Martin Gen Pharm Flashcards
Pharmcodynamics
the study of drug effects and their mechanism of action.
The study of what drugs do to you.
Pharmacokinetics
quantitative descriptions of the time course of drug and drug metabolite concentrations in the plasma, tissues, or urine.
Drug fate or what you do to the drug.
Actions vs Effects
Drug action: molecular mechanism of action
Drug effect:
- desired therapeutic effect
- undesired side effect
Effect is usually known
Action may or may not be known
Effect is observable; action is not
Routes of administration: Enteral
means via the gastrointestinal tract
Oral
Sublingual
Rectal
Routes of administration: Parenteral
often taken to mean injected but also includes other non-oral routes
SQ, IM, IV, inhalation, intranasal, intraarticular, etc.
Sublingual Administration
warm, moist, high blood flow
rapid absorption, ** no first pass effect **
unpleasant taste
Example: nitroglycerin
Oral Administration- barriers, variations, best place of absorption
(per os, PO)
Barriers to oral absorption:
Drug must first dissolve and be free in solution
– Variations – compare drug already dissolved in water, to dry powder, to a soft tablet, to a hard tablet, to a capsule, to a capsule with slow-dissolving capsule, etc.
Most drugs - absorption from stomach less than from small intestine
Large surface area of small intestine
Two barriers for drug to cross
- epithelial cells
- capillary wall
Oral administration absorption patterns affected by…
highly variable among patients
gastric and intestinal pH
gastric emptying time
presence or absence of food
co-administration of other drugs
Oral administration: advantages
By far the most used route of administration
convenient
Safe, drug recall is possible (emesis or lavage)
Inexpensive
Oral administration disadvantages
Slow absorption
Highly variable between patient
Highly variable at different times in same patient
Some drugs inactivated by acid, enzymes, or bacteria
First-pass metabolism by liver
Requires conscious, cooperative patient
G.I. irritation can occur
Intravenous Injection: advantages
No barriers to absorption
Rapid onset and subsequent control of drug concentration is possible
Unsuitable for non-aqueous solutions, drug must be soluble
Large fluid volumes are possible
IV injection: disadvantages
High cost compared to oral
Difficult - must have trained personnel
Inconvenient - in-patient only! (usually)
Irreversible - no recall, better get it right!
Infections, embolism possible
Subcutanteous Injection key points
Lower blood flow in SQ region leads to slower drug absorption
Slower absorption allows for sustained action
Allows injections of drugs poorly soluble in water
Drawbacks include discomfort, inconvenience, potential for injury
Example: insulin for diabetes, epinephrine for anaphylaxis
Intramuscular Injection key points
Fairly rapid absorption of water soluble drugs
Time course of absorption dictated by water solubility of drug and blood flow to the site
Allows injection of depot preparations
example - benzathine penicillin G
Painful, inconvenient
Possible hematoma
Factors Affecting Rate and Extent of Drug Absorption
Rate of drug dissolution Concentration gradient Blood flow Size of the absorbing surface Lipid Solubility pH, drug charge, & polarity Condition of the absorbing surface
Drug distribution
site of adminstration –> plasma –> interstitial space -> intracellular space
Drug redistribution
intracellular space–> interstitial space –> plasma
volume of Distribution (Vd)
hypothetical volume of fluid in which the drug is distributed
Body Fluid Compartments
Plasma compartment
Extracellular fluid
Total body water
Some reasons for uneven distribution of drugs
Adipose tissue (fat) and lipid solubility
Protein binding
Tissue binding sites
Blood-Brain Barrier
Endothelial cells of the CNS capillaries have tight junctions, no fenestrations
Lipid soluble drugs can diffuse across endothelial cells and basement membrane
Water soluble drugs cannot readily diffuse across BBB
Some drugs enter CNS via active transport processes
structure of endothelial cells in the liver
large fenestrations allow drugs to exchange freely between blood and insterstitium in the liver
Drug biotransormation
Parent drug –> enzyme-mediated biotransformation –> drug metabolites
Body’s basic strategy for drug elimination:
make the parent drug more water soluble so that is can be more easily excreted by the kidneys
Drug elimination processes
Hepatic metabolism
- Phase I and Phase II (conjugation reactions)
- Biliary secretion (in stools)
Renal elimination (in urine)
Minor routes - breath, sweat, tears, etc.
Phase 1 reactions
especially Cytochrome P450
genetic variation in Cyto P450 as a reason for patient variability in response or susceptibility to adverse side effects
Phase II reactions
conjugation, for example
Properties of Plasma Membranes re: drugs
Phospholipid bilayer provides a hydrophobic barrier between two aqueous environments.
Cell membranes do not have pores. Drugs cannot “filter” through membranes, they must diffuse through the phospholipid bilayer.
Passive Diffusion and major factors influencing it
Absorption and penetration into cells is mainly by passive diffusion.
The rate of passive diffusion varies directly with the concentration gradient.
Major factors influencing it:
- concentration gradient
- blood flow
- size
- charge (pH of environment)
- polarity
- lipid/ water solubility
Blood Flow
Blood flow is a major factor affecting the concentration gradient of drug throughout the body.
Higher local blood flow maintains steeper concentration gradients and, therefore, faster rates of drug movement from one compartment into another.
drug size
compare insulin MW = 6000 to l-dopa MW =197
lipid: water partition coefficient
the ratio of solubility in oils vs water
Lipid/water partition coefficient is a means for expressing whether a drug is more lipid soluble or more water soluble.
- Drug is mixed with a solution of oil and water, which then separates into two phases.
- The proportion of the drug in the oil and in the water phases is measured; the result is expressed as a ratio.
Example: Total Drug = 100 units Drug in lipid phase = 80 units Drug in water phase = 20 units Lipid/water = 80/20 = 4 This is a highly lipid soluble drug that will be rapidly and completely absorbed.
Water Soluble Drugs
Drugs that are charged and/or highly polar are more soluble in water.
Drugs readily soluble in water are said to be hydrophilic (“water liking”).
Hydrophilic drugs are repelled by the hydrophobic barrier of cell membranes.
Therefore, the extent of passive diffusion for hydrophilic drugs is limited.
Hydrophilic drugs are poorly & slowly absorbed but rapidly excreted in urine
Lipid Soluble Drugs
Drugs that are more soluble in lipid are said to be lipophilic or hydrophobic (“water hating”).
Lipophilic drugs more easily pass through membranes by passive diffusion are rapidly and more completely absorbed but only slowly eliminated in urine.
Drug Charge: Ionization
Most drugs are weak acids or weak bases. They exist in solution in both an uncharged (unionized) form and in a charged (ionized) form.
The concentration of charged and uncharged forms of a drug are determined by the pKa of the drug and the solution pH.
Henderson-Hasselbach Equation
pH = pKa + log ([A-] / [HA]) acids pH = pKa + log ([R3N] /[R3NH+]) bases
HA [H+] + [A-]
R3NH+ [H+] + [R3N]
Note that the effect of changes in pH on ionization is opposite for acids and bases
Effect of changes in pH
as pH goes down, [H+} goes up
Quaternary salts
neostigmine, for example
NR3H+
A reversible binding site for H+ ions on the nitrogen. Each R can be any other atom or group of atoms.
NR4+
The Rs are not hydrogen ions, and so cannot dissociate. This drug is a fixed ion: a quaternary salt. Such a drug crosses membranes very poorly (essentially no passive diffusion). Poorly absorbed from GI or lungs; if given IV, is rapidly eliminated in urine.
Protein Binding of Drugs
Many drugs are bound to plasma proteins.
Albumin is the principal binding protein in plasma.
The extent and affinity of drug-protein binding differs widely.
Total drug distribution is affected by protein binding.
Only free (unbound) drug can passively diffuse across cell membranes. **
Lipid soluble hormones have their own specific carrier proteins. Examples are thyroid hormone and steroid hormones; only free hormone (drug) is active.
Protein binding can affect loading dose and other pharmacokinetic decisions.
Bound drug can serve as a reservoir or buffer for free drug. **
Glomerular filtration and renal excretion are affected since bound drug is not filtered.
protein binding and drug interactions
Drug-drug interactions may result from the displacement of drugs competing for binding sites on plasma proteins.
The potential for clinically significant interactions is greatest when the displaced drug is highly protein bound, has a limited volume of distribution, is slowly eliminated, and has a low therapeutic index.
Fat Depots
Highly lipid soluble drugs become concentrated in fat cells and to a lesser extent in brain.
Drug “stored” in fatty tissues will redistribute drug back to the plasma as the concentration gradients change.
Redistribution
Clinically significant redistribution accounts for rapid offset of drug effects. The phenomenon is most frequently seen when the following conditions are met:
the drug is highly lipid soluble
It is given i.v. (absorption is very rapid)
target is a high cardiac output organ (e.g. CNS)
depot preparation
a special version of a drug that’s not as soluble in water, can be given as an injection that will release slowly for a long time
pH affects a drug’s distribution how?
the uncharged version can cross the plasma membrane
as pH changes, more or less of the uncharged drug is present and therefore can cross the cell membrane
