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Principles of Disease > PoD - Pharmacokinetics > Flashcards

PoD - Pharmacokinetics Flashcards

1
Q

what four factors determine drug pharmacokinetics?

A
  • absorption
  • distribution
  • metabolism
  • elimination
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2
Q

how are drugs absorbed?

A
  • oral, IV, subcutaneous, intramuscular, sublingual, rectal, inhalation, nasal, transdermal
  • to have biological action, most drugs must enter the blood stream and be distributed to a site for action
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3
Q

define absorption

A
  • the process of movement of unchanged drug from site of administration to the systemic circulation
  • there is a correlation between plasma concentration of a drug and the therapeutic response
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4
Q

what is the therapeutic concentration?

A
  • the more rapid the rate of absorption, the earlier the drug concentration peak (Tmax)
  • Increasing dose does not affect the time at which peak concentration is reached but does increase the peak concentration – Cmax
  • the are under the drug concentration-time curve represents the amount of drug that has reached systemic circulation (AUC)
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5
Q

what is the therapeutic range?

A
  • the range of concentration which the drug is active for
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6
Q

what is the AUC useful for?

A
  • The AUC allows us to estimate the amount of drug which reaches the circulation and which is available for action = BIOAVAILABILITY
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7
Q

what affects bioavailability?

A
  • formulation (slow release preparations)
  • ability of drug to pass physiological barriers
  • if it has to go through GI tract
  • first pass metabolism
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8
Q

what physiological barriers do drugs need to overcome?

A

Passive diffusion
- unionised form of drug will distribute across the membrane until there are equal conc either side (ionised drugs don’t cross). occurs along concentration gradient, depends on lipid solubility and degree of ionisation
- ionisation - as most drugs are weak acids or bases, the degree of ionisation depends on the pH of the environment
- lipid solubility - the ability of the drug to diffuse across a lipid barrier, drugs need to be lipid soluble
Filtration
- channels in the cell membrane (urea, water, sugars)
Active Transport
- relatively unusual, requires carrier and energy as against conc gradient
- to undergo active transport, drugs must resemble naturally occurring compounds
Facilitated diffusion
- require carriers but no energy required
- monosaccharides, AAs, vitamins
Ion-pair transport
Endocytosis

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9
Q

how does the gastrointestinal tract influence absorption?

A
  • speed of gastric absorption will affect speed at which drug reaches site of absorption
  • presence of specific food in GI tract can enhance/impair absorption
  • malabsorption from illness can increase or decrease rate of absorption
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10
Q

what is first pass metabolism?

A
  • metabolism of drug prior to reaching systemic circulation
  • can be a limit on oral route for some drugs
  • enzymes in gut lumen, wall, liver
  • may activate or deactivate drugs
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11
Q

what are the benefits/downsides of subcutaneous/intramuscular route?

A
  • needs a small volume
  • avoids first pass metabolism
  • rate depends on blood flow to the site
  • some drugs are not well absorbed from this route (water soluble better)
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12
Q

what are the benefits/downsides of sublingual/buccal route?

A
  • bypasses first metabolism

- enter blood circulation directly

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13
Q

what are the benefits/downsides of rectal route?

A
  • drugs bypass first pass metabolism
  • absorption is slow
  • rectum is often used for drugs which cause irritation of the stomach
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14
Q

what are the benefits/downsides of inhalation?

A
  • relatively rapid absorption
  • avoids problems with oral absorption (nausea)
  • better for volatile agents
  • not all drugs suitable
  • depends on patient technique
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15
Q

what are the benefits/downsides of transdermal route?

A
  • avoids first pass metabolism
  • can provide controlled release
  • few substances well absorbed
  • need to be non-irritant
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16
Q

what are the main considerations for mode of administration?

A
  • purpose and site of drug action (local absorption/need to avoid first pass metabolism)
  • disease effects
  • patients ability to take medicine
  • speed of action
  • reliability of absorption
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17
Q

what does drug distribution mean?

A
  • to be active, a drug must be able to leave blood stream and enter the extra-vascuular fluids and tissues - reversible process
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18
Q

what does the level of distribution depend on?

A
  • plasma protein binding
  • tissue perfusion
  • membrane characteristics (blood-brain barrier/blood-testes/ovary barrier/lipid solubility/active transport)
  • transport mechanism
  • diseases and other drugs
  • elimination
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19
Q

what is plasma protein binding?

A
  • many drugs bind to proteins in the plasma such as albumin
  • however, only the unbound drug is biologically active
  • binding is reversible
  • the drug must be more than 90% bound and the tissue distribution small
  • amount of the bound drug can be changed by: renal failure, hypoalbuminaemia, pregnancy…
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20
Q

how is volume of distribution relevant to drugs?

A
  • The greater the Vd the greater the ability of the drug to diffuse into and through membranes.
  • in theory the Vd should be 42L, if it stays in extracellular fluid but can’t penetrate cells = 12L, in highly protein bond = 3L
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21
Q

what is drug clearance?

A
  • the theoretical volume of which a drug is completely removed over a period of time
  • dependent on concentration and urine flow rate for renal clearance
  • dependent on metabolism and biliary excretion for hepatic clearance
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22
Q

what is the half life?

A
  • the time taken for the drug concentration in the blood to decline to half of the starting value
  • half life is dependent on volume of distribution and rate of clearance
  • prolongation of the half-life will increase the toxicity of a drug
    0. 5t = 0.693Vd/Cl
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23
Q

define drug elimination

A
  • the removal of active drug and metabolites from the body
  • this determines the length of action of the drug
  • dependent on drug metabolism (liver) and drug excretion (kidney)
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24
Q

what are the three mechanisms of renal excretion?

A
  • glomerular filtration (all unbound drugs will be filtered at the glomerulus as long as they’re not excessively large)
  • passive tubular reabsorption (passive diffusion along conc gradient allows drug to move back through the tubule to the circulation - distal tubule and collecting duct)
  • ## active tubular secretion (actively secreted into the proximal tubule, most important for protein bound cat/an-ionic drugs)therefore renal damage is v. important in causing drug toxicity
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25
Q

how does the liver secrete drugs?

A
  • drugs may be actively or passively secreted into bile
  • many drugs are then reabsorbed from bile into circulation
  • continues until drug is metabolised in the liver or excreted by the kidneys
  • metabolism in liver often leads to conjugation of the drug (not reabsorbed from intestine)
  • damage to liver may reduce rates of conjugation and biliary secretion - so may cause toxic build-up
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26
Q

what is drug metabolism?

A
  • drug metabolism is biochemical modification of pharmaceutical substances by living organisms, usually through specialised enzymatic activity
  • almost all drugs are metabolism, usually before excretion
  • purpose of metabolism is to deactivate compounds & to increase water solubility and to aid excretion
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27
Q

what are the main effects of metabolism?

A
  • loss of pharmacological activity
  • decrease in activity, with metabolites that show some activity
  • increase in activity, more active metabolites (activation of a pro-drug)
  • production of toxic metabolites
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28
Q

what is the role of enzymes in drug metabolism?

A
  • enzymes metabolise drugs

- individual drugs can be metabolised by more than one enzyme

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29
Q

how many phases are in drug metabolism?

A
  • phase 1 (oxidation, reduction, hydrolysis) - activates or inactivation
  • phase 2 (glucuronidation) - conjugation products
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30
Q

describe phase 1 metabolism

A
  • involves hydrolysis, oxidation, reduction
  • increases the polarity of the compound and provides an active site for phase 2 metabolism
  • the cytochrome P450 enzymes = super family of metabolising enzymes
  • 3 families which have been identified as important in oxidative drug metabolism (CYP1/2/3)
  • CYP3A4 = metabolises up to 70% of drugs. Found in the liver (sometimes in gut). Diazepam, methadone, simvastatin metabolised
  • CYP2D6 = responsible for some antidepressants, antipsychotics and the conversion of codeine to morphine. 5-10% of population has reduced or absent expression
  • CYP1A2 = induced by smoking, metabolises theophylline which is an antidepressant (smokers need a higher level of drug)
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31
Q

describe phase 2 metabolism

A
  • involves conjugation
  • conjugation increases water solubility and enhances excretion of the metabolised compound
  • conjugation involves the attachment of glucuronic acid, glutathione, sulphate or acetate to the phase 1 metabolised drug
  • conjugation usually results in inactivation, however some drug metabolites may still be active
32
Q

what factors affect metabolism?

A
  • other drugs/herbal/natural
  • genetics
  • hepatic blood flow
  • liver disease
  • age
  • sex
  • ethnicity
  • pregnancy
33
Q

what is enzyme induction?

A
  • many of the drug metabolising enzymes can be induced by other compounds
  • means there is increased metabolism of drugs metabolised by that enzyme = decreased drug effect
  • most common drug inducers = alcohol & smoking
    example
  • St John’s Wort induces hepatic enzymes which significantly speeds up metabolism of HIV drugs - taking it out-with the therapeutic range
  • clarithromycin is an antibiotic that increases drug metabolism enzyme
34
Q

what is enzyme inhibition?

A
  • most commonly used drugs, herbal medicines and certain foods may inhibit drug metabolising enzymes
  • inhibition of hepatic enzymes increases length of time in body, increases risk of toxicity
    example
  • grapefruit juice inhibits enzymes meaning a hypertension drug stays within the therapeutic rage for longer (almost toxic levels) and drastically reduces BP to dangerous levels
35
Q

how can genetics impact drug metabolism?

A
  • Lack or decreased activity of an enzyme often results in increased drug toxicity.
  • Less commonly there may be multiple expressions of a particular metabolising enzyme, which may result in enhanced metabolism and reduced drug effect or drug resistance.
    examples
  • CYP2D5 polymorphisms - 10% of caucasians are poor metabolisers, 20-30% of SA/ethopinas are ultra-rapid metabolisers
  • CYP2C9 polymorphs - warfarin clearance is greatly reduced in individuals with mutation
36
Q

how can age impact drug metabolism?

A

children
- enzymes often deficient or reduced in young children
- renal function is also deficient so drug and metabolites can rapidly build up to toxic levels
- from 2yrs - puberty, children can metabolise drugs more rapidly than adults
Elderly
- volume of plasma protein, lean body mass and liver weight decrease significantly - alters drug metabolism
- chronic, multimorbidity is also more common - so drug interactions

37
Q

how can gender impact drug metabolism?

A
  • receptor distribution is different in females, therefore response can vary
  • women seem to have greater activity of the most important hepatic enzymes
  • pregnancy = increased induction of certain drug metabolising enzymes occurs in 2/3rd trimester
  • hormonal changes during development have a profound effect on drug metabolism
38
Q

how can ethnicity impact drug metabolism?

A
  • there are many incidences of racial differences in the genetic expression of cytochrome P450 isoforms
  • slow acetylation - 50% caucasians or 5% asians
  • deficient CYP2D6 oxidation - 5-10% caucasian or 1% asian
  • deficient CYP2C18 oxidation - 3-5% caucasians or 20% asians
39
Q

what are the main methods of drug delivery?

A
  • tablets/capsules
  • solutions
  • ointments/creams
  • inhalation
  • injections
  • suppositories
  • pessaries
40
Q

what factors determines the drug delivery systems?

A
  • the dose of the drug to be given
  • the frequency of administration
  • the timing of administration
  • desired speed of onset
41
Q

what delivery systems are absorbed in the GI tract?

A
  • oral medication (solutions, capsules, tablets)
  • buccal
  • sublingual
  • rectal
42
Q

what are the benefit of solutions/suspensions?

A
  • useful for patients with swallowing difficulties
  • can be made more appealing w/ flavourings
  • can be given via naso-gastric tubes
  • extremely fast absorption
  • suspensions are dispersions of course drug particles in a liquid phase - better tolerated for unpalatable drugs
43
Q

what are the benefits/disadvantages of tablets & capsules?

A
  • convenient
  • accuracy of dose
  • reproducibility
  • drug stability
  • cheap and easy to take
  • can have a coating to delay disintegration by stomach acid (enteric coating)
    however, tablet break down is rate limiting step
44
Q

what are prolonged/delayed release formulations useful?

A
  • contains more of the active drug but releases over a prolonged period…useful because
  • most disorders need prolonged therapy
  • maintains drugs levels within a therapeutic range
  • reduces the need for frequent dosing
  • patient compliance is improved
  • improved nursing and doctor compliance
45
Q

benefits of buccal/sublingual administration

A
  • ideal for drugs which have extensive first pass metabolism
  • can take a very low dose of the drug - prevents side effects
  • sublingual tablets are small and dissolve slowly under the tongue or in buccal cavity
46
Q

benefits of rectal administration

A
  • suppositories, creams, liquids
  • good for patients unable to swallow
  • useful for conditions in the rectal area, or to achieve systemic absorption
  • bypasses pre-systemic metabolism
47
Q

benefits of injection-based drug delivery systems

A
  • provide fast systemic effects bypassing first-pass metabolism
  • drugs can be administered in unconscious or comatose patients
  • drugs with short half-life can be infused continuously
48
Q

list benefits/disadvantages for intravenous administration

A
  • a rapid onset of action
  • can be monitored carefully
  • can be given slowly to prevent toxicity
  • continuous infusion ensures accurate control of blood levels
    however, piercing skin increases likelihood of infection
49
Q

benefits of intramuscular/subcutaneous injections

A

intramuscular
- allows a more sustained duration of action up to months but can be painful
subcutaneous
- easy to use and bypasses need for venous access

50
Q

benefits/disadvantages of inhaled drugs

A
  • good for drugs directly targeting the lungs/respiratory system
  • has a rapid effect
  • small doses used
  • little systemic absorption
  • reduced adverse effects
    however, patient education is essential
51
Q

what are carrier-based drug delivery systems?

A
  • drugs bound to a carrier that is trained to target and impact a very specific tissue
52
Q

what carrier-based drug delivery systems are available?

A
  • monoclonal antibodies (mAbs can bind to a cancer specific antigen and induce immunological response to cancer cells. mABs have been modified for delivery of a toxin/cytokine/other drug)
  • antibody drug conjugates - liposomal drug delivery (shown to reduce toxicity and enhance efficiency - drugs dissolved in lipid or water centre - can target plasma membrane directly)
  • genetic transfer system (natural virus is removed of genes required for viral replication, replaced with therapeutic gene, the virus can then go on to infect and deliver the therapeutic genes to target cells)
  • immunotherapy-CAR T cell (adoptive cell transfer, collect and use patients’ own T cells, using a disarmed virus, the T cells are genetically engineered to produce chimeric antigen receptors on their surface which can target specific tumour antigens)
53
Q

what is an adverse drug reaction?

A
  • any response to a drug which is harmful or unpleasant that is unintended and occurs at doses used in man for prophylaxis, diagnosis or treatment
54
Q

what are important statistics in adverse drug reactions?

A
  • 6.5% of all hospital admissions occur as a result of an ADR (~1m admissions annually)
  • 10-20% of all inpatients suffer from an ADR
  • 0.25-3% of all hospital deaths occur as a result of ADR
55
Q

how can onset of the event be classified?

A
  • acute (occurs w/in 60 mins, bronchoconstriction)
  • sub-acute (1-24 hours, rash/serum sickness)
  • latent (> 2 day, eczematous eruptions)
56
Q

how can severity be classified?

A
  • mild (bothersome but requires no change in therapy)
  • moderate (requires change in therapy, additional treatment, hospitalisation)
  • severe (disabling or life-threatening)
57
Q

how can we classify ADRs?

A
  • Type A - augmented (dose related)
  • Type B - bizarre
  • Type C - chronic
  • Type D - delayed
  • Type E - end of treatment
  • Type F - failure of treatment
58
Q

what are type A reactions?

A
  • entirely predictable and dose dependant reactions
  • due to excess pharmacological action
  • easily reversible on reducing the dose or stopping the drug
  • not usually life threatening
59
Q

what are the reasons for type A ADRs?

A
  • too high a dose
  • pharmaceutical variation
  • pharmacokinetic variation (absorption, distribution, metabolism - impaired/enhanced hepatic action, elimination - renal disease)
  • pharmacodynamic variation
  • pharmacogenetic (acetylation - slow metabolisers)
  • disease (renal/hepatic impairment, cardiac failure)
60
Q

what are type B reactions?

A
  • bizarre, unpredictable reactions
  • cause serious illness or death
  • unidentified for months or years
  • unrelated to the dose
  • not readily reversed
    Caused by
  • drug allergy or hypersensitivity
  • genetic abnormalities may lead to abnormal and unpredictable responses to drugs
61
Q

what are type C reactions?

A
  • chronic, long-term ADRs
  • related to duration of treatment as well as the dose and does not occur with a single dose
  • predictable but can’t determine what patients are going to get them
62
Q

what are type D reactions?

A
  • these ADRs occur a long time after treatment
  • teratogenesis = abnormal congenital malformations in the foetus following in-utero exposure due to maternal medication use during 1st trimester of pregnancy
  • carcinogenesis = drugs given for hodgkin’s lymphoma ‘cure’ cancer at the time and a secondary cancer is experienced later down the line
63
Q

what are type E reactions?

A
  • adverse effects which occur when a drug treatment is stopped, especially suddenly following long-term use
  • drugs like steroids, opiates, benzodiazepines, beta-blockers and corticosteroids need to have their dose reduced gradually - weaning off
64
Q

what are type F reactions?

A
  • failure of therapy ADRs
  • common, dose related, frequently caused by drug interactions
    (failure of the oral contraceptive pill when administered with hepatic enzyme inducers/antibiotics)
65
Q

who is most at risk of ADRs?

A
  • young and old
  • multiple medications
  • multiple morbidities
  • inappropriate medication prescribing/use/monitoring
  • end-organ dysfunction
  • altered physiology
  • prior history of ADRs
  • extent of dose and duration
  • genetic predisposition
66
Q

list common drugs involved in ADRs

A
  • antibiotics
  • antineoplastics
  • anticoagulants
  • CV drugs
  • hypoglycaemics
  • antihypertensives
  • NSAIDs
  • CNS drugs
  • Opiates
67
Q

how should ADRs be reported?

A
  • through the Yellow Card Reporting scheme
68
Q

what are drug-drug interactions?

A
  • a drug interaction has occurred when the pharmacological effect of two or more drugs given together is not just a direct function of their individual effects
69
Q

what do object drugs and precipitant mean?

A
  • the drug whose activity is effected by such an interaction = OBJECT DRUG
  • the agent which precipitates such interaction = PRECIPITANT
70
Q

who is susceptible to drug-drug interactions?

A
  • those on multiple medications
  • the elderly
  • the young
  • the critically ill
  • patients undergoing complicated surgical procedures
  • those patients who have chronic conditions (liver disease, renal impairment, diabetes, epilepsy, asthma)
71
Q

what are pharmacokinetic interactions?

A
  • it is possible for one drug to alter the ADME of another drug
  • absorption interactions
  • distribution interactions
  • metabolism interactions
  • elimination interactions
72
Q

how can absorption impact drug-drug interactions?

A
  • formation of insoluble complexes
  • altered pH - H2 antagonists/proton-pump blockers/antacids reduce H so increase pH
  • altered bacterial flora - antibiotics destroy normal gut flora
  • altered GI Tract motility - complexes formed, affect gastric emptying
73
Q

how can distribution impact drug-drug interactions?

A
  • protein-protein displacement - reduction in the extent of plasma protein available due to other drug, displacement of a drug from plasma protein = increased bioavailability of displaced drug - unbound drug is pharmacologically active
  • two most important proteins are albumin and a1-glycoprotein
74
Q

how does metabolism impact drug-drug interactions?

A
  • one drug induces or inhibits the metabolism of another
  • metabolism occurs in the liver via the cytochrome p450 system
  • clarithromycin, erythromycin and omeprazole inhibit the system (inhibit each other, warfarin, diazepam and alcohol)
  • barbiturates, carbamazepine, phenytoin, tobacco induce the system
  • st john’s wort increase metabolism of cyclosporin by inducing CYP3A4
75
Q

how does elimination impact drug-drug interactions?

A
  • most drugs are excreted in urine or bile
  • changes in glomerular filtration rate or tubular secretion
  • digoxin - inhibits excretion
  • loop diuretics/lithium - increase tubular reabsorption
76
Q

what are pharmacodynamic interactions and how do they impact drug-drug interactions?

A
  • actions of the drug are changed due to presence of another drug either acting directly on the same receptor or indirectly on different receptors
  • direct (beta-blockers such as atenolol will block the actions of agonists - bronchodilators such as salbutamol)
  • indirect (indirect agonism - benzodiazepines and tricyclics/alcohol or indirect antagonism - NSAIDs and antihypertensive medication)
  • antagonistic
  • synergistic/agonistic (when two drugs with the same pharmacological effect acting on the same receptor are given concurrently - may be additive)

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