Pharmacokinetics Flashcards
What drug characteristics affect transport across cell membranes?
- molecular size and structural features
- degree of ionization
- relative lipid solubility of ionized/non-ionized forms
- affinity and binding to serum and tissue proteins
Passive Transport
- cell membranes are relatively permeable to water
- bulk flow of water can carry small water soluble substances across cell membranes
- Typically limited to unbound forms of drugs
What is passive flux across membranes driven by?
- Drug concentration gradient across membrane
- Solubility of drug (lipid-water partition coefficient - greater the coefficient, faster the diffusion)
- Surface area of the membrane
- Membrane thickness
Do ionized or unionized forms of weak acid/base drugs more readily diffuse across cell membranes?
unionized
pKa
pH at which 50% of a drug is ionized and 50% is not
Will a weak acid drug accumulate on the side of the membrane where pKa < pH or pKa > pH?
It will accumulate on the side of the membrane where pKa < pH because this is the side where the ionized form of the drug will be favourable
(When pH is greater than pKa (lower acidity), there are less protons to form the HA version of the acid, thereby favouring the ionized A- version of the acid)
Will a weak base drug accumulate on the side of the membrane where pH > pKa or pH < pKa?
pH < pKa because this is the side where the ionized form of the drug will be favourable
(When pH is less than pKa (more acidic environment), there are more protons available to favour the BH+ version / ionized version of the drug.
ion trapping
Drug accumulation on side of cell membrane where ionization is highest:
* basic drugs accumulate in acidic fluids
* acidic drugs accumulate in basic fluids
* pH on either side of the cell membrane determines the degree of ionization
Carrier-mediated Transport
- molecules too large for passive diffusion
- molecules not soluble in lipid for passive diffusion
- carriers are saturable, selective and inhibitable
Active Transporters
- move molecules against their concentration and electrical gradient
- requires energy in the form of ATP
Facilitated Transporters
- move large/lipid insoluble molecules DOWN their electrochemical gradient
- no energy required
Absorption
Following administration, most drugs must be absorbed into the systemic circulation from the site of administration to get to the target sites
What administration routes DO NOT require absorption
- intravenous
- intrathecal
- topical
What affects the rate of absorption?
- onset
- duration
- intensity of action
What physiologic factor has the greatest effect on drug absorption?
- regional / local blood flow
- large concentration gradients between site of drug administration and surrounding tissue drives the uptake of drug into the circulation
- blood flow is able to maintain a large concentration gradient favouring drug absorption
Drug Formulation
Physical form and chemical ingredients of a medication (includes active drug and inactive chemicals)
How does the modification of a drug to slow or delay the release of the API affect the drug’s usefulness?
- more convenient because drug is less frequently administered
- dose-dumping / erratic absorption are potential concerns
What drug characteristic is typically modified to slow or delay the release of the API for absorption
dissolution phase is prolonged
Bioavailability
Fraction of administered dose that reaches the systemic circulation unchanged
What is Bioavailability affected by?
- precipitation of drug at injection site
- capability of GI tract to absorb the drug
- “first pass” elimination effect following oral administration of a drug (liver metabolism inactivating drug before absorption)
What are the advantages/disadvantages of the enteral:oral administration route of drugs?
Advantages:
* convenient for self-administration
* economical
* safer than injection
* minimal infection risk
* vomiting can remove drug if needed
Disadvantages:
* erratic absorption
* issues with patient compliance
* emesis/GI irritation
* “first pass elimination”
Sublingual route of administration
- type of oral transmucosal in which a drug is administered underneath the tongue
- absorption from the oral mucosa
- can potentially bypass “first pass” by venous drainage to SVC
Buccal route of administration
- type or oral transmucosal rout in which the drug is administered betweent the cheek and the gum
- Absorbed from oral mucosa
Rectal route of administration
- estimated that 50% of drug administered by rectum will bypass first pass effect
- absorption can be erratic and incomplete
- potential for irritation
- less nausea
Parenteral route of Administration
- injectable drugs are most common form
- drug availability more rapid and predictable over oral
- bypasses first pass effect
List the advantages and disadvantages of subcutaneous injection
advantages:
* suitable for solid pellets
* suitable for insoluble suspensions
* easier administration than IV
disadvantages:
* absorption slower than IM route
* can be erratic depending on blood flow to site
* not suitable for large volumes
* pain/necrosis with irritating injectable drug solutions
* technical skills needed for some injections
* once injected drug is irretrievable
Subcutaneous injection (SC/SQ)
Injection administered in the tissues lying below the skin
Intramuscular Injection (IM)
Injection administered into the muscle
List the advantages and disadvantages of intramuscular injection
advantages:
* absorption is typically rapid for drugs in aqueous solution (only suspensions will form depot)
* safe and easier than IV
disadvantages:
* local pain and swelling with irritating solutions
Intravenous Injection
Drug is administered into an accessible vein
Topical route of administration
drugs applied topically to eye, skin and mucus membranes (nasopharynx, vagina, urethra, urinary bladder)
List the advantages and disadvantages of IV injections
advantages:
* emergency administration of drugs
* large volumes can be given via this route
* bioavailability is complete; dose delivery is controlled
* route with the most rapid onset of action
* irritating solutions given via this route
disadvantages:
* must inject many solutions slowly
* not for oily suspensions
* adverse reactions can occur due to higher blood levels achieved rapidly copared to other routes
List the advantages and disadvantages of topical administration of drugs
advantages:
* drugs delivered locally and can achieve a very high concentration
disadvantages:
* may be absorbed systemically
* may not remain at desired site
Transdermal administration route
drugs applied to skin and absorbed into systemic circulation
List the advantages and disadvantages of Transdermal administration
advantages:
* absorption enhanced by abraded, denuded or burned skin
* controlled release results in prolonged duration of action
* bypasses first pass effect
disadvantages:
* therapeutic blood levels are slow to achieve; delayed onset of action
Distribution
Drugs must reach their target site in adequate concentrations to be effective. Distribution of a drug is achieved primarily through the systemic circulation with minor contributions from the lymphatics
What are the three possible routes a drug can take once it is in the systemic circulation?
- remain in vascular space
- distribute to enter interstitial fluid
- further distribute to enter intercellular fluid
What affects the distribution of a drug in the body?
- Physicochemical properties:
* lipid solubility
* size
* degree of ionization - anatomy and physiology of patient: tissue perfusion
* organs and tissues vary in proportion of systemic blood received - Non-target binding of drug:
* plasma protein binding - drugs circulate in blood bound to plasma which affects their distribution
* tissue binding - many drugs will accumulate in tissues at higher levels than interstitial fluid which can prolong drug action and result in binding to non-target sites
What plasma protein acts as a carrier for weak acids?
albumin
What plasma protein binds drugs that are weak bases?
a1-acid glycoproteins
Volume of Distribution
extent to which a drug partitions between blood and tissue compartments
What are the two ways that drigs are eliminated from the body?
- unchanged via excretion
- converted to metabolites via biotransformation
What is meant by the phrase “elimination kinetics of majority of drugs is first order”
Constant fraction of drug in the blood is eliminated per unit of time
Clearance
- indicates efficiency of elimination of drug from blood and therefore the body
- expressed as apparent complete removal of drug from a certain volume of plasma per unit time per unit body weight
Extraction Ratio
- extent to which an organ contributes to drug clearance
Are polar or non-polar compounds eliminated more efficiently by excretory organs
polar
What is the most important excretory organ?
kidney
Where does filtering of unbound drug occur in the kidney? (non-saturable and non-selective process)
glomerular capillaries (aka glomerulus)
Where does active drug secretion occur in the kidneys and how does it work?
- in the proximal convoluted tubule
- drug added to urine
- saturable, selective and inhibitable by other drugs
Do lipid soluble or water soluble drugs typically get reabsorbed from urine back into blood? Why?
lipid soluble drugs can readily diffuse back into tubules and blood, water soluble drugs tend to remain in the urine due to ion trapping
Drug Biotransformation / Metabolism
change in the chemical structure of an absorbed drug within a living organism, usually by enzyme-catalyzed chemical reactions
What is the main metabolizing organ?
Liver
First Pass Effect
- orally administered drugs taken to liver via portal system can be extensively metabolized before reaching the systemic circulation
- Reduces bioavailability of drug for target site
- prevents some drugs from being given orally
What is a prodrug and why are they useful?
- drugs that are administered inactively and are activated by metabolism
- improve bioavailability
- decreases GI toxicity and prolong elimination from the body
Phase I reactions
- oxidation, reduction, hydrolysis reactions
- drugs converted to more polar metabolites and are either excreted or undergo phase II reactions
- introduce or unmask functional groups (-OH, -NH2, -SH, -COOH)
Phase II reactions
- Conjugation reactions
- substance from the diet is attached to the functional group derived from phase I reactions
- creates a more polar, excretable product
What are the enzymes involved in phase I reactions
- involve 1+ cytochrome P-450 (CYP) enzymes in smooth ER
- CYP2C, CYP2D, CYP3A subfamilies are most important
Glucuronic acid conjugation
- phase II reaction
- some phase II metabolites can be excreted into bile for elimination in feces
- glucoronidases in gut bacteria can hydrolyze the conjugate off and free the drug
- drug can be reabsorbed into enterohepatic recirculation which prolongs drug elimination half life
Sulphate Conjugation
- type of phase II reaction
- phenols and alcohols conjugated to sulphate
Acetylation
- Type of phase II reaction
- occurs in drugs with -NH2 group conjugated to COCH3
Glutathione Conjugation
- Type of phase II reaction
- epoxides, arene oxides conjugated to glutathione
What four key parameters govern pharmacokinetics/drug disposition and dosage regimens?
- Bioavailability
- Volume of Distribution
- Clearance
- Elimination half life
Half Life (t12)
- describes rate of drug elimination
- time required for blood drug concentrations to decrease by 50%
For clinical purposes, after how many half lives is a drug considered essentially eliminated from blood?
4-5 half lives
How much drug remains in the blood after 1,2,3 and 4 half lives?
1 - 50%
2 - 75%
3 - 87.5%
4 - 93.75%
How is prolonged efficacy of a drug typically achieved? Why is this the method used?
- administering multiple small doses of drug to maintain drug concentration above the minimum effective concentration for desired effects
- Increasing dosage for prolonged duration above MEC may produce peak concentration that yields adverse effects
After how many half lives is a plateau / steady state reached (drug input = drug eliminated) when a drug is given every half life to achieve accumulation
after approximately 5 half lives
What four things do dose regimens consist of?
- dose (amount of drug given in mg)
- route of administration
- frequency of administration
- duration of therapy
Loading Doses
used to achieve target therapeutic drug levels quickly
Maintenance Doses
Used to maintain drug levels in target therapeutic range
What factors primarily effect drug elimination half life? How do they impact the half life?
Drug Interaction
- change in magnitude or duration of a pharmacologic effect of a drug due to the presence of another drug, food or environment factor
- increased probability with polypharmacy
- increased probability with duration of use
Pharmaceutical interactions
- in vitro effects
- occur before drug is absorbed by patient
- usually when combined in same syringe or IV fluids
- Can also occur in GI tract lumen
- Affects total dose available for absorption if given orally, or for injection if given by IV
Pharmacokinetic Interactions
- most drug interactions of clinical significance are due to changes in drug pharmacokinetics
- absorption interactions: stomach pH, GI motility, P-glycoprotein (MDR efflux pump), GI CYP450s
- Distribution interactions: plasma protein binding or tissue protein binding displacement, changes in tissue blood flow
- metabolism interactions: metabolizing enzymes; inhibition and induction
- Excretion interactions: urine pH, tubular secretion, renal blood flow
Induction
- increased metabolism of inducing drug
- reduced elimination half life and decreased blood drug levels necessitating increased dosage adjustments to accommodate the induction effect
- Takes time to be realized clinically
ex: induction of P450 enzymes produces an increase in the expression of the enzyme, primarily through increased gene transcription
Inhibition
- onset of inhibition effects on other co-administered drugs pharmacokinetics is faster than induction
- necessitates decreasing dosage to accommodate the inhibition effect
ex: inhibition of P450 enzymes directly inhibited by affecting drug
