Pharmacokinetics: Routes, Formulation, and Absorption Flashcards
1
Q
Pharmacokinetics
A
- what the body does to drug
- absorption, distribution, metabolism, elimination (ADME)
2
Q
what factors affect a drug’s ability to pass through membrane?
A
- molecular weight
- solubility
- ionization status
- concentration gradient
3
Q
molecular weight physiochemical properties
A
- smaller drugs cross membranes easier
- 400-500 Da
- range where most therapeutic drugs fall
- exceptions
- monoclonal antibodies
- 20-50000 Da
- drugs bound to protein
- monoclonal antibodies
4
Q
plasma protein binding
A
- drug enters circulation and binds to protein
- protein bound drugs remain in plasma until no longer protein bound
5
Q
albumin plasma protein binding
A
- albumin - weak acids, decreased with inflammation
6
Q
a1 acid glycoprotein plasma protein binding
A
- a1 acid glycoprotein - weak bases, increased with inflammation
7
Q
solubility physicochemical properties
A
- lipids vs. water
- lipophilic drugs cross membranes easily and distribute widely
- intracellular, abscesses, CNS, etc.
- hydrophilic - confined to plasma and ECF
8
Q
ionization physicochemical properties
A
- unionized drugs distribute more widely and become more lipophilic
- depends on pH and pka
- “like unionized in like”
9
Q
pka
A
- pH at which 50% drug ionized and 50% is unionized
10
Q
concentration gradient
A
- higher concentration = more drugs for diffusion
- can alter with dose and route
- assume there is enough blood flow to area to deliver drug
- affected by disease
11
Q
passive diffusion
A
- no external energy
- equilibrium net transfer is zero
- non selective
- non saturable - first order (linear)
- rate diffusion
- proportional to (Ch-Cl)
- concentration gradient
- can pass through aqueous pores if water soluble, lipid soluble will go right through membrane
12
Q
carrier mediated transport
A
- drugs lacking sufficient lipid solubility for passive
- carrier may be specific for drug
- competition for carrier
- transport mechanism can be saturated
- typically for drugs mimic endogenous substances (epi or norepi)
13
Q
carrier mediated facilitated diffusion
A
- special transport proteins in membrane
- goes with gradient
- does not require energy
14
Q
active transport
A
- carrier mediated
- goes against gradient
- requires energy
15
Q
clinical relevance of absoprtion
A
- drug must be absorbed across membranes into systemic circulation in order to reach its site of action
- routes play important role
16
Q
how do you chose a route of administration?
A
- formulation available of drug
- therapeutic indiction (seizing cannot give oral drug)
- pathophysiology of disease
- target species
17
Q
what are the main routes of administration?
A
- IV
- IM
- SQ
- oral
18
Q
intravenous
A
- drug injected directly into bloodstream - skipping absorptive phase (100% absorption, cannot be more)
19
Q
advantages IV
A
- highest concentrations
- highest efficacy
20
Q
disadvantages IV
A
- highest risk toxicity
- technically most difficult
- risk of intracarotid injection goes straight to brain causes seizure, coma, blindness, death
21
Q
clinical relevance of IV injection
A
IV route preferred for ER for very sick animals whenever possible, ensures drug delivered
22
Q
intramuscular injection
A
- muscles highly vascular and absorption from IM route often high
23
Q
advantages IM
A
- easy to perform - large animal with large muscle masses (neonates and small animals do not)
24
Q
disadvantages IM
A
- possibility of administering drug in a vessel
- painful
- drug may cause muscle necrosis, abscess, infection
25
Q
clinical relevance IM
A
- often 2nd choice for ER if cannot hit vein, take into account drug formulation
26
Q
subcutaneous injection
A
- absorption moderate to high, more variable than IM
27
Q
advantages of SQ injection
A
- easy to perform
- less painful than IM
28
Q
disadvantages SQ
A
- during dehydration and/or shock skin receives less blood flow
29
Q
clinical relevance of SQ
A
- moderate to severe dehydration or shock can decrease absorption from SQ injection
30
Q
how are water soluble drugs given SQ absorbed
A
- go from blob between cells (leave blob quickly bc lipophilic) absorbed faster
31
Q
how are lipid soluble SQ drugs absorbed
A
- can go through cells
- takes longer bc do not want to leave lipid blob quickly
- more likely to form depot in IM/SQ space
- does not mean less will be absorbed
32
Q
sustained release formulation
A
- drug vehicle affects solubility and absorption
33
Q
fastest to slowest formulation absorption
A
- slowest: solid dose form
- oil based suspensions
- oil based solutions
- aqueous suspensions
- fastest: aqueous solutions
34
Q
intravascular
A
- IV - directly inject into vein (or artery(
- assume 100% absorption
35
Q
extravascular
A
- every other route
- assume less than 100% absorption
36
Q
enternal
A
- administration via the GI tract
- oral (per os; PO; by mouth)
- per rectum, oral/buccal transmucosal
37
Q
parental
A
- everything else
- IV/IM/SC
38
Q
oral
A
- absorption ranges from 0-100%
- most variable
- slowest
- species differences
- monogastrics vs ruminants
- effects of feeding/diet
- fat content
39
Q
clinical relevance of oral
A
- oral is not preferred route for ER situations
40
Q
advantages oral
A
- cheap
- easy (in most animals)
41
Q
disadvantages oral
A
- drug loss
- administration
- vomit/reflux
- degradation by stomach acid
- rumen/colon microbes
- affect on GI flora
42
Q
reasons for poor oral bioavailability
A
- drug not delivered from its formulation to absorption site in GIT
- water soluble to go into solution
- lipid soluble to be absorbed across GI membrane
- formulations may have solubility enhancers - compounding
- drug must go into solution before it can be absorbed, may be rate limiting step for lipid soluble drugs
- drug decomposed in GIT - gastric acid or rumen microbes
- drug complexed in GIT - chelate with cations
- needs carrier mediated transport (too big, too water/lipid soluble, too ionized)
- ion trapping
- first pass metabolism
43
Q
ion trapping
A
- stomach is highly acidic, weak acid is unionized in stomach and becomes trapped in gastric surface epithelial cells bc basic (problems with NSAIDs)
- higher absorption of basic drugs in SI and higher surface area
44
Q
first pass metabolism
A
- for some drugs large % of drug absorbed immediately metabolized in gut or liver prior to absorption into systemic circulation
45
Q
how to avoid first pass metabolism
A
- alter route of administration
46
Q
oral transmucosal
A
- aka buccal or sublingual
- membranes are relatively permeable
- rich blood flow
- rapid uptake of drug into systemic circulation to avoid first pass metabolism
47
Q
other transmucosal routes
A
- inhalation, nasal, ocular, vaginal, rectal
48
Q
advantages of per rectum
A
- access (unconscious or vomiting patients)
- taste (none)
- can recover drugs before absorption is complete
49
Q
disadvantages of per rectum
A
- limited surface area, lower fluid content, microbes (degrade drug)
- too far cranial drains to portal vein through cranial rectal vein
- drug may not stay where you put it
50
Q
transdermal
A
- drug absorbed through skin into circulation
51
Q
transdermal vs. topical
A
- topical stays on skin, transdermal goes into circulation not the same
52
Q
Cmax
A
- maximum plasma concentration
- units ug/mL (ng/mL)
- typically highest for IV doising
- typically lower for PO/IM/SC
53
Q
Tmax
A
- time to maximum plasma concentration
- units hr (min)
- for IV dosing occurs within 2-3 minutes or less
- highly variable for PO/IM/SC
54
Q
clinical relevance of Cmax and Tmax
A
- Cmax determines the magnitude of effect and adverse effects
- Tmax tells you when the effect/adverse effect will occur; used for drug monitoring
55
Q
area under curve
A
- influenced by Cmax and Tmax
- indicates how much drug is absorbed
56
Q
bioavailability (F%)
A
- % of administered drug that appears in bloodstream after dosing
- two types - absolute and relative
- absolute compares EV drug to IV drug
57
Q
relative bioavailability (F%)
A
- compares EV drug to EV drug
- may be routes of administration
- may be different formulation
58
Q
bioequivalence
A
- two drugs have same effect
- +/- 20%
59
Q
flip flop phenomenon
A
- absorption phase is prolonged
- sustained release or depot formulations
60
Q
clinical relevance of absorption
A
- a drug needs to be absorbed to have an effect except topical
- low bioavailability means no effect
- high bioavailability still better most of the time
61
Q
gastrointestinal disease affect on absorption
A
- enteral vs. parenteral
- d+
- proliferative diseases
- v+/refluxing
- oral admin is not best route for GI
62
Q
liver disease affect on absorption
A
- can decrease first pass metabolism and therefore increase oral absorption of some drugs that normally undergo high first pass effects
