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BIOM 3090 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

how were the elements believed to relate to disease

A

each element believed to correspond to a jumour in the body (cold, hot, dry and moist), healthresults when these are in balance if not led to diease

Wind: hot & moist = blood

Water: cold & moist = phlegm

Fire: Hot & dry = yellow bile

Earth: cold & dry = black bile

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2
Q

what was the origins of medicine in china based off of

A

excessive shade is associated with cold illnesses

excessive sunshine is associated hot illnesses

excessive wind is associated disorders of the extremities

excessive rain is associated abdominal disorders

excessive dark is associated disorders involving mental confusion

excessive light is associated disorders of the heart and mind

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3
Q

what is bloodletting?

A
  • french physician routinely bled patients suffering from pneumonia and most recovered
  • upon statistic analysis discovered that it increased mortality not decreased

*line of thinking was administered a treatment and they healed, but this ignored natural healing

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4
Q

how can you determine is a treatment works or if its natural healing

A
  • can only know averages (how diseases behave on average, and how people respond to medicines on average)
  • ust compare borups to avoid bias
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5
Q

why is absorption important, what must be considered

A
  • Following administration, a drug must reach the systemic circulation
  • drug must not be inactivated before reaching target tissue
  • natural defense may limit the bioavailability
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6
Q

what is bioavailability?

A
  • fraction of administered dose of the drug that reaches the systemic circulation
  • can depend on route of administration, chemical form and various patient specific factors

Bioavailability = Quantity of drug reaching systemic circulation/ quantity of drug administered

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7
Q

must drugs are _____

A

weak acids or bases

  • necessary bc must be able to pass through membranes and dissolve in stomach and blood
  • if too acidic or basic wont be able to pass through mem
  • if not acidic or basic at all it wont dissolve well so wont be carried efficiently thoguhout the body
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8
Q

cell membranes are permeable to ___

A

non-ionized (lipid solbule) molecules

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9
Q

how is ionization state of drug determined?

A

pH and pKa

pKa is the pH at which 50% of drug is ionized

pKa - pH = Log (prot/deprot)

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10
Q

will a weakly acidic drug with a pKa of 4.4 be better absorbed from the stomach or intestine

A

* want neutral, since drug is acidic want it protonated, acidic protonated when below pKa so abs in stomach

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11
Q

what is ion trapping

A
  • drug accumulates on the side of the membrane where ionization is highest
  • degree of ionization may differ on diff sides of the membrane (Ion trapping)
  • generally, basic drugs accumulate in acidic fluids and acidic drugs accumulate in basic fluids

*tissue pH determines the degree of ionization

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12
Q

how are routes of administration chosen, what are the 2 main classifications

A
  • suually according to transport molecules and other mechanisms that can be taken advanage of to aid with drug entry
  • can be Enteral (oral) or Parenteral
  • enteral is the simplest and parental does directly into systemic circualtion (not introduced in stomah or intestines)
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13
Q

what are other routes of administration other than enteral and parentral

A
  • intraperitoneal injection (IP),

intradermal injection (ID),

intrathecal,

intrarectal (suppository)

inhalation.

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14
Q

what are the advantages and disadvantages or oral drugs

A

* drugs administered orally are carried by the portal system to the liver before entering systemic circualtion (first pass metabolism)

  • liver enzymes may inactivate a fraction of ingested drug so dose must account
  • drugs administered by other routes are not subject to first pass metabolism
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15
Q

advantages and disadvantages of subcutaneous injection (SC or SQ)

A

admin of a drug into a poorly vascularized adispose tissue

Advantage

  • Suitable for solid pellets, insoluble suspensions, oily vehicles (“depot” formulations)
  • easier than IV
  • Abs slower than by IV or IM routes (can also be a disadvantage)

Disadvantage

  • not for large volumes
  • pain or necrosis with irritating drugs
  • abs can be very slow
  • infection possible at inj site
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16
Q

Advantages and disadvantages of intramuscular injection (IM)

A

*administration of a drug intoa well-vascularized intramuscular space

Advantages

  • suitable for moderate volumes, oily vehicles (depot formulations)
  • safer, easier than IV

Disadvantages

  • local pain, swelling and infection possible
  • avoid during anticoagulant treatment )extrensive hemorrhage/bruising may occur)
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17
Q

advantages and disadvantages of intravenous injection

A
  • direct injection of a drug into systemic ciruclation

Advantages

  • emergency use (rapid onset of activity)
  • controlled drug delivery (continuous infusions)
  • can deliver large volumes

Disadvantages

  • higher risk of adverse effects (infection)
  • often must innject slowly due to cardian toxicity risk
  • not for oily or insoluble drugs
  • requires mroe skill for administration
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18
Q

advantages and disadvantages for sublingual administration

A
  • administration under the tongue. absorption occurs across roal mucosa and does not invovle the intestine

Advantage

  • nof irst pass metabolism

Disadvantage

  • patient must cooperate (not swallow drug)
  • significant proportion of dose may be swallowed despite effrots not to
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19
Q

Advantages and disadvantages of topical administration

A
  • applied to skin with intention of having it absorbed itno systemic circulation to produce effect elsewhere

advantage

  • controlled release with prolonged duration of action (ex fentanyl patches)
  • abs through damaged skin is enhanced (not always desireable)

Disadvantage

  • slow onset of action
  • excessive abs may occur if blood flow to skin is excessive (ex in animasl that sweat) and toxic conc may be achieved in systemic ciruclation
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20
Q

what is drug formulation

A
  • refers to the physical form of a medication as well as its chemcial ingredients
  • most inactive ingredients serve to balance pH, alter flavour, or produce desired physical form (aqueous solution, suspension, syrup, gel, solid etc.)
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21
Q

absorption vs distribution

A
  • absorption is a prerequist for establishing adequate plasma drug levels
  • distribution achieved by circulatory system and to a lesser degree the lymphatic system
  • following abs into systemic it can reach target organ

*most of the drug does where it is not needed only a small fraction reaches receptor sites of the target organ

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22
Q

explain protal circulation and the first pass effect

A
  • drugs admin PO are abs by the GI tract and then delivered via portal vein to the lvier
  • liver metabolized the drug ebfore it reaches systemic circulation (first pass effect)
  • drugs admin intravenously, transdermally or subcutaneously enter systemic circulation directly
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23
Q

what factors affect drug distribution

A
  • physical cehmical properties
  • anatomy and physiology of patients
  • plasma protein binding
24
Q

explain how physicochemical properties influence drug distribution

A
  • degree of ionization
  • size and molecualr weight

*influecnes the solublity

25
Q

how does the anatomy and physiology of the patient influence drug distribution

A
  1. Tissue perfusion (brain, kidney, heart, liver recieve 20% of cardiac output)
    • once drug enters the lood it distributes to entire blood volume in 1-2 min
    • oranges with higher blood flow get more drug
    • disease or trauma can reduce blood flow to an organ which changes results
  2. BBB
  • Capillaries in the brain are much less permeable to some water-soluble substances due to the presence of glial cells
  • Totally impermeable to plasma proteins
  • Water soluble substances will enter CNS very slowly (systemic administration of these is useless if intended site of action is the CNS)
  • Drugs with high lipid solubility and low protein binding cross BBB well
26
Q

how does plasma protein binding effect drug distribution

A
  • mainly albumin (many drugs bind readily to it)
  • represents 50% of total plasma protein

protein-bound drug cannot enter tissues and cannot be eliminated via kidneys which results in inert reservoir of the drug

27
Q

what is Volume of Distribution (Vd)

A

Drugs do not distribute equally to all tissues

  • some remain almsot exclusively in the blood (7% of body volume)
  • tohers dsitribute readily to other tissues
  • Vd describes the extent to which a drug partitions between the plasma and tissue compartments
  • represents the fluid volume requred to contain the total amount fo abs drug in bdoy at conc equiv to that in plasma at steady state
28
Q

how id Vd calculated

A

Vd = amount of drug in body / plasma drug concentration

29
Q

ex: a 57 kg patients (body volume = 1L/Kg BW) given a dose of 400 mg, the plasma conc is 100mg/L

A

Vd = 400mg / 100mg/L

  • drug appears to ahve been dissolved in 4L of fluid
30
Q

if some drug leaves the blood stream Vd will be ____ than 7% body volume

A

Vd will be larger

ex: 57 kg patient, dose = 400 mg plasma conc = 50mg/L

Vd = 8L

*this emans that 1/2 the dose remained in the blood stream and the other half has entered the tissue

**Blood is about 7% of body volume so 57 x 0.07 = 4L (so half is in the blood and half is in tissue)

31
Q

ex a 57 kg patient given 400 mg of drug and plasma conc is 1mh/L

A

vd =400/1

vd = 400L (drug appears to have been dissolved in 400 L of fluid

  • not possible, means that drug has distributed preferentually into tissues outside the blood steam maybe due to ion trapping, lipid solubility, irreversible bindind
32
Q

ex: given 100 mg of drug IV to a 60 kg patient, drug conc in blood is 10mgL

A

Vd = 100mg / 10 mg/L

Vd = 10L

* 60 kg patient so 60 x 0.07 = 4.2

  • just over half has distributed into toher tissues
33
Q

Give 1,000 mg of furosemide IM to a 60kg patient

[drug] in plasma = 200 mg/L

A

Vd = 1000mg / 200mg/L

Vd = 5 mg/L

  • patient has 4.2L of blood, almost all drug has remained in vasculature
34
Q

500 mg given to 60 kg patient, [drug] = 8 mg/L

A

500/8 = 62.5L

  • patient only ahve 4.2 L of blood so drug is distributed uniformly through body
35
Q

10 mg digoxin given to 60 kg patient, [drug] in plasma is 0.02

A

10/0.02 = 500 L

  • drug appears to have distributed to volume greater than the entire body (ion trapping, irreversible binding etc.
36
Q

describe metabolism

A
  • also called biotransoformation
  • refers to a change in chemcial structure of an absorbed drug by enzyme catalyzed rxns fo parent drug to metabolite
37
Q

what role to enzymes play in metabolism

A
  • inactivate drugs and make easier to excrete
  • why some drugs are administered as prodrugs
38
Q

What is the major site of metabolism for xenobiotics

A

liver

  • can also uccur in lungs, GI tract, kidneys and brain
39
Q

what catalyzes biotransformation reactions?

A
  • cellular enzymes located in endoplasmic reticulum (smooth ER), cytoplasm, mitochondria, nuclear or cell membrane and lysosomes
40
Q

The metabolizing enzymes are present mainly in ____ which are ___ consisting of _____

A
  • metabolizing enzymes are present mainly in microsomes which are vesicles consisting of membranes of ER
  • thse contain membrane-bound P450 enzymes (mediate Phase I metabolism) and the cytosol which has cytoplasmic fluid and soluble Phase II enzymes.
41
Q

what is phase 1

A
  • enzymatic reactions: oxidation/reduction/hydrolysis
  • oxidation is most common, add an oxygen or remove a hydrogen
  • goal to make more polar metabolites to be excreted or go onto phase II
  • makes it more reactive
42
Q

what is phase II metabolism

A
  • conjugation
  • engogenous substances combine with the functional group derived from phase I reactions to produce a polar excretable product
  • ex of conjugating substances = glucuronic acid, sulfate, glutathione, methyl groups, glycine, cysteine, methionine and acetic acid.
43
Q

what enzyme does metabolism usually involve

A
  • cytochrome P-450 (CYP) enzymes found in smooth ER
  • heme containing proteins which maxamally abs light at 450 nm
  • ex= carbon hydroxylation of pentobarbital, mitro reduction of chloramphenicol and hydrolysis of esterases for acetyl choline
  • introduce or unmask -OH, -NH2, -SH
44
Q

describe

A
  • many drug metabolism rxns involve a system of hepatic P450 microsomal enzymes that oxidize drugs
  • reaction is a series of oxidation/reduction steps in which iron moiety acts as an electron carrier to transfer electrons from NADPH to molecular oxygen
  • reduced oxygen then transferred to drug resulitng in additional -PH on drug
  • hydrophilicity and rate of excretion is inc
45
Q

what are teh steps of P450 mechanism

A
  • 6 steps
  1. drug complexes with oxidized CYP 450
  2. NADPH donates an electron to flavoprotein reductase, which reduces the P450-drug complex
  3. oxygen joins the complex and NADPH donates another electron creating activated oxygen-P450 complex
  4. ^ steps 3-4
  5. iron is oxidized witht he loss of water
  6. oxidized drug product is formed
46
Q

what are the most common CYP 450s?

A

1A2, 2C9, 2C19, 2D6, and 3A4

  • these acount for 95% of the oxidative metabolism of drugs
47
Q

what are the types of phase II reactions

A
  1. Glucuronic acid conjugation: (UDP glucuronosyl transferase)
    • very importnat, for large drugs (>500 MW) are excreted in bile (elim in feces)
    • glucuronidases in gut bacteria can hydrolyze conjugate and free drug to be reabsorbed (enterohepati recirulation)
    • individuals deficient in glucuronide synthesis are slow to metabolize certain drugs
  2. Sulphate conjugation (sulfotransferases)
    • Phenols & alcohols conjugated to sulphate (SO4)
    • acetaminophen , morphine
  3. Acetylation (N-acetyltransferases)
    • occurs in drugs with -NH2 group conjugated to COCH3
    • most sulfonamide antimicrobial dugs
  4. Glutathione conjugation (glutathione S-transferase)
    • epoxides, arene oxides conjugated to GSH
    • ex: some anticancer drugs (alkylating agents)
48
Q

what factors affect drug metabolism

A
  • Enzyme induction & inhibition
  • Multidrug therapy
  • Distribution
  • Age
  • Genetics
  • Disease
49
Q

describe renal excretion

A
  • most common mechanism of drug elimination
  • kidneys receive approx 25% of CO ensuring that they are continuously exposed to any drug in blood
  • glomerular capillaries are highly porous and permeable: filtration of unbound drug is non saturable and non selctive
  • rate of elimination depends on renal blood flow, glomerular filtration and drug binding to plasma protein

*inc bloof flow an filtration rate an dec plasma binding to inc elim

50
Q

describe active tubular secretiona nd tubular reabsorption

A
  • also eliminates drugs
  • transporters in proximal tubules actively pump a minority of drug types into urine and active transporters in the distal tubules reabsorb some filtered drugs from provisional urine
51
Q

describe drug filtration, secretion and reabsorption in the kidney

A

(1) filtered at the renal glomerulus, (2) secreted into the proximal tubule, (3) reabsorbed from the tubular lumen and transported back into the blood, and (4) excreted in the urine.
- relative balance of these rates determines the kinetics of drug elimination by the kidney
- enhancing blood flor, inc glomerular filtrationa and dec plasma protein bidning all cause a drug to be excreted more rapidly

*some drugs like penicillin are actively secreted into proximal tubule

52
Q

describe biliary excretion

A
  • small number of drugs excreted in bile then delivered to duodenum and removed in feces
  • involves drugs not bound to plasma proteins and are metabolized by hepatocytes of liver

entrohepatic recylicing = bilary excretion combined with intestinal reabsorption

^ creates a reservoir of drugs in our body, and prolong the exposure of our body to the drug.

  • drugs reabs are returned to liver via portal blood
53
Q

why has charcoal been used for drug overdoses?

A

oral administration binds the drug and prevents its absorption from the intestine which will interrupt the cycle

54
Q

If drug leaves blood stream to enter tissue Vd is ___ than 7% body volume

A

greater than 7%

55
Q

If drug goes everywhere in the body what will be the value of Vd

A

BIOM 3090 (22 decks)

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