Pharmacokinetics-absorption, administration Flashcards
Absorption, distribution, metabolism, and excretion of a drug
involves transport across cell membranes, which is affected by
several drug characteristics:
- Molecular size & structural features
- Degree of ionization
- Relative lipid solubility of ionized/non-
ionized forms - Affinity and binding to serum and
tissue proteins
Passive diffusion of drug thru cell membranes is generally limited to
_________
unbound
True or False: Large lipophilic drugs typically pass thru membranes
True
True or False: Passive diffusion thru cell membranes dominates transport for most drugs
True
Paracellular passage of molecules happens thru __________ _______
Intracellular gaps
What can limit paracellular flow
“Tight intercellular junctions
Passive flux across membranes is driven by
-Drug concentration gradient across membrane
-Solubility of drug ie. lipid-water partition coefficient
(greater the coefficient, faster the diffusion)
-Surface area of membrane
-Membrane thickness
Flux (molecules/unit time) equation
(C1-C2) x Area x Partition Coefficient/ Membrane Thickness
Many drugs are weak acids or weak bases present in solution as
both ________ and ________species
un-ionized and ionized
Unionized species (weak acids and bases) are
More lipid soluble, more readily diffuse across cell membrane
Ionized species (weak acids and bases) are
Less lipid soluble, less able to cross thru cell membranes directly
Transmembrane distribution of a weak electrolyte is influenced by its ________ and the ____ gradient across the cell membrane
pKa, PH
pKa
pH at which 50% of drug is ionized and 50% is unionized
pKa is usually between
pH 3 and pH 11
Henderson-Hasselbach equation
log x [Protonated/Unprotonated] = pKa-pH
Drug accumulates on side of cell membrane where ionization is _______
highest, (this is called ion trapping)
Basic drugs accumulate in ________ fluids
acidic
Acidic drugs accumulate in ________ fluids
basic
What determines degree of ionization of drug
pH on either side of cell membrane
Will a weakly acidic drug (aspirin) with a pKa of 6.5
accumulate more in intestinal juices (assuming
a pH = 5.4) or in the blood space (assuming a pH
= 7.4) ??
Blood space
Will a weakly basic drug (methamphetamine) with a
pKa of 10.0 accumulate more in the urine (assuming
a pH = 6.0) or in the blood space (assuming a pH
= 7.4) ??
Urine
2 forms of carrier-mediated transport
-Active transport
-Facilitated transporters
Carrier-mediated transport is importantfor molecules: (2)
-too large for passive diffusion
-not soluble in lipid for passive diffusion
Carriers are: (3)
-Saturable
-Selective
-Inhibitable
Active transporters
move molecules against their concentration and
electrochemical gradient, requires energy in form of ATP
Facilitated transporters
move large/lipid insoluble molecules down their
electrochemical gradient, no energy input required
Example of active transporter
Na+-K+-ATPase pumps of
excitable cells such as cardiac myocytes or neurons
Example of facilitated transporters
eg. glucose via GLUT 4 transporter
Pharmacokinetics: what does it mean and list the 4 main points
Processes affecting the movement of drugs through
the body ie. what the body does to the drug
* Absorption
* Distribution
* Metabolism
* Excretion
Absorption first requires _________of active drug (active pharmaceutical
ingredient) from its dosage form (formulation) before entering circulation for solid
or semi-solid dosage forms
dissolution
Rate of absorption affects
-onset
-duration
-intensity of action
Absorption is required for most routes of drug administration except:
Intravenous route; intrathecal route, topical route, other minor routes
What affects rate of absorption from site of administration
-Physiochemical drug factors
-Physiologic factors
-Drug formulation
Physiologic factors
A large concentration gradient between site of drug administration and
surrounding tissue drives the uptake of drug into the circulation
Regional or local _______ ______ has the greatest effect on maintaining a _______ concentration gradient favouring drug absorption
Blood flow, large
Drug formulation
Physical form and chemical ingredients of a medication
Drug formulation includes both
Includes both the active drug (active pharmaceutical ingredient) and any
inactive chemicals (binders, excipients, preservatives, etc) that comprise a pharmaceutical product ready for administration to the patient by a specified route of administration
(Drug formulation) Modifications of the active pharmaceutical ingredient and/or final formulation can be employed to
Slow or delay the release of the API for absorption
4 points of slowing or delaying release of API for absorption by modifying API
- More convenient as drug is less frequently administered
- Usually for drugs with short elimination half lives
- Modifications aimed at prolonging dissolution phase of absorption
- “Dose-dumping or erratic absorption are potential concerns
Bioavailability
fraction (%) of administered dose that reaches the
systemic circulation unchanged
Bioavailability can be reduced or affected by
- Precipitation of drug at injection site (SC, IM); unavailable for absorption
- Unable to be absorbed by G.I. tract
- ‘First pass” elimination effect following oral administration of drugs
Unable to be absorbed at G.I tract
- Physicochemical property of drug
- Reverse transport protein (P-glycoprotein)
- ‘First pass” elimination effect following oral administration of drugs
- Primarily due to liver metabolizing enzymes inactivating drug
- Enzymes in G.I. tract wall can also metabolize drug
- Drug can also be excreted in bile
Most common method of administration of drugs
Enteral: Oral
Advantages of enteral (oral) route of administration
- Most convenient for self-administration
- Most economical route
- Usually safer than injection
- Minimal risk of infection
- Can induce vomiting to potentially remove drug
Disadvantages of enteral (oral) route
- Absorption may be erratic
- Enteric coating protects some drugs against gastric juices/acids
- Patient compliance problems
- Not for unconscious patients
- Emesis and G.I. irritation possible
- “first pass elimination” effect possible
Enteral:other minor routes
-Oral transmucosal (sublingual and buccal)
-rectal
Routes of administration
-Enteral: oral
-Enteral:other minor routes
-Parenteral
-Parenteral:other routes
Enteral: other minor routes
-Oral transmucosal (sublingual and buccal)
-Rectal
Parenteral
-Subcutaneous injection
-Intramuscular injection
-Intravenous injection
Parenteral: other routes
-Topical
-Transdermal
Subcutaneous injection
Injection is administered in the tissues lying below the skin
Advantages of subcutaneous injection
- Suitable for solid pellets eg. Contraceptives
- Suitable for insoluble suspensions
- Easier to administer than IV
Disadvantages of subcutaneous injection
- Absorption slower than IM route
- Can be erratic depending blood flow to site
- Not suitable for large volumes
- Pain and/or necrosis with irritating injectable drug solutions
- Technical skills needed for some injections
- Generally, drug is irretrievable once injected
Intramuscular injection
- Injection is administered into the muscle
- gluteus maximus,
- vastus lateralis of the thigh
- deltoid of upper arm
- other minor sites
Advantages of intramuscular injection
- Absorption is typically rapid for drugs in aqueous solution; oily
suspensions will form depot - Safe, easier than IV
Disadvantages of intramuscular injection
- Local pain and swelling with irritating solutions
Topical (parenteral:other routes)
Drugs are applied topically to the eye, skin and the mucus membranes
(conjunctiva, nasopharynx, vagina, urethra, urinary
bladder)
Advantages of topical route
drug delivered locally; can achieve very high conc’n
Disadvantages of topical route
- may be absorbed systemically
- may not remain at desired site
Transdermal route (parenteral:other route)
Drugs applied to skin absorbed into the systemic circulation
Advantages of transdermal route
- absorption enhanced by abraded, denuded or burned skin
- controlled release eg. nicotine and fentanyl patches
- prolonged duration of action
- by passes “first pass elimination” effects
Disadvantages of transdermal route
therapeutic blood levels are slow to achieve; delay onset of action
