INTRO TO PHARMACOKINETICS AND PHARMACODYNAMICS Flashcards
WHAT IS CLINICAL PHARMACOLOGY?
THE SCIENCE OF DRUGS (MOLECULES THAT HAVE A PHYSIOLOGICAL EFFECT WHEN INGESTED OR OTHERWISE INTRODUCED INTO THE BODY) AND THEIR USE IN HUMANS
BIOAVAILABILITY?
THE PROPORTION OF ADMINISTERED DRUG WHICH REACHES THE SYSTEMIC CIRCULATION UNCHANGED AND IS THUS AVAILABLE FOR DISTRIBUTION TO THE SITE OF ACTION
WHAT TYPE OF DRUG ADMINISTRATION ACHIEVES 100% BIOAVAILABILITY AND WHAT KIND OF EFFECTS DOES IT HAVE?
INTRAVENOUS INJECTION
- ALL OF THE DRUG REACHES THE SYSTEMIC CIRCULATION UNCHANGED
- VERY RAPID AND POWERFUL ACTION
- INCONVENIENT FOR LONG-TERM THERAPY; EXPERIENCED HCP SKILL NEEDED
CHARACTERISTICS OF ORAL ROUTE OF DRUG ADMINISTRATION?
- VERY COMMON, OFTEN SAFEST AND MOST CONVENIENT AND ECONOMICAL
- ALWAYS LESS THAN 100% BIOAVAILABILITY ACHIEVED
- EXPOSURES TO pH, ENZYMES AND MICROBIAL ACTIVITY IN THE GUT
- EXPOSURE TO FIRST PASS METABOLISM
- ABSORPTION DEPENDS ON RATES OF GI TRANSIT
- REQUIRES PATIENT COMPLIANCE
CHARACTERISTICS OF MUCOSAL ROUTES OF DRUG ADMINISTRATION?
CAN BE:
- SUBLINGUAL
- BUCCAL
- NASAL
- EYE
- VAGINAL
- RECTAL
- ACHIEVES RAPID TRANSIT TO SYSTEMIC CIRCULATION
- AVOIDS FIRST PASS METABOLISM
- DRUG STABILITY (E.G. pH IN THE MOUTH IS NEUTRAL COMPARED TO ACIDIC IN THE STOMACH)
CHARACTERISTICS OF INHALATION ROUTE OF DRUG ADMINISTRATION?
- AEROSOLS; E.G. FOR AIRWAY DISEASE
- LIPID SOLUBLE ANAESTHETICS; RAPID ABSORPTION
- AVOIDS FIRTS PAS METABOLISM
CHARACTERISTICS OF TRANSDERMAL ROUTES OF DRUG ADMINISTRATION?
- OUTER SKIN LAYER INFLUENCES RATE OF ABSORPTION
- LOW INPUT RATES CAN AID LONGTERM USE
- E.G. HORMONE REPLACEMENT THERAPY (E.G. ESTROGEN OR PROGESTERONE PATCHES)
CHARACTERISTICS OF SUBCUTANEOUS INJECTION ROUTE OF DRUG ADMINISTRATION?
- CONSISTENT ABSORPTION FROM SMALL VOLUMES (E.G. INSULIN, FOR WHICH ORAL ROUTE WOULD BE INAPPROPRIATE DUE TO INSULIN DEGRADATION IN STOMACH AND GI TRACT)
- PASSIVE DIFFUSION INTO THE BLOODSTREAM OCCURS VIA ABSORPTION ACROSS CAPILLARY WALLS
CHARACTERISTICS OF INTRAMUSCULAR INJECTION ROUTE OF DRUG ADMINISTRATION?
- LARGE BLOOD FLOW IN MUSCLES OF UPPER ARM
- ROUTE IS RELIABLE AND SUITABLE FOR IRRITANT DRUGS
- GOOD FOR DEPOT PREPARATIONS (LONG LASTING)
- RAPID ABSORPTION AND GOOD FOR LARGER VOLUMES COMPRED TO SUBCUTANEOUS INJECTIONS
- ABSORPTION CAN BE PERFUSION LIMITED (INCREASED WITH EXERCISE VIA RAISED BLOOD FLOW)
- E.G. ANTIPSYCHOTIC DRUGS
PHARMACOKINETICS?
STUDY OF DRUG MOVEMENT WITHIN THE BODY (WHAT THE BODY DOES TO A DRUG)
PHARMACODYNAMICS?
STUDY OF DRUG EFFECTS ND MECHANISMS OF ACTION (WHAT THE DRUG DOES TO THE BODY)
THE 4 PHASES OF PHARMACOKINETICS
ACRONYM: ADME
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
DESCRIBE THE ABSORPTION PHASE OF PHARMOKINETICS
FOR AN ORALLY-ADMINISTERED DRUG MOLECULE TO REACH THE SYSTEMIC ARTERIAL CIRCULATION INTACT, THE DRUG MUST:
- BE ABLE TO CROSS GASTROINTESTINAL TRACT
- AVOID METABOLISM BY THE GI TRACT AND LIVER
- MOST DRUG ABSORPTION OCCURS VIA PASSIVE DIFFUSION THROUGH LIPID BILAYER (BUT THERE IS ALSO DIFFUSION THROUGH OPEN ION CHANNELS, FACILITATED DIFFUSION, ACTIVE TRANSPORT..)
- THE LIPID SOLUBILITY OF A DRUG CAN INCREASE ABSOPRTION RATE
ABSORPTION RATE OF DRUGS FORMULA
RATE = PERMEABILITY x SURFACE AREAS x CONCENTRATION DIFFERENCE
FACTORS AFFECTING GI DRUG ABSORPTION RATE
SURFACE AREA/BLOOD FLOW
- INTESTINAL SURFACE AREAS IS x1000 GRATER THAN STOMACH
- BLOOD FLOW OF INTESTINE IS x8 GREATER THAN STOMACH
- THE SMALL INTESTINE IS THE MAIN SITE OF GI DRUG ABSORPTION
GI MOTILITY
- PRESENCE OG GI MOTILITY DRUGS (E.G. LAXATIVES)
- PATHOPHYSIOLOGICAL/PSYCHOLOGICAL STATE
MALABSORPTIVE STATES (E.G. COELIAC DISEASE)
FOOD TYPE
- MEAL COMPOSITION (E.G. FAT INTAKE DELAYS GASTRIC EMPTYING)
- SPECIFIC DRUG FOOD INTERACTIONS (E.G. DAIRY AND TETRACYCLINE)
WHAT IS THE MAIN SITE OF GI DRUG ABSORPTION?
THE SMALL INTESTINE
FIRST PASS METABOLISM?
THE EXTENT OF METABOLISM OCCURING BEFORE THE DRUG ENTERS THE SYSTEMIC CIRCULATION
ORGANS AND TISSUES INVOLVED:
- GUT LUMEN: E.G. ORAL INSULIN INACTIVATED BY GASTRIC ACID AND PROTEOLYTIC ENZYMES
- GUT WALL: ENZYMES THAT METABOLISE AND ALTER DRUGS
- MOST IMPORTANT: LIVER!!!!!
WHAT IS THE MOST IMPORTANT FIRST PASS METABOLISM ORGAN?
LIVER
DESCRIBE THE DRUG DISTRIBUTION PHASE OF PHARMACOKINETICS
DISTRIBUTION = PROCESS BY WHICH DRUG IS TRANSFERRED FROM SYSTEMIC CIRCULATION INTO TISSUES (SOME SHARED PRINCIPLES WITH DRUG ABSORPTION)
RATE AND EXTENT OF DISTRIBUTION DETERMINED BY:
- ABILITY OF DRUG TO PASS THROUGH TISSUE MEMBRANES
- LIPID SOLUBILITY OF DRUG (I.E. HIGH LIPID SOLUBILITY USUALLY INCREASES DISTRIBUTION)!!!!!
- BINDING OF DRUG TO PLASMA PROTEINS!!!!!!
- ACTIVE TRANSPORT OF SOME DRUGS ACROSS CELL MEMBRANES
- PRESENCE OF OTHER DRUGS IN THE BODY
- PERFUSION RATE LIMITATIONS (E.G. REGIONAL BLOOD FLOW)
VOLUME OF DISTRIBUTION? (VD)
THEORETICAL VALUE!
THE VOLUME OF WATER TO WHICH THE DRUG WOULD HAVE TO BE ADDED TO GIVE THE SAME CONCENTRATION AS THAT IN THE PLASMA
LIPID SOLUBLE: HIGH VD
PROTEIN BOUND: LOW VD
VD = TOTAL AMOUT OF DRUG IN THE BODY/DRUG BLOOD PLASMA CONCENTRATION
HIGH VD CAN INDICATE SEQUESTRATION IN BODY FAT AND LONG DRUG HALF-LIFE (UP TO SEVERAL WEEKS)
SOME EXMPLES OF VD: WARFARIN = 8L ETHANOL = 30L DIAZEPAM = 150L CHLOROQUINE = 15000L
VOLUME OF DISTRIBUTION (VD) FORMULA
VD = TOTAL AMOUT OF DRUG IN THE BODY/DRUG BLOOD PLASMA CONCENTRATION
WHAT TYPES OF DRUGS USUALLY HAVE HIGH VOLUME OF DISTRIBUTION (VD)?
LIPID SOLUBLE
DESCRIBE THE DRUG BINDING TO PLASMA PROTeiNS
- DRUNGS CAN BIND REVERSIBILY AND NON SPECIFICALLY TO PLASMA PROTEINS (ALBUMIN=MOST IMPORTANT!!!!!!!!!!!!!!!!!!!!) WITHOUT SIGNIFICANT EFFECTS ON PRPOTEIN FUNCTION
- ONLY NON-PROTEIN-BOUND DRUG MOLECULES CAN TRAVERSE MEMBRANES TO GAIN ACCESS TO CELLS AND TARGETS
- CHANGES IN PROTEIN BINDING CAN LEAD TO CHANGES IN DRUG DISTRIBUTION
CRITERIA FOR PROTEIN BINDING TO SIGNIFICANTLLY AFFECT DRUG DISTRIBUTION
- THE PROTEIN BOUND PROPORTION OF THE DRUG MUST ONSTITUTE 90% OF THE TOTAL DRUG IN THE PLASMA
- EXTENT OF DISTRIBUTION OF THE DRUG TO THE TISSUES MUST BE SMALL
HOW DOES HIGH PROTEIN BINDING AFFECT DRUG HALF-LIFE?
IT CAN DRAMATICALLY INCREASE IT
EXAMPLE OF DRUG WITH HIGH RPOTEIN BINDING?
WARFARIN (USED TO TREAT COAGULATION/RISK)
- CCA 99% OF THE DRUG MEASURABLE IN PLASMA IS TYPICALLY PROTEIN BOUND
FOR DRUGS WITH HIGH PROTEIN BINDING, THERE IS A RISK OF PROTEIN DISPLACEMENT BY A CO-ADMINISTERED DRUG.
GIVE AN EXAMPLE
A PATIENT ON WARFARIN LATER TAKES ASPIRIN
- WARFARIN IS TAKEN LONG TERM TO MANAGE COAGULOPATHY AND IS NORMALLY >99% PROTEIN BOUND
- ASPIRIN IS ALSO A HIGH RPOTEIN BOUNDER, AND IF TAKEN TOGETHER, IT WILL DISPLACE WARFARIN FROM PLASMA PROTEINS AND THEREFORE INCREASE LEVELS OF UNBOUND WARFARIN IN THE BLOOD
- THE EFFECTIVE CONCENTRATION OF WARFARIN INCREASES LEADING TO SAFETY RISKS (E.G. WARFARIN TOXICITY CAN LEAD TO EXCESSIVE BLEEDING)
- IF ASPIRIN IS WITHDRAWN THE REVERSE WILL HAPPEN - ALSO POSING A RISK (WARFARIN EFFECT WILL BE REDUCED AND THE PATIENT WILL BE AT GREATE RISK OF UNWANTED TROMBOSIS EVENT
DESCRIBE THE METABOLISM PHASE OF PHARMAOKINETICS
LIVER = MAJOR SITE OF DRUG METABOLISM (OTHER TISSUES INCLUDE KIDNEYS, GI TRACT, SKIN)
DRUG METABOLISM, 2 PHASES:
1) PRODUCTS PRODUCED ARE USUALLY MORE CHEMICALLY REACTIVE, AND OFTEN MORE TOXIC THAN THE PARENT DRUG (E.G. OXIDATION, REDUCTION, HYDROLYSIS, DEMETHYLATION), CYTOCHROME P450 ENZYMES IMPORTANT
2) CONJUGATES ARE OFTEN MEDICALLY POLAR (MORE WATER SOLUBLE) AND READILY CLEARED BY THE KIDNEY (E.G. CONJUGATION-SULPHONATION, GLUCURONIDATION, ACETYLATION)
WHICH PHASE OF DRUG METABOLISM ARE CYTOCHROME P450 ENZYMES IMPORTANT IN?
PAHSE 1
WHAT EFFECTS DOES DRUG METABOLISM HAVE ON DRUG ACTIVITY?
- CONVERSION OF DRUGS TO INACTIVE COMPOUNDS (MOST COMMON FATE OF ACTIVE DRUGS, CONVERSION AND INACTIVATION OF DRUGS BY THE LIVER USUALLY ALSO PROMOTES EXCERTION OF THE CONVERTED DRUG MOLECULES BY KIDNEYS)
- PRO-DRUGS; CAN UNDERGO METABOLISM IN THE LIVER FOLLOWING INGESTION TO BECOME PHARMACOLOGICALLY ACTIVE DRUGS (PREPARATIONS LIKE THESE CAN HAVE ALTERED ABSORPTION KINETICS, PREVENT ADVERSE EFFECTS, IMPROVE DISTRIBUTION AFTER INGESTION…)
- ACTIVE METABOLITES (LESS COMMON, BUT CAN BE IMPORTANT, E.G. CODEINE IS INACTIVE AND CONVERTED TO MORPHINE, WHICH IS ACTIVE, BY CYP2D6 ACTIVITY IN THE LIVER)
FACTORS AFFECTING DRUG METABOLISM?
- LIVER DISEASE
- ADVANCING AGE
- GENETIC POLYMORPHISMSM IN DRUG METABOLISING ENZYMES
- COMPETITION BETWEEN DIFFERENT DRUGS FOR THE SAME METABOLISING ENZYMES