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Pharmaco > Class 1- pharmacokinetic > Flashcards

Class 1- pharmacokinetic Flashcards

1
Q

Pharmacokinetics include

A

absorption, distribution, metabolism, elimination

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2
Q

pharmacokinetics definition

A

«What the body does to the drug »

• All the reactions that occur after the introduction of a drug into the body

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3
Q

ABSORPTION definition

A

Transition of the drug from its delivery site to the systemic circulation

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4
Q

ABSORPTION Influenced by:

A

o Physical-chemical properties of drugs (weight, liposolubility, ionization)
o Pharmaceutical form (e.g. tablets, capsules, solutions)
o Route of administration

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5
Q

PO administration absorption

A

intestines=blood=liver=systemic circulation=brain

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6
Q

2 steps in PO absorption

A
  1. Releasing the active ingredient

2. Absorption of the drug (passive diffusion or active transport)

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7
Q

PO, RELEASING THE ACTIVE INGREDIENT depends

on the following factors :

A 
o gastric pH
o Drug formulation
• Capsule
• Tablet
• Coated tablet
• Extended/controlled release tablet
• Oral solution
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8
Q

Other factors that may influence: PO absorption

A

o Gastric emptying
o Time of contact with the intestinal wall
o Bowel perfusion
o Food: Food has an impact on gastric emptying, as well as the speed at which drugs are absorbed (↑, ↓ ou ∅ )
o Formation of non-absorbable complexes

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9
Q

o Gastric emptying definition

A

Some medications influence intestinal motility, thus altering the rate at which other drugs are absorbed

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10
Q

FORMATIONS OF NON-ABSORBABLE COMPLEXES def

A

CHELATION
Calcium/iron/dairy products form complexes not absorbed with certain medications
Examples: - Levothyroxine (SynthroidTM)
need an interval of 2h

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11
Q

Hepatic first-pass

A

When a drug is taken orally, it is absorbed into the
systemic circulation, which passes through the liver
before going to other sites of action.
Part of the drug is metabolized by the liver before it reaches the blood « LOSS » by hepatic elimination

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12
Q

BIOAVAILABILITY

A

Fraction (%) of an administered drug unchanged that reaches the systemic circulation

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13
Q

Parenteral administration bioavailiability

A

100%

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14
Q

ORAL ADMINISTRATION

EXTENDED-RELEASE DRUGS

A

o Reduces the frequency of
administration
o Less variable plasma concentrations = less side effects, same efficacy

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15
Q

ORAL ADMINISTRATION PROS

A 
o Simple
o Practical
o Economic
o Safe
o Several formulations available
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16
Q

ORAL ADMINISTRATION CONS

A 
o First hepatic pass
o Incomplete bioavailability
o Delay of action
o Gastrointestinal side effects
o Adhesion monitoring more difficult
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17
Q

ABSORPTION OF PSYCHOTROPIC DRUGS – ORAL

ADMINISTRATION, generally

A

o Good absorption through the gastrointestinal tract
o Maximum concentrations reached in about 1 to 6 hours
o Variable bioavailability
o Fast-dissolving drugs: still need to be absorbed through the gastrointestinal tract

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18
Q

SUBLINGUAL ADMINISTRATION

A

doesn’t go through gut
o Thin and highly vascularized epithelium
o Promotes absorption if sufficient contact time

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19
Q

SUBLINGUAL ADMINISTRATION

PROS

A

o Faster absorption
o Avoids the hepatic first-pass
o Not modified by the gastrointestinal system

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20
Q

SUBLINGUAL ADMINISTRATION CONS

A

o Substance should be powerful and active at low doses

o Irritating local effect

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21
Q

RECTAL ADMINISTRATION

PROS

A

o Useful if nausea, vomiting or patient unable to swallow
o Not modified by the gastrointestinal system
o Decrease in the hepatic first-pass

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22
Q

RECTAL ADMINISTRATION CONS

A

o Erratic absorption
o Irritation of the mucous membranes
o Absorption sometimes uncomfortable for patients

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23
Q

PARENTERAL ADMINISTRATION PROS

A

o Faster action
o Avoids the hepatic first-pass
o Useful if substance not absorbed by other routes
o Useful if the patient is not able to swallow or unconscious

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24
Q

PARENTERAL ADMINISTRATION CONS

A

o Requires sterile material
o Usually requires a third party
o Possible pain at the injection site
o Risks of infections or complications

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25
Q

DISTRIBUTION

A

Shifting of the drug in the body and distribution to tissues or organs

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26
Q

DISTRIBUTION

Influenced by :

A

o Blood perfusion of the organ: The best perfused organs will have more medication
Heart, brain, lungs, kidneys, liver > skin > muscles, bones, tendons
o Physical and chemical characteristics of the drug: Hydrophilic (blood) vs. lipophilic drugs (fat stores and organs)
Lipophilic drugs have more ease to pass through the membranes ** ** Blood-brain barrier
o Plasma protein binding
o Drug tissue affinity

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27
Q

BLOOD-BRAIN BARRIER

A

o Endothelial cells with tight junctions
o Limits the passage of molecules (drugs, toxins)
o Only lipophilic molecules can pass (most psychotropic drugs)

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28
Q

DISTRIBUTION – 2 types of binding

A

o Bounded to plasma proteins
- Binding to proteins serves as transport or storage for the drug
o Free (unbound)
- Only the unbound drug is available to spread to tissues where pharmacological effects take place
- Unbound concentration in the bloodstream reflects the concentration of the drug at the site of action

29
Q

DISTRIBUTION – BINDING TO PLASMA PROTEINS

Influenced by a number of factors, including

A
  1. Amount of available proteins
    o Possible decrease in albumine under certain conditions
    - Aging
    - Undernutrition
    - Alcohol use disorder (lowers albumin= more free Rx = toxicity)
  2. Drug interactions
30
Q

Lab results of medication give us free + bound, true or false

A

true

31
Q

DISTRIBUTION OF PSYCHOTROPIC DRUGS

Generally

A

o Quick blood distribution àbrain
o Brain concentration > blood ( 10 to 40 x )
o Low steady-state drug concentration in blood
o Strong bonding to plasma proteins
o Apparent high distribution volume

32
Q

Psychotropic drugs are removed from the body by two processes :

A
  1. Metabolism: mainly in the liver, The majority of psychotropic drugs are fat-soluble and must be metabolized to the liver to create less fat-soluble metabolites and allow elimination. Drug turns into metabolite
  2. Elimination: mainly to the kidney
33
Q

METABOLISM

PHASE I and PHASE II reactions

A

o PHASE I: involvement of cytochromes P450

o PHASE II: conjugation reactions

34
Q

METABOLISM – PHASE I REACTIONS

Possible results of this biotransformation

A
  1. Drug metabolized into an inactive metabolite

2. Drug metabolized into an active metabolite

35
Q

METABOLISM – PHASE I REACTIONS

3 types of active metabolites

A

A. Drug metabolized into an active metabolite (another existing drug) that may contribute to the therapeutic (or toxic) effect : amitriptyline into nortriptyline
B. Drug metabolized into an active metabolite (non-existent drug) that may contribute to therapeutic (or toxic) effect: clozapine to norclozapine
C.3. Inactive drug requiring liver metabolism to become active (pro-drug): lisdexamfetamine is the pro-drug of dexamphetamine

36
Q

CYTOCHROMES P450 (CYP)

A

Enzymes involved in the biotransformation of the drug
o Significant variability between people
o Genetic polymorphisms
o Responsible for many drug interactions

37
Q 
CYTOCHROMES P450 (CYP)
Drugs can be :
A

I. Substrates of CYP
II. Inhibitors of CYP
III. Inductors of CYP

38
Q 
CYTOCHROMES P450 (CYP)
SUBSTRATE
A

Which is modified by an enzyme
o The majority of psychotropic drugs are substrates of CYP2D6, CYP3A4, CYP1A2 or CYP2C19
o Some drugs are substrates of several enzymes
They become active/ inactive because of the enzyme

39
Q 
CYTOCHROMES P450 (CYP)
INHIBITORS
A

o Inteferes with the ability of an enzyme to perform metabolism
• ↓ CYP activity
• ↓ metabolism of drugs that are substrates of this enzyme
§ ↑ plasma concentrations of the drug *
§ ↑ toxicity or side effects *
* In the event that the metabolite is inactive, as in example 1

40
Q

MAIN CYP INHIBITORS

A
  • Fluoxetine
  • Fluvoxamine
  • Paroxetine
  • Ciprofloxacin
  • Fluconazole
  • Grapefruit juice
41
Q 
CYTOCHROMES P450 (CYP)
INDUCTORS
A

o Accelerates enzyme activity
• ↑ CYP activity
• ↑ metabolism of drugs that are substrates of this enzyme
§ ↓ plasma concentrations of the drug *
§ ↓ drug effectiveness *
* In the event that the metabolite is inactive, as in example 1

42
Q

MAIN INDUCTORS OF THE CYP

A 
• Carbamazepine
• St John’s Wort (natural product): increases metabolism of oral contraceptives
• Phenobarbital
• Phenytoin
• Hydrocarbons contained in cigarette or
cannabis smoke
43
Q

GENETIC POLYMORPHISMS, CYP2D6 POLYMORPHISMS

A

o 7% of the Caucasian population are «slow metabolizers » of CYP2D6
Ø Intolerance to a normal dose of a CYP2D6 substrate drug
Ø Generally require lower doses
Ø It is possible to identify these patients using genotyping (not routinely in practice)
o > 20% of North Africa’s population are « fast metabolizers » of CYP2D6
Ø Ineffective at a normal dose of a CYP2D6 substrate drug
Ø Generally require higher doses

44
Q

METABOLISM OF PSYCHOTROPICS DRUGS

Generally

A

o Important liver metabolism :
Ø CYP
Ø UGT
o Genetic polymorphisms of CYP2D6

45
Q

ELIMINATION

A

Allows definitive elimination of the drug
o Clearance = fully filtered blood volume of a drug per unit of time
o Expressed in mL/min
o Total clairance = renal clearance + liver clearance + other clearances

46
Q

Elimination routes :

A

o The kidney is the main excretion organ

o Other: liver, digestive tract, saliva, lungs, sweat, tears, etc.

47
Q

RENAL ELIMINATION

A

o Glomerular filtration àgoes into the urine
o Tubular secretion àgoes into the urine
o Tubular reabsorption àreturns to blood

48
Q

Serum creatinine:

A

Estimating kidney function using glomerular filtration rate (GFR)
from muscle metabolism (↑ men / black; ↓ women / elderly)
high creat = low creat clearence = eliminate drug less
well
good creat clearence: 100mL / min
below 60: make adjustment
bewlo 15: need dialysis

49
Q

Kidney failure

A

o Cretinine’s clairance decreased

o ↓ renal elimination of the drug à↑ plasma concentrations à↑ effectiveness and toxicity of the drug

50
Q

FACTORS THAT MAY INFLUENCE PHARMACOKINETICS

A 
AGE
- Pediatrics
- Geriatrics
SEX
Women (vs men) :
- ↓ BMI
- ↓ muscle mass
- ↑ fat mass
PREGNANCY
COMORBIDITIES
Examples :
- Kidney failure
- Liver failure
- Heart failure
GENETIC
Differences between
individuals
OBESITY
- ↑ fat mass
- ↑ elimination
- choice of ideal or
dosage weight (vs real)
51
Q

HALF-LIFE

A

«The time required for a given drug’s blood concentration to be reduced by 50 % »
o Expressed in minutes, hours or days
o Reflects the speed at which a drug is eliminated
o Important for judging the interval of administration between doses
Generally :
o Approximate half-life of 12 to 36 hours
o Some exceptions, e.g. :
Ø Long half-life: aripiprazole, fluoxetine
Ø Short half-life: quetiapine, ziprasidone

52
Q

Complete elimination of the drug =

A

about 5 x its half-life

53
Q

STEADY STATE

A

When the drug concentration in blood is stable

when we repeat the dose and arrive at a plateau

54
Q

Time to reach the steady state is determined by :

A
  1. Half-life (5 x half-life)

2. Dosage / administration schedule

55
Q

LOADING DOSE

A

o Quickly achieves the desired drug concentration in blood at steady state
o Subsequently: maintenance doses keep the drug’s concentrations at steady state

56
Q

True or false: concentration of the drug is lower in the brain than in the blood

A

false

57
Q

THERAPEUTIC INDEX

A

«Gap between effective plasma concentration and toxic plasma concentration of a drug »
o Indication of «margin of safety » of a drug
Ø Narrow therapeutic index: higher risk of toxicity
Ø Broad Therapeutic Index: Safer

58
Q

OTHER INDICATIONS OF TDM

A

o Suspicion of non-compliance
o Lack of efficacy/adverse effects at a recommended dose
o Relapse under maintenance therapy
o Determining optimal plasma concentration when the patient has achieved the intended therapeutic goal
o Drug interaction
o Change in the formulation
o Genetic polymorphisms
o Abnormally low or high BMI
o Pregnancy/breastfeeding
o Pediatrics / Geriatrics
o Comorbidities having an effect on pharmacokinetics (e.g. kidney failure, liver failure, inflammatory disease, bariatric surgery)

59
Q

Metoclopramide (MaxeranTM) is a drug that increases gastrointestinal motility and gastric emptying. What phase of pharmacokinetics would be influenced by taking this drug?

A

Absorption

60
Q

Taking antacid medications (e.g. TumsTM or MaaloxTM) reduces stomach pain by decreasing stomach acidity. How can this affect the absorption of drugs?

A

Alter pH of stomach = alter absorption, releasing the active ingredient
It contains calcium: formation of non absorbable complexes

61
Q

Some medications should not be taken at the same time as calcium or magnesium supplements. What’s the reason?

A

FORMATIONS OF NON-ABSORBABLE COMPLEXES Calcium/iron/dairy products form complexes not absorbed with certain medications

62
Q

Explain the phenomenon of first liver passage according to the different routes of administration.

A

PO: loses some of it’s active ingredients by going through the liver
Parenteral: no first liver passage
SL: no hepatic first pass

63
Q

What property of psychotropic drugs allow them to pass through the blood-brain barrier?

A

They are liposoluble

64
Q

Diazepam is a drug that is strongly bounded (about 98%) to plasma proteins.
What happens if a second drug is given that has a stronger affinity for plasma proteins? Would
the effect be the same if diazepam was 5% bounded to plasma proteins?

A

It may become toxic. Unbound part will increase.

If it’s 5%, if you have 95% unbound, the clinical effect from 95% too 100% doesn’t change much.

65
Q

A patient has been taking clozapine for several months. He has been smoking about 20 cigarettes a day for several years. If he decides to quit smoking, what will happen to serum clozapine levels?

A

Smoking is an inductor of CYP, therefore if he decides to quit, the metabolism of drugs can be decreased = increase dose in blood = toxicity
Less norclazapine = less side effects

66
Q

The half-life of olanzapine is about 30 hours. A patient has been receiving 15 mg die olanzapine for about two weeks, but decides to stop treatment because he feels very drowsy during the day. How soon will the drug be completely removed from its blood?

A

150 h

67
Q

Name 5 clinical situations where it would be appropriate to do a therapeutic monitoring of a drug.

A

o Suspicion of non-compliance
o Lack of efficacy/adverse effects at a recommended dose
o Relapse under maintenance therapy
o Determining optimal plasma concentration when the patient has achieved the intended therapeutic goal
o Drug interaction

68
Q

What factors can affect the kidney elimination of a drug?

A 
Age 
Sex 
Ethnicity (black, increased)
Kidney failure 
High creat

Pharmaco (11 decks)

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