passive/simple diffusion
1)passive diffusion:
-small water soluble compound
depend on compound molecular weight
May pass between cells in some tissues (depending on the barrier)
Small molecules may utilize aquaporin channels (passive diffusion into the hydrophilic pores)
Ex: pores width 8-10 A therefore allows hydrophilic molecules
< 150-200 DA passage
lipid soluble molecule diffusion
2)lipid soluble molecule
Compound must diffuse across bi lipid membrane
- The rate of diffusion depends on…..
A. Drug Concentration
-Rate of permeation increases with drug dose/conc.
-higher dose =higher permeation (linear relationship)
80% of 100 or 1000 molecule (very difference proportion)
B. Pow (how lipid soluble)
-needs to have enough lip solubility
-higher Pow = more easily absorbed in lipids = rapid absorption (linear increase)
-hydrophilic barrier associated with glycocalyx disrupt the phenomenon (Cut off phenomenon)
C. degree of ionization (how much is charged)
important for weakly acidic and weakly basic drugs
* Extent of ionization depends on the drug’s pKa and the pH of the medium (stomach vs small intestine)
* Only unionized (uncharged) drug can permeate
Lipid membranes
Examples:
-Caffeine(charge in both environment, less charge in basic)
-Morphine (little charge in the basic environment compared to acid, that is why it has higher absorption)
What does the ionized charge molecule do?
Wait to get change to an unionized/uncharged state (still floating around)
D. surface area of membrane
More surface area = more diffusion
Ex: small intestine surface area → most drugs are absorbed quickly regardless of their ionization (faster rate of absorption = faster rate of action)
-rate of absorption related to rate of emptying
Ethanol → absorbed a lot more in 10 minutes from the small intestine (since it has a larger surface area), compared to absorption in the stomach(lesser surface area)–> that is why we should not drink alcohol in an empty stomach because it could be quickly moved out of the stomach unabsorbed to the small intestine where is quickly absorb and we get drunk
E.*Size = doesn’t really play a part in lipophilic small molecule ( unless it is very large)
facilitated diffusion (ex: OAT-2 receptor)
suitable for “larger drug”
-NOT energy dependent
* Can transfer molecules in either direction down the conc. gradient
− Amino acids into brain
− Bile salts into liver
− Nucleotide analogs or anti-metabolites
Initially: the more drug you add, the faster the transport rate rises since transporters are still empty(more than enough transporters) →increase rate of absorption
As you increase concentration/dose:
V max (max.velocity) is reached, adding more drug will not increase rate of absorption since every available transporter is occupied and saturated
-Transport proteins:
May be primary, secondary transport or facilitated
* Can increase drug absorption & distribution
* Transport in either direction
→ Uptake(in) Transporters:
e.g., organic anions(OAT), organic cations(OCT), dipeptides, nucleosides, monocarboxylates…
→ Efflux (out) Transporters:
e.g., MDR family of ABC proteins
→P-glycoprotein (primary active transport)
transcytosis ( endo and exocytosis)
For VERY LARGE drug more than >1000 Da
Drug bind to protein outside of the cell and gets endocytose from lumen and gets exocytose to interstitial fluid
drug distribution
-plasma protein-drug binding complex :
Plasma protein binding to drug (drug-protein complex)
*Drugs within intravascular fluid (blood zone) volume can bind to plasma proteins…
* Drug may reversibly associate with protein constituents through noncovalent interaction (easily reversible)
* alpha1- acid glycoprotein, albumin, and lipoproteins
– Albumin(plasma protein) often accounts for most drug binding
– Generally more binding to acidic drugs
* *plasma protein-bound drug cannot permeate (move through) biological barrier → plasma protein-bound molecules confined to vasculature (vascular system) = amount of drug distributed out of plasma depend on if it is plasma protein bound or not
-tissue binding:
Tissue binding to drug
Drugs may preferentially localize to certain tissues because….
– Tissue-specific binding sites can retain drug in that
tissue
– Highly lipid soluble drugs can localize and accumulate
in adipose tissue(pesticide, anesthetize)
– Results in an uneven distribution of drug in the body
* Drug concentration is higher at the tissue of localization than in fluid compartments (e.g. plasma)
– Drug is retained in the body for longer periods of time
total body of water component
Total body of water (TBW)
=The total water content of the body
(intracellular in cell and extracellular plasma blood +interstitial fluid)
– ~60% of the individual’s body weight (42 L in a 70 kg individual) but can vary
intracellular fluid (ICF)=
The water content in all cells in the body
– ~40-44% of total body weight in cell (28 L in 70 kg person)
* Compounds must be able to permeate cell membranes
to distribute to ICF
– Essential for drugs that work on intracellular targets
Extracellular fluid(ECF):
Water content outside of cells…
– Intravascular fluid (blood) + interstitial fluid (bathing cells)
– 16-20% of total body weight (~4% plasma, 12-16% ISF)
(*faster distribution→ since it does not have to cross membrane into cell) – many act on cell surface receptors
→ onset of action faster if the drug
acts on cell surface than if the site of action is within cells
A) intravascular fluid volume: whole blood is composed of blood cells suspended in plasma -for very large hydrophilic or plasma-protein bound drug
- Plasma
– Water (>90%),
-proteins, clotting factors, glucose, lipids…
– Serum is plasma without clotting factors - Form element(Hematocrit) – % packed erythrocytes (red blood cells)
→* larger hematocrit (red blood cell) → smaller plasma amount→less distribution + absorption of drug – Can vary 37-52%
total body of water effecting factors
Sources of variability:
– Body composition (obese = more adipose fat tissue→less total body of water→ required more highly lipid soluble drug vs. lean individuals→ more muscle mass= more total body of water→ required more lipophobic/hydrophilic drug)
– Age (children(more lean) vs. adults vs. elderly (less lean→more adipose→decrease total body of water ))
– Gender
-women (more adipose tissue → less muscle → less water→less fluid to diffuse drug and alcohol)
- Small molecules like ethanol and some antibiotics, with
no significant protein binding or tissue accumulation,
equilibrate with TBW
volume of distribution(Vd)
actual type
apparent type
actual type Vd
Anatomical volume accessible to the drug (charged molecule) → 1:1
→ physical fluid compartments in human body (liters/70 kg man)
Plasma= 3-4 liters
ECF= 14 liters
TBW= 42 liters
Tissue = >42 Liters
*If a drug stays/distributed strictly within the blood (like large proteins or drugs bound heavily to albumin), its volume of distribution will match the actual volume of the plasma (Vd =3 L).
apparent type Vd
The hypothetical volume of plasma into which the drug appears to distribute(drug found in blood plasma vs other part of the body) –>Cannot be used to calculate exact anatomical volume
– Calculated following IV injection of known compounds using:
(volume of distribution) Vd = initial drug dose/plasma conc. drug dose (Co)
Conc. = mass/volume
– Vd (volume of distribution)= mL, L or mL/Kg, L/Kg
– Dose = g , mg, μg(microgram), ng…
– C0 = g ,mg ,μg or, ng / mL or L
Cannot be used to calculate exact anatomical/actual volume
1) Drug distributed in total body water: Drug found everywhere(TBW)
–> very high volume of distribution(Vd), very low in intravascular (plasma conc.)
2) drug distribute and bind to tissue only:
Drug found in tissue , very low in intravascular (plasma conc.) → indicate large volume of distribution (Vd)
3) Drug that distributes to extracellular fluid only (intravascular + interstitial fluid) :
-drug distributed to only ECF, a bit higher in plasma conc. —> lower volume of distribution(Vd)
4) Drug that distribute to plasma only: -
drug only distributed in plasma, very very low volume of distribution(Vd)
importance of Vd
Vd is not a physiological /anatomical/ actual volume but reflects the extent of drug distribution in the body
− To what extent the drug stays in the plasma as opposed to distributing to other areas in the body
Extent of distribution affects half life of drug:
− The larger the Vd the lower the fraction of drug located in the vasculature(plasma) that can be presented and absorb to eliminate organs(kidney and liver) → longer half life of drug :)
Vd does NOT provide information on:
− Drug’s mechanism of action(how well drug binds to target)
− If the drug is effective or not
- Knowing the Vd of a drug allows us to calculate
the dose required to achieve a desired plasma
concentration
factors of drugs that effect Vd value
Drug total volume distribution will depend on the drug’s…
A) -ionization:
-Unionized and sufficiently lipid soluble drugs readily permeate biological membranes→move out → ↑ Vd (distribution)
− Although most drugs will distribute out of the vascular
compartment and equilibrate with ISF(interstitial fluid), passage into cells (intracellular fluid) ICF is highly dependent on lipid solubility
− For weakly acidic and basic drugs, the pKa of the drug and the pH of the medium determine the degree of ionization and thus the ability to permeate membranes.
-Drug trapping may occur in some compartments
* Highly lipophilic drugs can distribute and accumulate in adipose tissue (happens slowly)→ ↑ Vd(high distribution)
-but Low blood flow to fat – long time to equilibrate with plasma drug concentration, long time to be removed
− Important site of storage (‘reservoir’) after prolonged exposure to highly lipophilic drugs − Ex. DDT
B) -Size:
Particularly important for hydrophilic compounds
– Only very small hydrophilic molecules can permeate
cell membranes by passive diffusion (via aquaporins)
and thus have relatively large Vd (volume of distribution)
– Large hydrophilic molecules generally have lower ↓Vd → may be confined to ECF or just intravasculature if very large (cannot cross through membrane)
– Ex. Heparin, insulin – too large to cross capillary wall
C)- Plasma tissue and protein binding:
Bound drugs are retained where they are bound
– Extensive binding to plasma proteins (in plasma) with low tissue binding/lipid distribution → low ↓Vd distribution
* Ex. Warfarin - 97-99% bound, Vd = 0.08 L/Kg
– Extensive binding to tissue/cellular proteins(outside plasma blood) → high ↑ Vd distribution
* Ex. Digoxin - muscle proteins (skeletal and cardiac)
- NOTE: Binding is reversible – free drug can permeate
membranes and distribute throughout the body
D) Drug transporter :
-Transporters may affect distribution of drugs to
specific organs and tissues
– Contribute to selective distribution of drugs and
accumulation in certain tissues expressing
Transporters
– Ex. Pravastatin – taken up by liver via active
Transport
- Effect on Vd depends on the tissue, whether
efflux or influx transporter, and localization of
transporters
