Principles Of Drug Therapy 2

Question 1

Abs w/ drug IV?

Answer 1

Absorption is bypassed

Question 2

How can a drug be abs and enter cells?

Answer 2

Since they’re not natural metabolites and have no carriers, must be soluble in water and fat (have fave partition coefficient)

Question 3

What’s partition coefficient?

Answer 3

[drug]oil/[drug]water

Question 4

Classes of most drugs?

Answer 4

Neutral and uncharged
Weak acids and bases
Salts of strong acids and bases

Question 5

What does the PC depend on?

Answer 5

C# and OH

Question 6

Weak acids and bases?

Answer 6

Can donate or accept H reversibly

Weak = both ionized and unionized forms of drug are present in equilibrium in aq solution

Question 7

Ka?

Answer 7

= base x H/ acid

B/A depends on pH and pK

Question 8

Salicylic acid? Diphenhydramine?

Answer 8

Typical weak acid drug

At pH 7, B:A = 10,000:1

Weak base
1:100

Question 9

Strong A and Bs?

Answer 9

Anions of acids

Cations of bases

Question 10

How do drugs w/ mult weak acids and bases act?

Answer 10

Like strong ones cuz the conc of uncharged species is negligible

Question 11

Ipratroprium?

Answer 11

Quarternary ammonium
Has + charge, no H to be removed
Atropine at pH 7, b:a, 1:500

Question 12

How are drugs transported?

Answer 12

Bilayer diffusion
Pores
Active or passive trans

Question 13

How to diffuse?

Answer 13

Fave PC, uncharged

So that there’s: Abs from GI, enter cells (intracell receptor), entering CNS (receptor in BBB)

Question 14

Passive diffusion?

Answer 14

Driven by conc gradient across membrane

Spontaneous downhill, dissipates the gradient

Question 15

Salicylic acid and Diphenhydramine in transporting a weak base?

Answer 15

They exist as 2 forms;

Acid: charged
Base: uncharged

Rate of trans depends on conc of base

W/ trans of weak acid, “” of acid

Question 16

What happens if ph isn’t same on each side of membrane?

Answer 16

Cation accumulates on side with lower pH

Question 17

What is ion trapping?

Answer 17

Diff in conc of weak A and Bs between blood and diff compartments cuz of pH diff

Question 18

What allows pore transport?

Where are pores?

Answer 18

Hydrostatic pressure gradient

Pores are in capillaries and glom

Question 19

Pores essential for?

Answer 19

Trans of quart amm drugs (succinylcholine)
-water soluble, charged

ONLY SIZE restricts

Most important way for most drugs to get into tissues

NOT IN BBB!

Question 20

How is heparin transported?

Answer 20

It’s too big, so limited to the plasma

Question 21

What limits rate of entry of drug into most tissues?

Answer 21

Blood flow!

Question 22

Pores and liver sinusoids?

Answer 22

Large regulated pores: fenestrae
No basement membrane
No barrier to proteins like albumin

Question 23

Features of drug active transport?

Answer 23

Couples trans to chem rxn or to trans of another species using cell E to drive transport

Can generate a gradient

Transported species:
-charged bases, anions of acids, fixed charge
-permanently charged quart drugs
Drugs with same charge can compete

Question 24

Transport proteins are used to?

Answer 24

Couple the input of E to drug mvmt

Only in cells that have the required transport proteins

Question 25

Key mechanisms of active trans?

Answer 25

NaKATPase in mem - Na in, K out gradients across mem - along w/ K channels: positive outside electrical mem potential These gradients drive drug transport

Question 26

What's the role of transporters if drugs only need good PC to enter?

Answer 26

To protect against xenobiotics Transporters in liver, kidney and intestine epithelia: roles in abs and elim Some in other tissues (brain, placenta, testis) can also limit distribution

Question 27

Features of most drug and xeno transporters? Locations?

Answer 27

From SLC (315 in 48 fam) and ABC (49 in 7) families Broad substrate selectivity, trans of many xeno *drug interactions PT of nephron (excretion) Hepatocytes, GI -into cells: biotransformation -out of cells: bile or blood Vasc endo in brain, Choroid plexus (barrier between blood and CSF), etc -protects tissue by pumping drugs out, limiting distribution and minimizing harm -problem when drug needs to get into brain

Question 28

Rate of abs depends on? Major sites?

Answer 28

Thickness of barrier How well site is perfused Area of surface exposed to drug GI, lungs, skin, injection sites

Question 29

How drugs are abs from GI?

Answer 29

Passive non ionic diffusion through epi cell mem Neutral drugs: abs rate dependent on PC Weak A+B: "" PC, pH, pK in GI Fixed charge drugs: poorly absorbed

Question 30

What can be abs from stomach?

Answer 30

Weak acids | Weak bases CANT b/c conc on uncharged base is low

Question 31

Abs from SI?

Answer 31

Almost all drugs taken orally cuz of its large surface area

Question 32

How are drugs abs from GI moved?

Answer 32

To liver via hepatic portal vein b4 entering systemic circulation; GI transporters

Question 33

First pass effect?

Answer 33

Metabolism of oral drug by liver and GI before reaching systemic circ Nitroglycerin, morphine, etc Drugs with high first pass met are given another route

Question 34

What's bioavailability?

Answer 34

When the unmet drug goes into sys circ = (100-x-y-z)%

Question 35

Why might oral bioavailability be <100%?

Answer 35

Abs less than 100%, low PC or P-gp transport Metabolism in GI or liver b4

Question 36

Drug with 0% bioavailability?

Answer 36

Useful if the metabolite is the active agent

Question 37

Other routes to avoid liver?

Answer 37

Sublingual (all of drug to sys), rectal (50% of drug to sys b4 liver, incomplete abs)

Question 38

Major routes of parenteral admin?

Answer 38

IV, IM, SC, topical

Question 39

Pros and cons of IV?

Answer 39

Pros: Fast, no abs! Control over blood conc ``` Cons: Blood conc can rise quickly Adv effects Drug must be in aq solution Can't be reversed!! ```

Question 40

Pros and cons of IM?

Answer 40

Abs via cap pores or lymph for larger, depends on blood flow and fat content Pros: Varied abs rate (fast from aq) Slow but sustained abs of poorly water soluble drugs Cons: Painful Avoid w/ anticoagulants

Question 41

Pros and cons of SC?

Answer 41

Abs via cap pores or lymph for larger, depends on blood flow and fat content Pros: Varied abs rate (fast from aq) Slower for insoluble -- sustained effect Solid pellets insertion for long term release Cons: Can't be used with drugs that irritate the tissue

Question 42

Features of tropical and transdermal drugs?

Answer 42

Local effect, minimize sys exposure Patches: Slow continuous sys supply of drug Need to be potent and have fave PC to be abs thru skin Inflamm skin increases abs Site of admin is important: ventral forearm has 1% abs

Question 43

What does distribution rate depend on?

Answer 43

Perm of cap Blood flow to tissues Drugs reach peak conc in organs with most blood, quickly

Question 44

What's volume of distribution?

Answer 44

The apparent volume of a drug after it's been abs and distributed =(f)(Xadm)/[X]blood Vol/kg May not correspond to a real volume if drug conc is diff in each tissue

Question 45

Whats Vd?

Answer 45

Relationship between the amount of drug in the body and the plasma drug conc Dose x f = desired [X]blood x Vd

Question 46

What determines a drug's Vd?

Answer 46

Ability to leave blood -drug properties -plasma protein binding keeps more in blood -if all drug is in blood, Vd = blood vol Ability to enter cells Extra vascular drug reservoirs and storage -protein binding in xtravasc tissues -if drug leaves blood, Vd rises above blood vol -if 0% drug in blood, Vd to infinity

Question 47

Plasma protein binding features?

Answer 47

Acidic drugs bind to albumin in blood, basic to alpha 1 acid glycoprotein As free drug disappears, more drug dissc from protein protein binding buffers free drug conc

Question 48

Drug distribution to the BBB?

Answer 48

- Tight junctions in brain - Capillaries surrounded by glial cells, not ECF - endothelial cells have transporters (p-glycoprotein) that actively pump drug out) Drugs enter CNS thru passive non ionic diff across 4 bilayers, need good PC Chemoreceptor trigger zone and hypothalamus lack the barrier

Question 49

Placental distribution?

Answer 49

No pores Fail to cross: large, mult charged with low lipid solubility Lipophilic with good PC enter by simple passive diff P-glycoprotein to export drugs Fetal blood more acidic at 7.2

Question 50

Distribution to other organs?

Answer 50

``` Testes and prostrate: Sertoli cells: -tight junctions -transporters -No pores ``` Joints/synovial fluid: -no pores unless joint is inflamed Lungs: -large cap surf area

Question 51

How do drugs get into secreted fluids?

Answer 51

Passive non ionic diffusion

Question 52

What's ion trapping?

Answer 52

When pH of secreted fluids differs from that of plasma

Question 53

What factors affect plasma protein binding?

Answer 53

Drug interaction, disease, age

Question 54

Drug storage?

Answer 54

Plasma protein binding Tissue accumulation w/ slow release (drugs w/ aff for Ca or phosphate acc in bone or teeth: tetracycline antibiotics and heavy metals)