Last updated 04/10/00 12:26 PM
Give a drug to effect change for desired outcome( NS, HR, bioelectric process), and effect a pathophysiological process( medical pharm is a reason to treat, diagnose, prevent a fundamental purpose
A drug is a substance that interacts with a biological process, and interact with a receptor molecule, on the cell membrane or in the cell. Drugs are formulated for action and for delivery. Its concidered a ligand which is a substance that interacts with a biological process by fitting into a receptor molecule.
Nutritional substances are drugs which do not undergo rigorous testing
How to get drug to target site solubility(water or lipid) & where receptor is
Solubility concider route if the target isnt in the GI then drug needs to cross gut membrane, so the process involves absorption of drug into the compartment of the body its designed for.
Process of absorption
PHARMACOKINETICS - solubility, absorption, distribution, elimination( metabolism & excretion), active ingredient & formulation such that it augments
WHAT THE BODY DOES TO THE DRUG
PHARMACODYNAMICS - WHAT THE DRUG DOES TO THE BODY
Ligands size- small size increases specificity and distribution
Shape- inc specificity, isomers (levo & dextro) used in racemic mixtures but the inc in the selectivity is in one shape or the other RT where it fits this inc specificity.
Heparin is a big molecule 50K Daltons, and therefore it does not distribute into the intracellular space. Think of heparin vs lovenox.(low molecular weight)
electrical properties( extent of ionization) interactions with, receptor types, facilitate absorption and distribution. There are agonists & antagonists. Competitive antagonists, non competitive antagonist, mass action . Ligands can directly interact with ion on the nicotinic receptors
Receptor specific affect or cascade of effects. There are spare, desensitizing, upregulating, downregulating
Know the classification of drugs, and side effects related to the calsses
Graphs linear, logarithmic, efficacy, potency, response, EC50, Emax, therapeutic goals related to EC50,
Toxicity, potency, rt shift
Integrate text to give us a foundation @ how drugs work, get in. Learn @ concepts and relate them to clinico pharmaco therapeutics
This course is rote memorization. Katzung is good its in the library
FIGURE 2 8 ligands bind to receptor and receptor now interacts with another molecule such as an enzyme( JAK,STAT) Ligand binds to a receptor ΰ cascade pf eventsΰ cellular response IE ach binds to channelΰ channel opens ΰ Na goes into cell ΰ action potential vs NO or steroid enter the cell and then interact via cascade effect ΰ turn on genes and cause its effect (this one is longer lasting and also takes longer to act)
FIGURE 2.6 ligands interact with receptor to activate or inhibit.
Ligands agonist form- binds to receptor and activates a process ΰ direct effect such as opening a Na channel & indirect effect like G protein activatedΰ adenylate cyclase ΰ stimulates c AMP from ATP ΰ acts as a 2nd messanger (amplification)
Antagonist blocker binds to a receptor and blocks or prevents event receptor acitivation
Radio or histo chamicals label ligands and trace where they go.
We need to learn how to look at graphs FIG 1
MI patient beta block and nervous patient overcomes beta blockade via endogenous chatech release
Max response altered with dec # receptors to hook with drug, but EC50 is the same
Efficacy prop to # receptors blocked, but EC50 not affected secondary tp diminished mass action response, spare receptors??????????? Dose dependent . If knock out 20% of the receptors then knock out 20% or the response, this relationship is proportional.
Graded dose response curve looks at biological cells as opposed to a group of study participants.
Agonists stimulate binded receptors Full agonist
Partial agonist stimulates receptors but not as well as FA, see inc HR but not as well as with max response. FIG 6
Agonist if FA or PA depending on its affinity and whether phosphoralation is saturated
Cascade and amplification determine whether agonist is FA or PA see pg 10 CPMRS
O conc partial agonist competes with FA but doesnt elicit full response, but dampens the effect of the FA, check HR in presence of inc conc. Mass action plays a role
Antagonist (blocker), CA usually reversable, NCA usually 1 block, RA reversable, IA irreversable
CA - competes with some binding site as agonist weak bonds and mass action
NA weak bonds, come onn and off. Doesnt compete with some sites as agonists usu irreversable
blocker, covalent bonding means high affinity
Alpha, AR phenoxybenzamide high affinity, not reversable, receptors need to be downgraded
regulated. So NC IB ΰ downgrading so new receptors need to be made.
Inderal is a CA and there is no change in EMAX FIG
Fig 9 B = blocker
Look and compare the NCB it takes away the # of receptors in process and no change in affinity occurs so the EC50 is the same
Dose response curve is good at comparing the different concentrations of drugs.
Therapeutic Index - TI
Quantal response it is or it isnt FIG 2 19 in handout
TI. Potency for individual, check for partial conc graded dose response curve vs. Quantel dose effect, QDE. Potency is graded on DR Curve. QDR curve ~ population and looks at different drugs comparatively.
GDR potency individual drug, selectivity, drug x vs cough supression look at response close to receptors. Max effect yes
QDE potency pop drug drug,
selectivity sense of marker relationship to dose.
Max effect no because one may or may not have a headache at a specific conc
Titration occurs and start woth lower dose 1st this gives some sense of what variability of how
Reasons why drugs ?????????
NC agonist EC50 the same, max response is ½
Can swithc to see what does what antagonist to agonist and visa, check EC50, efficacy, potency, and what changes, what parameters are affected..
PHARMACOKINETICS goal is to get drug to receptors. Most drugs are designed toward specific receptors but exceptions do exist mannitol osmotic diuretic, but it changes osmolarity by pulling water out of bloodΰ urine excr there is an end effect.
Most drugs have affinity for a specific receptor so as to ellicit a specific response ie B2 inc HR and bronchodilates
Absorption is affected by molecule size( usu < 1 KD) , type of transport across the cell membrane(SD, AT, CMT) PCN is via AT thru renal tubules, solubility lipo, hydro
HENDERSON H eq (HA = weak acid)
HA < H+ + A- this is for a weak acid where HA gives up a proton, (becomes charged)
BH+ < H+ + B (the B gives up the H charged part of the molecule, now its not charged)
An acid in > acidic environment is uncharged
A base in > basic environment is uncharged
Get drug across cell membrane, make it uncharged
A charged molecule attracts water because its polar, so give drug which works in blood a charge
Water goes to an acid with a charge A-
Water goes to a base BH+ with a charge
Ionization constants most drugs are weak bases
Most weak acids have low pKa but not tylenol
HA, if pH is lower than pKa , then there is > uncharged molecules, more drug is unionized
If HA is in a > acidic environment, then the pKa is low and > molecules are uncharged, the acid is
The further away the pH is from the Pka there is a higher # of charged molecules present.
PH < pKa ΰ charged
PH > pKa ΰ uncharged & bases end up uncharged
Distribution is influenced by blood flow brain, heart, liver is determined by the
by cap perm (placental or BBB vs kidney or spleen fenestrations/junctions in cap walls)
by plasma protein binding, major ones ( albumin, globulin, lipoprotein, RBCs)
drug reaches target place if free from PP- inc PP binding keeps drug in circulatory system.
PP bound drug has inc ½ life and a changed rate of clearance, there are enzymes in the lung and
blood. Drugs bound to PP are not filtered by the kidney. HA have inc affinity to PP, ASA coumadin
Weak bases have low affinity - ethanol.
Pts with dec albumin need to change dose ie burns and dec albumin CL = clearance
Metabolism = biotransformation changes soluability of parent compound from lipid to aq soluability,so it will be excreted from the kidney. Lipid soluble doesnt get filtered out of kidney so phase 1 and phase 2 reactions are necessary.
Metabolic activity varies precursor-prodrug maintain parent and metabolite ie benzidiazepines, also think of activity.
1st pass after Po through liver. Most biotransformation occurs in the cells microsomes smooth ER lisosomes, mitochondria & change lipids to aq in the microsomes.
Oxidation is via an independent family of enzymes called cytochromeP450 CP450, which exists in all cells mostly in liver, and they are responsible for Ph 1 biotransformation.and also for upregulation & downregulation.
These induce ph 1 -- CYP3A & CYP2B- liver, 60% relevent drugs , genes to them exist
Drug metabolism lipid to keep lipid soluable.
Toxicity usually less with metabolism though exceptions do exist ie: tylenol undergoes ph 1 ΰ toxic
Metabolite ΰ ph 2(glutathione conjugation) ΰ detoxified
If there is too much toxins , there may not be enough enzyme or GSH to get rid of the toxins, & since liver is so involved and has so much CP450 th eliver can become toxic ie tylenol OD.
Gluco upregulates CYP3A and dec enzymes activity for ph 1 biotransformation for metabolites
Side effects every thing causes side effects. o2 oxidizes protein; and water intox can cause death reaking havoc with lytes etc, so everything is toxic toxicity is dose dependent ie water a lot is required to be lethal, and botulism a very small amount is lethal. LD is lethal dose. Understand the distance between the ED & LD. Drugs with a wide TI are safest. Know TI
Toxicity lethal, carcinogenic, tetragenic, mutogenic, so its not so much death but the other variables.
Next time follow drawing HA through organs
Drug A not metabolizedby liver, is freely filtered by kidneys, is a weak acid, pKa of 6.5, if urine ph is 5 what happens to drug. Does it stay in tubulus, get reabsorbed, or get excreted.
Think about precursor of ASA GI why it gets ols where it does, is it metabilized, how is it destroyed and excreted.
Thes renal excretion other poreres.
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