 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 / [drug_plasma]** * 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

Question 29

What is the use for Vd in pharmacokinetics? What does a Vd of below 5 L indicate? And one higher than that?

Answer 29

* 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)

Question 30

In studying drug distribution pharmacokinetics... how can the body compartments be divided by their relative **perfusion**?

Answer 30

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

Question 31

What types of molecules tend to accumulate in... total body water? extracellular fluid? blood/plasma? fat? bone? (examples?)

Answer 31

* _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)

Question 32

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

Answer 32

* 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

Question 33

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)

Answer 33

* 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)

Question 34

How does plasma protein binding affect pharmacokinetics AND -dynamics? What are the factors affecting the amount of bound drug?

Answer 34

Bound drugs are not pharmacologically active + may be metabolized / excreted more slowly. ## Footnote **1) drug concentration**, **2) binding affinity** and **3) protein concentration** affect drug-plasma protein binding.

Question 35

What 3 mechanisms account for the selectivity of the BBB?

Answer 35

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

Question 36

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

Answer 36

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**

Question 37

What is **bioavailability**? (from slide) [How is it determined? (from book)]

Answer 37

* 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

Question 38

What 4 factors influence bioavailability? (from Lippincott)

Answer 38

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")

Question 39

What is **first pass metabolism**? Where does it occur? ... Give some examples of drugs affected in each location.

Answer 39

* 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