PHARMACODYNAMICS
WHAT DRUG IS DOING W/IN FUNCTIONAL SYSTEM
PHARMACOKINETICS
HOW DRUG GETS METABOLIZED W/IN SYSTEM
PHARMACOLOGY
STUDY OF PRECISE CONTROL OF BIOLOGICAL FUNCTIONS OF EXOGENOUS APPLICATIONS OF CHEMICALS
CENTRAL PRINCIPLE - FUNCTIONAL RELATIONSHIP BETWEEN DRUG CONCENTRATION AND BIOLOGICAL RESPONSE = THE DOSE RESPONSE FUNCTION
LIGAND
BINDS TO A BIOMOLECULE (I.E. PROTEIN RECEPTOR/CHANNEL)
BIOMOLECULE
LIPIDS, CARBOHYDRATES, PROTEINS, NUCLEIC ACIDS (RECEPTORS - BIOMOLECULES THAT INITIATE A BIOLOGICAL FUNCTION WHEN A LIGAND BINDS TO IT)
AGONIST
(TYPE OF LIGAND) STIMULATES A BIOLOGICAL RESPONSE (CAN BE INHIBITORY OR EXCITATORY)
4 MAJOR CATEGORIES OF PROTEIN RECEPTORS
- ) CELL-SURFACE RECEPTORS
- ) TRANSPORTERS AND PUMPS
- ) ENZYMES - CAN INHIBIT OR PROMOTE
- ) KINASES - REGULATE ACTIVITY OF OTHER PROTEINS IN THE CELL
CELL-SURFACE RECEPTORS
(GPCRs, ION CHANNELS) TRANSLATE INFO ON OUTSIDE OF CELL TO BIOLOGICAL MEANINGFUL RESPONSE ON THE INSIDE
TRANSPORTERS AND PUMPS
MOVE IONS/MOLECULES ACROSS MEMBRANES (EFFLUX PUMPS)
*PARTICIPATE IN MAINTAINING THE CHEMICAL GRADIENT AND REUPTAKE NEUROTRANSMITTERS IN CLEFT BACK INTO THE CELL
ENZYMES
CONVERT STARTING MATERIAL INTO NEW USABLE PRODUCTS
KINASES
REGULATE ACTIVITY OF OTHER PROTEINS THROUGHOUT CELL BY PHOSPHORYLATION (REMOVE PHOSPHATE FROM ATP AND RE-LIGATING IT TO A PROTEIN IN NEED)
AFFINITY
ABILITY OF A DRUG TO GET TO A RECEPTOR
AT EQUILIBRIUM (BINDS AND DISASSOCIATES), A SPECIFIC AMOUNT OF DRUG WILL OCCUPY A FIXED PERCENTAGE OF RECEPTORS AT ANY GIVEN MOMENT IN TIME
DRUGS THAT ENGAGE W/ A RECEPTOR FOR > PERIODS OF TIME => > AFFINITY
BASED ON THE 3D STRUCTURE OF MOLECULE AND ITS ABILITY TO BIND TO THE ENZYME/RECEPTOR
(Kd) - DRUG CONCENTRATION AT WHICH 50% OF RECEPTORS ARE OCCUPIED
K2/K1 = Kd (RATE OF DISSOCIATION/RATE OF ASSOCIATION)
DRIVES PHARMACOLOGICAL ACTION - IF DRUG CAN’T GET TO RECEPTOR NOTHING WILL HAPPEN
AGONIST
BIND TO RECEPTORS VIA A WEAK, REVERSIBLE BOND (A + R –> AR –> EFFECT)
EFFICACY -
EFFECT IS COMPLETELY RELATED TO DOSE
RESPONSE TO AGONIST IS NOT ALWAYS LINEARLY PROPORTIONAL TO THE NUMBER OF RECEPTORS OCCUPIED
BOTH EFFICACY AND AFFINITY ARE BASED ON 3D STRUCTURE
EFFECT RESPONSE
SUPERAGONIST/HIGH EFFICACY AGONIST (FEW RECEPTORS OCCUPIED => FULL EFFECT) > PARTIAL AGONIST (100% RECEPTORS OCCUPIED) > ANTAGONISTS (NO INTRINSIC EFFICACY)
ANTAGONISTS
BLOCK RECEPTORS TO PREVENT AGONSTS FROM BINDING
PRODUCE NO EFFECT
BLOCK ACTION OF AGONIST - ONLY HAVE TO BLOCK/ALTER OPENING TO FUNCTION
DOSE RELATED EFFECTS
ANTAGONISTS ARE EITHER COMPETITIVE OR NON-COMPETITIVE
BIND VIA WEAK, REVERSIBLE CHEMICAL BONDS
EC50
EFFECTIVE DRUG CONCENTRATION AT 50% EFFECTIVE = USED TO COMPARE POTENCY
AFFINITY OF PARTIAL AGONIST/FULL AGONIST = SAME; HOWEVER, EFFICACY IS DIFFERENT
HIGH POTENCY = HIGH EFFICACY
NON-COMPETITIVE ANTAGONIST
BIND TO ALTERNATIVE SITE ON RECEPTORS WHICH CHANGES THE 3D SHAPE OF AGONST-BINDING SITE
DIFFERENT PHARMACOLOGICAL RESPONSE THAN COMPETITIVE ANTAGONIST
FULL EFFECT OF AGONIST IS NOT ACHIEVED
AGONIST CONCENTRATION DOES NOT MATTER B/C IT IS NOT COMPETING W/ THE SAME SITE
CAN’T COMPARE THE EC50 OF AGONIST
COMPETITIVE ANTAGONIST
BIND TO THE SAME SITE AS AGONIST
IC50
WHAT CONCENTRATION OF ANTAGONIST => 50% BLOCKADE
PHARMACOKINETICS (ADME)
ABSORPTION - ACHIEVING SIGNIFICANT BLOOD CONCENTRATION OF A DRUG W/ A SPECIFIC ADMINISTRATION
DISTRIBUTION - GETTING DRUG TO THE TARGET
METABOLISM - PROCESSING OF THE DRUG ONCE IN THE BODY
ELIMINATION - GETTING RID OF THE DRUG
DRUG CONCENTRATION AT TARGET DETERMINED BY THESE FACTORS
GRAPHING DRUG CONCENTRATION TO TIME
INCREASED DOSE TO CMAX = ABSORPTION
TMAX = TIME REQUIRED TO REACH MAX BLOOD CONCENTRATION FOR A SPECIFIC DOSE
CMAX = MAX BLOOD CONCENTRATION FOR A SPECIFIC DOSE
T1/2 = HALF LIFE OF A DRUG - IMPORTANT FOR DOSING A DRUG TO MAKE SURE THAT THE BODY ISN’T COMPLETELY DEPLETED OF A DRUG
ADME HELPS W/ DOSING
BIOAVAILABILITY
AMOUNT OF A DRUG AVAILABLE FOR THERAPEUTIC ACTIVITY
IV = 100% > INTRAMUSCULAR > SUBCUTANEOUS > INHALATION > TRANSDERMAL > RECTAL (PARTIALLY BYPASSES 1ST PASS EFFECT (AS DOES IV ADMIN.)) > SUBLINGUAL > SPINAL/BRAIN > ORAL
IM/SC DELIVERY REQUIRES A LIPOPHILIC DRUG => LONG ONSET
IV = 100% JUST MEANS THAT 100% OF THE DRUG IS IN THE BLOOD DOESN’T MEAN AMOUNT AVAILABLE FOR ACTION
ORAL ADMINISTRATION
ORAL = SUBJECT TO 1ST PASS EFFECT WHERE MOST DRUGS GET ABSORBED IN THE STOMACH/SM. INTESTINE
- WHATEVER IS ABSORBED HERE –> LIVER => METABOLIZED DRUGS
- METABOLIZED IN THE LIVER OR LUNGS (CYTOCHROME P450) => MORE HYDROPHILIC METABOLITE (FAVORS EXCRETION)
TRANSDERMAL ADMINISTRATION
TD = GOOD FOR PPL W/ GI ISSUES (DRUG PERMEATES SC LAYER)
LIVER METABOLISM
50% OF ALL DRUGS METABOLIZED BY CYP-3A (DRUG COMBINATIONS CAN EXCITE OR INHIBIT CYP-3A ACTIVITY)
SMOKING INHIBITS CYP-3A ENZYMATIC ABILITY - DOSE OF DRUG DECREASES
DRUG:DRUG INTERACTIONS
FACTORS THAT MODIFY DRUG METABOLISM
GENETIC POLYMORPHISM
DOSE OVERLOAD OF ENZYME CAPACITY
AGE - ENZYME MAKEUP - OLD AND YOUNG AT RISK FOR DRUG METABOLISM ISSUES
DISEASE (DOSE-ADJUSTMENT COMMON) - I.E. LIVER DISEASE, RENAL DISEASE
SEX - M/F SEX DIFFERENCES
SMOKING
DIET - VEGANS HAVE LESS ENZYMES
SPECIAL PROPERTIES OF A DRUG TO PAY ATTENTION TO:
- ) TARGET
- ) WHAT ENZYMES METABOLIZE IT
- ) EXCRETION
ENZYME-INDUCED DRUG
DRUG:DRUG INTERACTION -
WHEN A DRUG IS ONBOARD, METABOLISM OF WHATEVER IS BEING BROKEN DOWN BY PARTICULAR ENZYME WILL INCREASE (CYP2D6)
ASPIRIN = ENZYME-INDUCED (CAUSES AN INCREASE IN METABOLISM OF THE DRUG IN COMBINATION - GRAPE FRUIT JUICE AS WELL)
INCREASED METABOLISM => DECREASED EFFICACY/POTENCY
ENZYME-INHIBITING DRUG
DRUG:DRUG INTERACTION -
WHEN A DRUG IS ONBOARD, METABOLISM OF WHATEVER IS BEING BROKEN DOWN BY PARTICULAR ENZYMES WILL DECREASE (CYP2D6)
INCREASED POTENCY AND POSSIBILITY OF OVERDOSING
POLYMORPHISMS IN LIVER
CAUSE DIFFERENTIATION BETWEEN PEOPLE AND THEIR METABOLISM OF THE SAME DRUG (PHARMACOGENOMICS)
PERSON:DRUG INTERACTIONS
RAPID METABOLIZERS - DECREASED DRUG POTENCY/EFFICACY
SLOW METABOLIZERS - INCREASED DRUG POTENCY/EFFICACY (CAUSES TOXICITY)
DOSE RESPONSE CURVE
CONCENTRATION = EXOGENEOUS FLUID (MG/ML) DOSE = EXOGENEOUS FLUID ADMINISTERED TO A PATIENT (MGML^-1KG^-1)
SHOWS EFFICACY AND AFFINITY
AFFINITY AND POTENCY ARE VERY CLOSELY RELATED
COMPARE DRUGS @ EC50
W/ ADDED ANTAGONIST, AGONIST CURVE WILL SHOW PARALLEL SHIFTS TO THE RIGHT (COMPETITIVE - DOESN’T MATTER FOR NON-COMPETITIVE) - CAN OVERWHELM ANTAGONIST W/ HIGHER CONCENTRATIONS OF AGONIST
W/NON-COMPETITIVE ANTAGONIST - SHIFT = TO THE RIGHT AND DOWN B/C AGONIST CAN NEVER GET TO FULL EFFECT B/C IT CAN’T BIND
NON-SURMOUNTABLE ANTAGONIST
BINDS JUST LIKE THE COMPETITIVE ANTAGONIST AND DOESN’T DISASSOCIATE - SEE THE SAME PATTERN OF ANTAGONISM AS A NON-COMPETITIVE ANTAGONIST
PORTAL SYSTEM
UPPER 1/3 OF INTESTINE SYSTEM THAT ABSORBS THE MEDICINE TO THE LIVER
SOME METABOLISM OCCURS IN LUNGS AS WELL
METABOLITES
WHEN METABOLIZED - PARENT DRUG BREAKS DOWN INTO METABOLITES
LESS POTENT B/C THEY ARE MORE HYDROPHILIC AND THIS PROMOTES EXCRETION
THEY ARE LESS ACTIVE THAN PARENT DRUG - EXCEPT PRO-DRUGS
