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INT > INTRO TO PHARMACOKINETICS AND PHARMACODYNAMICS > Flashcards

INTRO TO PHARMACOKINETICS AND PHARMACODYNAMICS Flashcards

1
Q

WHAT IS CLINICAL PHARMACOLOGY?

A

THE SCIENCE OF DRUGS (MOLECULES THAT HAVE A PHYSIOLOGICAL EFFECT WHEN INGESTED OR OTHERWISE INTRODUCED INTO THE BODY) AND THEIR USE IN HUMANS

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2
Q

BIOAVAILABILITY?

A

THE PROPORTION OF ADMINISTERED DRUG WHICH REACHES THE SYSTEMIC CIRCULATION UNCHANGED AND IS THUS AVAILABLE FOR DISTRIBUTION TO THE SITE OF ACTION

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3
Q

WHAT TYPE OF DRUG ADMINISTRATION ACHIEVES 100% BIOAVAILABILITY AND WHAT KIND OF EFFECTS DOES IT HAVE?

A

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
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4
Q

CHARACTERISTICS OF ORAL ROUTE OF DRUG ADMINISTRATION?

A
  • 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
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5
Q

CHARACTERISTICS OF MUCOSAL ROUTES OF DRUG ADMINISTRATION?

A

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)
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6
Q

CHARACTERISTICS OF INHALATION ROUTE OF DRUG ADMINISTRATION?

A
  • AEROSOLS; E.G. FOR AIRWAY DISEASE
  • LIPID SOLUBLE ANAESTHETICS; RAPID ABSORPTION
  • AVOIDS FIRTS PAS METABOLISM
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7
Q

CHARACTERISTICS OF TRANSDERMAL ROUTES OF DRUG ADMINISTRATION?

A
  • 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)
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8
Q

CHARACTERISTICS OF SUBCUTANEOUS INJECTION ROUTE OF DRUG ADMINISTRATION?

A
  • 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
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9
Q

CHARACTERISTICS OF INTRAMUSCULAR INJECTION ROUTE OF DRUG ADMINISTRATION?

A
  • 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
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10
Q

PHARMACOKINETICS?

A

STUDY OF DRUG MOVEMENT WITHIN THE BODY (WHAT THE BODY DOES TO A DRUG)

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11
Q

PHARMACODYNAMICS?

A

STUDY OF DRUG EFFECTS ND MECHANISMS OF ACTION (WHAT THE DRUG DOES TO THE BODY)

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12
Q

THE 4 PHASES OF PHARMACOKINETICS

A

ACRONYM: ADME

ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION

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13
Q

DESCRIBE THE ABSORPTION PHASE OF PHARMOKINETICS

A

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
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14
Q

ABSORPTION RATE OF DRUGS FORMULA

A

RATE = PERMEABILITY x SURFACE AREAS x CONCENTRATION DIFFERENCE

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15
Q

FACTORS AFFECTING GI DRUG ABSORPTION RATE

A

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)
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16
Q

WHAT IS THE MAIN SITE OF GI DRUG ABSORPTION?

A

THE SMALL INTESTINE

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17
Q

FIRST PASS METABOLISM?

A

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!!!!!
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18
Q

WHAT IS THE MOST IMPORTANT FIRST PASS METABOLISM ORGAN?

A

LIVER

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19
Q

DESCRIBE THE DRUG DISTRIBUTION PHASE OF PHARMACOKINETICS

A

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)
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20
Q

VOLUME OF DISTRIBUTION? (VD)

A

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
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21
Q

VOLUME OF DISTRIBUTION (VD) FORMULA

A

VD = TOTAL AMOUT OF DRUG IN THE BODY/DRUG BLOOD PLASMA CONCENTRATION

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22
Q

WHAT TYPES OF DRUGS USUALLY HAVE HIGH VOLUME OF DISTRIBUTION (VD)?

A

LIPID SOLUBLE

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23
Q

DESCRIBE THE DRUG BINDING TO PLASMA PROTeiNS

A
  • 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
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24
Q

CRITERIA FOR PROTEIN BINDING TO SIGNIFICANTLLY AFFECT DRUG DISTRIBUTION

A
  • 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
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25
Q

HOW DOES HIGH PROTEIN BINDING AFFECT DRUG HALF-LIFE?

A

IT CAN DRAMATICALLY INCREASE IT

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26
Q

EXAMPLE OF DRUG WITH HIGH RPOTEIN BINDING?

A

WARFARIN (USED TO TREAT COAGULATION/RISK)

- CCA 99% OF THE DRUG MEASURABLE IN PLASMA IS TYPICALLY PROTEIN BOUND

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27
Q

FOR DRUGS WITH HIGH PROTEIN BINDING, THERE IS A RISK OF PROTEIN DISPLACEMENT BY A CO-ADMINISTERED DRUG.
GIVE AN EXAMPLE

A

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
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28
Q

DESCRIBE THE METABOLISM PHASE OF PHARMAOKINETICS

A

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)

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29
Q

WHICH PHASE OF DRUG METABOLISM ARE CYTOCHROME P450 ENZYMES IMPORTANT IN?

A

PAHSE 1

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30
Q

WHAT EFFECTS DOES DRUG METABOLISM HAVE ON DRUG ACTIVITY?

A
  • 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)
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31
Q

FACTORS AFFECTING DRUG METABOLISM?

A
  • LIVER DISEASE
  • ADVANCING AGE
  • GENETIC POLYMORPHISMSM IN DRUG METABOLISING ENZYMES
  • COMPETITION BETWEEN DIFFERENT DRUGS FOR THE SAME METABOLISING ENZYMES
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32
Q

DESCRIBE THE EXCRETION PHASE OF PHARMACOKINETICS

A

KIDNEYS!!
- MAJOR ROUTE OF DRUG EXCRETION IS VIA THE URINE
- THERE ARE ALSO SOME GI ROUTES OF EXCRETION (E.G. BILE INTO INTESTINE, FAECAL DRUG EXCRETION..)
(DRUG EXCRETION CAN ALSO OCCUR IN THE LUNGSM SWEAT, TEAR, SALIVA AND BREAST MILK, BUT THESE ARE MINOR ROUTES)

  • SOME DRUGS ARE MOSTLY EXCRETED UNALTERED IN THE URINE (E.G. BETA BLOCKER DRUG ATENOLOL AND HF DRUG DIGOXIN) - THIS IS VERY IMPORTANT TO CONSIDER IN PATIENTS WITH RENAL IMPAIRMENT
33
Q

WHAT IS THE RATE OF DRUG ELIMINATION?

A

THE AMOUNT OF DRUG ELIMINATED FROM THE BODY PER UNIT TIME

  • DETERMINED FROM MEASUREMENT OF DRUG IN PLASMA OVER A RANGE OF TIME INTERVALS FOLLOWING ADMINISTRATION
  • KNOWLEDGE OF DRUG ELIMINATION KINETICS CAN GUIDE RATIONAL DOSAGE REGIMENS AND TO MODIFY THEM ACCORDING TO INDIVIDUAL NEEDS
34
Q

FIRST ORDER ELIMINATION KINETICS?

A
  • MOST DRUGS NORMALLY OBEY FIRST ORDER ELIMINATION KINETICS, WHEREBY DRUG CONCENTRATION DECREASES EXPONENTIALLY OVER TIME
  • RELATIONSHIP BETWEEN THE NATURAL LOGARITHM OF DRUG CONCENTRATION AND TIME IS LINEAR
  • THE RATE OF ELIMINATION IS PROPORTIONAL TO THE AMOUNT OF DRUG IN THE BODY (defining feature of first order elimination kinetics)

(similar mathematical pattern to radioisotope decay and electrical capacitor discharge)

35
Q

WHAT CAN BE DETERMINED FROM THE DRUG ELIMINATION CURVE?

A

DRUG HALF LIFE

36
Q

DRUG HALF LIFE ? (t1/2)

A

THE TIME IT TAKES FOR THE PLASMA DRUG CONCENTRATION TO HALVE IRRESPECTIVE OF THE STARTING DOSE (DOES NOT DEPEND ON THE SIZ EOF THE ADMINISTERED DOSE!, A CONSTANT VALUE)

  • DIFFERENT DRUGS HAVE VARIED HALF-LIVES, RANGING FROM A FEW MINUTES TO SEVERAL WEEKS
  • DRUG USUALLY ABSENT AFTER 5 HALF LIVES HAVE ELAPSED
  • EXAMPLES: PARACETAMOL CCA 2 HRS, ATENOLOL CCA 6HRS, WARFARIN CCA 2 DYS. CHLOROQUINE CCA 6 WEEKS

NOT A MEASURE OF A DRUG’S EFFECT BUT PRESENCE IN THE BODY!!!!!!!, CANNOT USUALLY BE GUESSED, BUT DETERMINED BY A EMPIRICAL FORMULA

37
Q

DRUG IS USUALLY ABSENT FORM THE BODY AFTER HOW MANY HALF LIVES HAVE ELAPSED?

A

5

38
Q

TYPES OF PHARMACOLOGICAL ACTION OF DRUGS

A

1) VIA DIRECT EFFECTS ON CELLULAR RECEPTOR FUNCTION
2) VIA ACTION ON ION CHANNELS
3) VIA ACTION ON MEMBRANE TRANSPORT PROCESSES
4) VIA ENZYME INHIBITION

39
Q

DESCRIBE DRUG ACTION VIA TARGETING CELLULAR RECEPTORS

A
  • RECEPTORS ARE SPECIFIC PROTEINS WITH DISTINCT BINDING SITES AND SIGNAL TRANSDUCTION PROPERTIES
  • SITUATED IN CELL MEMBRANES (FAST RESPONSES - SECONDS) OR WITHIN CELL CYTOPLASM (SLOWER RESPONSES - HOURS/DAYS)
  • LIGANDS - OR BINDING PARENTERS FOR RECEPTORS INCLUDE: AGONISTS (STIMUALTE THE RECEPTOR), ANTAGONISTS (BLOCK THE RECEPTOR), PARTIAL AGONISTS (STIMULATES THE RECEPTOR, BUT CANNOT ELICIT THE SAME LEVEL OF BIOLOGICAL RESPONSE AS A FULL AGONIST)
40
Q

RECEPTOR LIGAND TYPES:

A

AGONISTS (STIMUALTE THE RECEPTOR) E.G. SALBUTAMOL, USED TO TREAT ASTHMA

ANTAGONISTS (BLOCK THE RECEPTOR), E.G. ATENOLOL (USED TO REDUCE HEART RATE AND EXERTION)

PARTIAL AGONISTS (STIMULATES THE RECEPTOR, BUT CANNOT ELICIT THE SAME LEVEL OF BIOLOGICAL RESPONSE AS A FULL AGONIST) —-> E.G. BUPRENORPHINE (STIMULATES THE SAME RECEPTORS AS MORPHINE, BUT NOT AS STRONGLY, CAN BE USED IN REHABILITATION)

41
Q

TYPES OF RECEPTOR ANTAGONISTS

A

COMPETITIVE ANTAGONISTS; COMPETE FOR THE SAME BINDING SITE AS THAT FOR THE AGONIST (E.G. ATENOLOL)

NON COMPETITIVE ANTAGONISTS; ALTER THE RECEPTOR BINDING SITE ‘FIT’ FOR THE AGONIST, REDUCING AGONIST ACTIVITY (E.G. KETAMINE, USED AS AN ANAESTHETIC)

42
Q

DESCRIBE DRUG ACTION VIA TARGETING ION CHANNELS

A
  • ION CHANNELS INFLUENCE TH MOVEMENT OF IONS IN AND OUT OF CELLS ACROSS CELL MEMBRANES (E.G. Na+, K+, Ca2+, Cl-)
  • ION MOVEMENT INFLUENCES POLARISATION OF EXCITABLE CELL MEMBRANES, AND ALSO INFLUENCES INTRACELLULAR SIGNALLING CASCADES
  • DRUGS ACTING ON ION CHANNELS COMMONLY AFFECT NEURAL TRANSMISSION AND MUSCLE CONTRACTILITY
  • E.G. SODIUM CHANNEL BLOCKERS IN LOCAL ANASTHESIA (LIDOCAINE) AND CALCIUM CHANNEL BLOCKERS TO SLOW HEART RATE (VERAPAMIL)
43
Q

DESCRIBE DRUG ACTION VIA TARGETING TRANSPORTER FUNCTION + GIVE EXAMPLE

A
  • TRANSPORTERS MEDIATE THE MOVEMENT OF SPECIFIC ENDOGENOUS SIGNALLING MOLECULES AND NUTRIENTS IN AND OUT OF CELLS (E.G. NEUROTRANSMITTERS, GLUCOSE)

EXAMPLE: THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI) ANTIDEPRESSANT DRUG, SERTRALINE, BLOCKS THE NEURONAL SEROTONIN TRANSPORTER (SERT) LEADING TO RETENTION OF SEROTONIN IN NEURAL POST-SYNAPTIC CLEFT

44
Q

DESCRIBE DRUG ACTION VIA TARGETING ENZYMES + EXAMPLES

A
  • INHIBITING ENZYMES SO THAT THE SUBSTRATE CANNOT REACH THE ACTIVE SITE

EXAMPLES;

1) ACE-INHIBITORS, E.G. RAMIPRIL (BLOCKAGE OF ANGIOTENSIN CONVERTING ENZYME)
2) NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs), E.G. IBUPROFEN (BLOCKAGE OF CYCLOOXYGENASE)

45
Q

OVERVIEW OF DRUG INTERACTIONS

A

A DRUG INTERACTS WITH: OTHER DRUGS, FOOD, SUPPLEMENTS, UNDERLYING MEDICAL CONDITIONS
– THIS CAN LEAD TO DECREASE OF DRUG ACTION, INCREASE OF DRUG ACTION OR CAUSE ADVERSE EFFECTS

46
Q

PHARMACODYNAMIC DRUG INTERACTIONS?

A

INTERCATIONS BETWEEN DRUGS WHICH HAVE SIMILAR OR ANTAGONISTIC PHARMACOLOGICAL EFFECTS OR SIDE EFFECTS

  • THEY MIGHT OCCUR DUE TO COMPETITION AT RECEPTOR SITES, OR OCCUR BETWEEN DRUGS ACTING ON THE SAME PHYSIOLOGICAL SYSTEM
  • THEY ARE USUALLY PREDICTABLE FROM A KNOWLEDGE OF PHARMACOLOGY OF THE INTERACTING DRUGS; IN GENERAL, THOSE DEMONSTRATED WITH ONE DRUG ARE LIKELY TO OCCUR WITH RELATED DRUGS

EXAMPLE:
NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSAID) SUCH AS IBUPROFEN AFFECTS KIDNEY FUNCTION, LEADING TO INTERFERENCE WITH THE THERAPEUTIC MECHANISM OF AN ACE INHIBITOR DRUG SUCH AS RAMIPRIL

47
Q

PHARMACOKINETIC DRUG INTERACTIONS?

A
  • MORE COMPLEX AND LESS PREDICTABLE THAN PHARMACODYNAMIC DRUG INTERACTIONS
  • DRUG-DRUG INTERACTIONS CAN OCCUR AT ALL PK PHASES
  • MOST SIGNIFICANT CHECKPOINT IS THE METABOLISM PK PPHASE, WHERE DRUGS CAN DIRECTLY AFFECT THE ACTIVITY OF THE LIVER CYTOCHROME P450 ISOENZYME SYSTEM THAT INTERACT WITH A VERY WIDE RANGE OF DRUGS —> ENZYMES THAT OVERSEE THE PHASE 1 OF DRUG METABOLISM

6 IMPORTANT Cytochromes P450 (CYPs): CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6 AND CYP3A4 (ESPECIALLY THE LAST TWO!!!!)

  • SPECIFIC DRUGS CAN DRIVE EITHER THE INDUCTION OR INHIBITION OF SPECIFIC LIVER CYTOCHROME P450 ISOENZYMES - IN TURN AFFECTING THE METABOLISM OF OTHER DRUGS (INCREASE OR DECREASE METABOLISM, LEADING TO LOSS OF EFFECT OR TOXOICITY)
48
Q

PHASE OF PHARMACOKINETICS THAT IS MAJORLY SUSCEPTILE TO DRUG-DRUG INTERACTIONS?

A

METABOLISM PHASE

49
Q

WHAT RELATIONSHIP CAN DRUGS HAVE WITH ENZYMES?

A

THEY CAN BE:

  • INHIBITORS
  • INDUCERS
  • SUBSTRATES
50
Q

COMMON, IMPORTANT DRUGS AFFECTED BY P450 ENZYME INDUCTION/INHIBITION:

A

ACRONYM: COWPATS

CICLOSPORIN (IMMUNOSUPPRESANT) AND CITALOPRAM (ANTIDEPRESSANT)
ORAL CONTRACEPTIVE PILL
WARFARIN (ANTICOAGULANT)
PHENYTOIN (TREATMENT FOR EPILEPSY)
ACETYLCHOLINESTERASE INHIBITORS (E.G. DONEPEZIL, A TREATMENT FOR DEMENTIA)
THEOPHYLLINE (TREATMENT FOR SEVERE ASTHMA) AND TACROLIMUS (IMMUNOSUPPRESANT)
STATINS (FOR CHOLESTEROL LEVEL CONTROL) AND STEROIDS (BROAD IMMUNOMODULATION)

51
Q

PHARMACOGENETICS

A

Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup

52
Q

EXAMPLES OF CAUSES OF VARIATION IN INDIVIDUAL RESPONSES TO DRUGS

A
  • GENETIC POLYMORPHISMS EXIST IN DRUG METABOLISING ENZYME GENES, ESPECIALLY IN CYTOCHROME P450 ENZYMES (PHASE 1 DRUG METABOLIC ENZYMES), BUT ALSO IN SOME PHASE 2 ENZYMES AND SELECTED OTHER PHARMACOLOGICALLY PERTINENT GENES
  • THIS OPENS UP THE FIELD OF PERSONALISED MEDICINE

EXAMPLE: OPIOD ANALGESIC DRUG CODEINE WORKS BY METABOLISM TO MORPHINE BY CYP2D6, BUT 8% OF PEOPLE LACK THE ENZYME SO CAN’T METABOLISE IT SO THERE IS NO ANALGESIA EFFECT AND 1% HAVE EXTRA COPES OF THE ENZYME SO ARE RAPID METABOLISERS LEADING TO ENHANCED EFFECTS

53
Q

CYPs?

A

Cytochromes P450 (KEY ENZYMES IN PHASE 1 OF DRUG METABOLISM)

54
Q

HOW MANY 65+ Y.O. PEOPLE TAKE AT LEAST ONE MEDICTAION?

A

4/5

55
Q

% OF OLDER PEOPLE (65+) TAKING 4 OR MORE MEDICINES SIMULATENOUSLY

A

36%

56
Q

TAKING 4 OR MORE MEDICINES SIMULTANEOUSLY IS USUALLY CALLED:

A

POLYPHARMACY

57
Q

HOW MANY TIMES ARE OLDER ADULTS MORE LIKELY TO SUFFER ADVERSE DRUG REACTIONS?

A

3 TIMES

58
Q

% OF HOSPITAL ADMISSIONS ADVERSE DRUG REACTIONS ACCOUNT FOR IN OLDER ADULTS

A

5-12%

59
Q

% OF OLDER PATIENTS WHO DO NOT TAKE THEIR PRESCRIBED MEDICINES AS RECOMMENDED

A

UP TO 50%

60
Q

ADVERSE DRUG REACTIONS?

A

WHO DEFINITION:

UNDESIRBLE EFFECT OF A DRUG BEYOND ITS ANTICIPATED THERAPEUIC EFFECTS, OCCURING DURING CLINICAL USE

61
Q

DoTS CLASSIFICATION OF ADVERSE DRUG REACTIONS (ADRs)?

A

ADRs CAN BE RELATED TO:

  • DOSE
  • TIME-COURSE
  • SUSCEPTIBILITY
62
Q

THERAPEUTIC INDEX

A

The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

Therapeutic Index= LD50/ED50
LD{50}=median lethal dose
ED{50}=median effective dose

63
Q

DESCRIBE THE TYPES OF DOSE RELATED ADRs:

A

ABOVE THERAPEUTIC RANGE = TOXIC REACTION (E.G. BLEEDING FOLLOWING TOO HIGH DOSE OF ANTICOAGULANT)

  • TREATED BY REDUCING DOSE
  • PREVENENTED BY USING MINIMAL EFFECTIVE DOSE!

WITHIN THERAPEUTIC RANGE = COLLATERAL REACTION (E.G. DROWSINESS WITH ANTIDEPRESSANT)

  • MAY BE UNAVOIDABLE
  • MAY NOT BE REDUCED EVEN BY REDUCING THE DOSE (WITHOUT ALSO REDUCING THE DESIRED THERAPEUTIC EFFEC)

BELOW THERAPEUTIC RANGE = HYPERSUSCEPTIBILITY REACTION (E.G. PENICILIN ALLERGY)

  • AVOID BY USING FOREKNOWLEDGE OF PATIENT USCEPTIBILITY
  • PERMANENT AVOIDANCE OF DRUG
64
Q

DESCRIBE THE TYPES OF TIME-COURSE RELATED ADRs:

A

FIRST DOSE REACTION (E.G. HYPOTENSION AFTER 1ST DOSE OF ACE INHIBITORS)
- ADVICE/SPECIAL PRECAUTIONS MAY BE NEEDED

EARLY REACTION (E.G. NITRATE INDUCED HEADACHE)

  • PATIENTS BECOME TOLERANT TO THESE REACTIONS
  • PATIENTS CAN CONTINUE WITH TREATMENT, ADR SHOULD WEAR OFF

INTERMEDIATE REACTIONS (E.G. THROMBOEMBOLISM DUE TO ANTIPSYCHOTIC DRUGS)

  • REACTION OCCURS WITHIN A SPECIFIC TIME FRAME
  • IF NO REACTION HAS OCCURED AFTER THIS TIME, VIGILANCE CAN BE RELAXED

LATE REACTIONS (E.G. BRUISING DUE TO CORTICOSTEROIDS)

  • RISK OF ADR INCREASES WITH CONTINUED OR REPEATED EXPOSURE
  • IMPLIES NEED FOR LONG-TERM MONITORING
WITHDRAWL REACTIONS (E.G. SSRI ANTIDEPRESSANT DISCONTINUATION)
- SLOW WITHDRAWL OR REDUCTION  OF DOSE NEEDED TO PREVENT ADR
DELAYED REACTIONS (E.G. SEVERE WHITE BLOOD CELL LOSS FOLLOWING CERTAIN CHEMOTHERPY DRUG USE)
- AVOID USE OF DRUG IN PATIENTS WHO ARE SUSCEPTIBLE (IF KNOWN)
65
Q

DESCRIBE THE PATIENT SUSCEPTIBILITY RELATED ADRs:

A
  • GENETIC SUSCEPTIBILITY
  • ADVANCING AGE
  • SEX
  • SPECIFIC PHYSIOLOGICAL STATES (E.G. PREGNANCY)
  • DISEASES (E.G. HEPATIC/RENAL IMPAIRMENT)
  • EXOGENOUS FACTORS ( OTHER DRUGS, DIET)
66
Q

DRUG SENSITIVITY IN OLDER ADULTS

A
  • RECEPTOR RESPONSES DECREASE (E.G. LOWER BETA-ADRENOCEPTOR SENSITIVITY, ESPIMPORTANT WHEN THINKING ABOUT ADDRESSING CVD)
  • ALTERED COAGULATION FACTOR SYNTHESIS
  • CNS BECOMES MORE SENSITIVE TO PSYCHOTROPICS/HYPNOTICS
  • BARORECEPTOR RESPONSE LESS SENSITIVE
  • RENAL CLEARENCE REDUCED
  • THIRST RESPONSE BLUNTED
  • THERMOREGULATION BLUNTED
  • ALTERED IMMUNE RESPONSE
  • SLOWER GASTRIC EMPTYING
  • REDUCED PLASMA ALBUMIN
  • INCREASED RATIO OF ADIPOSE TO LEAN TISSUE
  • ALTERED LIVER METABOLISM

(LEADS TO MORE ADRs!!!!)

67
Q

OVER 65s MAKE UP WHAT % OF POPULATION AND CONSUME WHAT % OF THE DRUG BUDGET?

A

14% OF POPULATION, OVER 40% OF DRUG BUDGET

68
Q

HOW MANY MEDICATIONS ON AVERAGE DO CARE HOME PATIENTS TAKE SIMULTANEOUSLY?

A

8

69
Q

WHY IS SUBCUTANEOUSLY INJECTING INSULIN A PREFERRED METHOD OF INSULIN ADMINISTRATION IN PATIENTS WHO NEED IT (E.G. T1D)?

A

1) SUBCUTANEOUS INJECTION DELIVERS THE INSULIN CLOSE TO CAPILLARY BEDS AND IS RELATIVELY STRAIGHTFORWARD TO SELF-ADMINISTER
2) INSULIN NEEDS TO BE ADMINISTERED PARAENTERALLY (IF TAKEN ORALLY, THE DRUG IS DEGRADED AND RENDERED INACTIVE)
3) WITH A SUBCUTAENOUS INJECTION, THE INSULIN ENTERS THE BLOODSTREAM AT A STEADY RATE (DIRECT INJECTION INTO THE BLOODSTREAM COULD MAKE THE ACTION OF INSULIN TOO POWERFUL AND COULD BE HARMFUL)

70
Q

WHICH COMPONENT OF BLOOD IN PARTICULAR CAN SIGNIFICANTLY AFFECT THE RATE OF DRUG DISTRIBUTION?

A

ALBUMIN (HIGHLY ABUNDANT PROTEIN IN BLOOD PLASMA THAT IS RESPONSIBLE FOR MUCH OF THE NON-SPECIFIC ‘PROTEIN BINDING’ PHENOMENON THAT IS AN IMPORTANT CHARACTERISTIC OF MANY DRUGS)

71
Q

WHAT IS A KEY PHYSIOLOGICAL FUNCTIONAL OUTCOME OF THE PHASE II METABOLIC REACTIONS?

A

INCREASED DRUG WATER SOLUBILITY!!!!! TO ENHANCE ELIMINATION

72
Q

HOW MANY 75+ Y.O. PEOPLE ARE ON 3 OR MORE REGULAR DRUGS?

A

1/3

73
Q

EXPLANATION OF WHY DRUG HALF LIFE IS ALWAYS THE SAME (REGARDLESS OF THE AMOUNT INGESTED)?

A

EXPLANATION: FIRST ORDER KINETICS –> ‘ELIMINATION RATE OF A DRUG IS PROPORTIONAL TO THE AMOUNT OF DRUG IN THE BLOODSTREAM’ –> HALF LIFE REMAINS CONSTANT

74
Q

OPEN LABEL STUDY?

A

A STUDY IN WHICH PARTICIPANTS KNOW WHICH GROUP THEY ARE ASSIGNED TO

75
Q

WHICH ASPECTOF PHARMACOKINETICS IS LARGELY RESPONSIBLE FOR THE LONG HALF-LIFE OF SOME DRUGS/

A

DISTRIBUTION

76
Q

HOW DO ALBUMIN LEVELS INFLUENCE DRUG PHARMACOKINETICS?

A

ALBUMIN - PLASMA PROTEIN WITH HIGH BINDING POWER FOR DRUGS

  • IF THE LEVELS ARE LOW DISTRIBUTION ASPECT OF PHARMACOKINETICS WILL BE INCREASED, CAUSE MORE DRUGS WILL BE FREE/NOT BOUND
77
Q

HOW MIGHT LIVER IMPAIRMENT IMPACT BIOAVAILABILITY OF A DRUG?

A

IT COULD INCREASE THE BIOAVAILABILITY, BECAUSE LIVER IS THE MAJOR SITE OF DRUG FIRST PASS METABOLISM AND IF IT IS IMPAIRED, LESS DRUG WILL BE EXCRETED AND MORE WILL END UP IN THE BLOODSTREAM

78
Q

GENE POLYMORPHISM IN WHICH FAMILY OF GENES IS ESPECIALLY IMPORTANT IN PHARMACOGENETICS APPROACHES IN PATIENTS TAKING MULTIPLE MEDICINES?

A

CYTOCHROME P450 ENZYMES

79
Q

WHICH ATOM CAN CYTOCHROME P450 ENZYMES INTRODUC EFFICIENTLY INTO A DRUG MOLECULE BACKBONE AS A PART OF PHASE DRUG METABOLIC REACTION?

A

OXYGEN

INT (52 decks)

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