Pharmacokinetics Flashcards
Pharmacokinetics refers to the changing concentrations/ amounts of a drug and its ??? in blood plasma, urine and other body tissues and fluids
metabolites
Pharmacological and toxicological actions of drugs are primarily related to the ??? concentration of drugs
plasma
therapeutic failure of a drug occurs when there is not enough drug and plasma level is LESS than or MORE than (?) the MEC (minimal effective concentration)
less
a drug becomes toxic when there is too much drug/ too frequent and the plasma concentration levels are LESS or MORE than the MTC (minimal toxicity concentration)
More than
Therapeutic window: a range of doses which optimise between ??? and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.
efficacy
polymorphism is the ability of a ??? to exist in more than one crystalline form. the solubility and bioavailability is different according to each form
solid compound
LIBERATION or ABSORPTION is the process of release of drug from the formulation
Liberation
ABSORPTION or DISTRIBUTION is the process of a substance entering the blood circulation
ABSORPTION
DISTRIBUTION or METABOLISM is the irreversible transformation of parent compounds into daughter metabolites
Metabolism
ELIMINATION or DISTRIBUTION is the dispersion or dissemination of substances throughout the fluids and tissues of the body
distribution
ELIMINATION or TOXICITY is the elminiation of substances from the body
ELimination
TOXICITY or LIBERATION is the potential or real toxicity of the compound
Toxicity
drug administration can be parenteral through
- intra???
- intramuscular
- subcutaneous
intravenous
TRUE or FALSE: drug administration route depends on the properties of the drug (water/ lipid solubilities, ionisations etc) and the therapeutical objectives (rapid onset or long-term administration)
TRUE
- Self-administrated;
- Toxicities or overdose may be
overcome with antidotes;
these characteristics are advantages for ORAL or SUBLINGUAL administration of drugs?
ORAL
- Rapid absorption;
- Convenient administration;
- Low incident of infection;
- Avoidance of the harsh GI environment;
- Avoidance of first-pass metabolism;
these characteristics are advantages for ORAL or SUBLINGUAL administration of drugs?
SUBLINGUAL
- Complicated drug-absorption pathway;
- Exposed to the harsh gastrointestinal (GI) environment;
- Undergoes first-pass metabolism before entering systemic circulation;
- Not suitable for emergencies;
these characteristics are disadvantages for ORAL or SUBLINGUAL administration of drugs?
ORAL
- Interferes with eating, drinking, and talking,
unsuitable for prolonged administration. - Can’t be used when patient is uncooperative or unconscious.
- Smoking causes vasoconstriction of the blood vessels. This decreases absorption of medication.
these characteristics are disadvantages for ORAL or SUBLINGUAL administration of drugs?
SUBLINGUAL
??? Tablets are a form of oral dosage that defines a drug that is embedded in inert “carrier” meshwork extended or targeted (intestinal) release;
Matrix tablets
what type of oral dosage form has an oblong casing made from gelatin, containing drug liquid, powder or granulated form
capsules
Eudragit is an example of a ??? tablet that is targeted for release at or above pH 7 and is hence coated in a wax-like coating of highly specialised polymers to protect the actual drug
coated tablet
- Aqueous Solutions (with Sugar=Syrup)
- Mostly for ??? use;
- 20 drops = 1g;
- Alcoholic Solutions (=Tinctures)
- Often plant extracts;
- 40 drops = 1g;
- Suspensions: Insoluble drug particles in aqueous or lipophilic media;
paediatric use
Topical Administration is usually used for ??? effects
local
topical administration through skin is generally slow; enhanced by increased ???, by damage to stratum corneum, or by increased blood flow
lipophilicity
??? (DMSO) will readily penetrate the skin and carry the active ingredient along with it;
dimethylsulfoxide
TOPICAL or ORAL administration: Specific formulation determined by physicians/dermatologists
-based on skin type:
* dry vs oily
* young vs old
* intact vs injured
-based on drug properties
* hydrophilic vs lipophilic
* soluble vs insoluble
Topical
advantages of parenteral drugs are:
- Can achieve up to 100% “absorption”
- Drug directly enters the systemic circulation or other ??? tissues i.e. no first pass of metabolism or harsh GI environment
- Better bioavailability of hydrophilic drugs;
vascular
Disadvantages of ??? administration include:
- irreversible
may cause pain, fear, infections
parenteral administration
what type of parenteral administration is fastest acting, followed by intramuscular and then subcutaneous
intravenous
- Ampules
- Single use mostly with fracture ring
- Single and Multiple-dose Vials
- 10-100ml; Contain preservatives;
- Cartridge ampules
- Infusions
- Solution administrated over an extended period of time
these are all types of what drug administration?
parenteral
Rectal administration:
- minimises biotransformation by liver;
- prevents destruction by intestinal enzymes or low pH in stomach;
- erratic/incomplete absorption;
- suitable for persons with ??? and ???
nausea and vomiting.
Absorption: the transfer of a drug from its site of ??? to the bloodstream.
administration
Drugs usually must cross at least one cell membrane from site of administration to
site of action. this occurs via
* Passive diffusion (water-soluble vs lipid soluble)
* Active transport
* Pinocytosis OR phagocytosis?
Pinocytosis
TRUE or FALSE: most drugs can passively diffuse through aqueous pores
FALSE: most drugs CANNOT as the aqueous pores are too small
Mechanisms for absorption of drugs includes passive diffusion through lipids, passive diffusion through aqueous pores, active transport, and ???
pinocytosis
Factors influencing absorption- pH:
- many drugs are weak acids or bases, this affects the passage of an ??? drug through a membrane
uncharged
pH equilibrium:
pKa = pH + log [protonated species] /[??? species]
non-protonated
equilibrium of weak ???: pKa = pH + log [AH] / [A-]
acids
equilibrium of weak ???: pKA = pH + log [BH+] / [B]
bases
Factors influencing absorption: Blood flow to absorption site:
- Blood flow to the intestine is much GREATER or LESSER (?) than that to the stomach = absorption from the intestine is favoured over that from the stomach.
GREATER
Factors influencing absorption: Total surface area available for absorption:
- SA of the intestine is about 1,000-fold of that of the ??? = absorption across the intestine is more efficient.
stomach
Factors influencing absorption: Contact time at the absorption surface:
- a drug moves through GI tract very quickly (e.g. diarrhea), it is not well absorbed; the presence of food ??? the drug and slows gastric emptying = absorbed slowly.
dilutes
Bioavailability: the fraction of the administrated drug that reaches the ??? circulation
systemic
Factors influencing bioavailability include:
* ??? metabolism;
* Solubility of the drug;
* Chemical instability;
* Nature of the drug formulation;
First pass metabolism
Amount of Drug absorbed into the systemic circulation = (S) x (F) x (D)
S: fraction of ??? drug in the formulation
F: bioavailability
D: dose - how much was administrated
active
Determinants of Drug absorption from GIT:
* Dissolution
* Gastric emptying rate - affected by some drugs (e.g. metoclopramide)
* Intestinal motility – affected by drugs (Opiates, anticholinergics)
???
???
???
- Disease states (e.g. gastroenteritis)
- Drug interaction in the GI tract - food interactions (antibiotics)
- Passage through gut wall
Distribution: the process by which a drug REVERSIBLY or IREVERSIBLY (?) leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.
reversibly
distribution of drugs is affected by:
- blood flow
- capillary permeability
- binding of drugs to plasma ???
proteins
Apparent Volume of Distribution: a hypothetic volume of ??? into which a drug is dispersed.
fluid
Apparent Volume of Distribution:
Vd[ml or l] = Dose[mg] / Cp[mg/ml]
where Cp is the [???] after it has equilibrated in its distribution before significant fraction has been eliminated
drug in plasma
Plasma compartment: a drug has a very large MW or binds exclusively to ???, is effectively trapped in plasma (vascular) compartment.
Ex: anticoagulant Heparin Vd=4L
plasma protein
Extracellular fluids: a drug has a LOW or HIGH (?) MW and hydrophilic = can move through endothelia slit junction of capillaries into interstitial fluid.
Ex: antibiotic aminoglycoside Vd=14L
low
drugs that act on total body water: a drug has a low MW and is HYDROPHOBIC or HYDROPHILIC. High lipid solubility
Ex: ethanol, Vd=42L
Hydrophobic
TRUE or FALSE: Drugs do not penetrate uniformly throughout the body. Some tissues may behave similar and can be considered as a common compartment;
TRUE
One compartment distribution kinetics:
When a drug is ??? Or ??? passive diffusion is responsible for this, drug transport is often first order; i.e. rate is proportional to concentration gradient
absorption or elimination
One compartment distribution kinetics:
Cp = Cp(0) exp(-kel . t)
OR
ln Cp = ln Cp(0) - kelt
where Kel = elimination rate constant
yup
One compartment distribution kinetics:
zero-order kinetics = the rate of the
process is INDEPENDENT or DEPENDANT (?) of the drug’s concentration;
Cp = Cp(0) - kelt
independent
Most drugs follow first order kinetics
(only three drugs follow zero order kinetics for elimination: ethanol, high concentration of phenytoin, ???)
aspirin
TRUE or FALSE:
Two Compartment Kinetics: absorption and elimination are to and from compartment 1
TRUE
Binding of drugs to plasma proteins (usually albumin) is reversible and may show low or high capacity. Bound drugs are pharmacologically ACTIVE or INACTIVE (?)
INactive
Albumin has the strongest affinities for anionic drugs (weak acids) or ??? drugs.
hydrophobic
Clinical importance of drug displacement:
1. Warfarin (class I) is highly bound to albumin- only small fraction is free.
2. If a sulfonamide antibiotic (Class II) is administered, it displaces warfarin from albumin = rapid INCREASE or DECREASE (?) in concentration of free warfarin in plasma
increase
Class I or Class II (?) drugs: Dose is less than available binding sites
Class I
Class I or Class II (?): dose is greater than available binding sites
Class II
Drug Metabolism- the process of transformation of lipophilic drugs into more polar, readily excretable products- happens in which organse?
Liver
Kidney
Intestines
Phase I of drug metabolism: convert lipophilic molecules into POLAR or NON-POLAR (?) molecules by adding or unmasking a polar functional group, such as -OH, -SH, -NH2, -COOH etc via oxidation, reduction, and hydrolysis etc.
POLAR
TRUE or FALSE: Phase I or drug metabolism may increase, decrease, or leave unaltered the drug’s pharmacological activity;
TRUE
Metabolism Phase I - Oxidation
- Oxygen is incorporated into the drug molecule (e.g. hydroxylation)
- Oxidation causes loss of part of the drug molecule (e.g. oxidative ???, dealkylation)
deamination
Metabolism Phase I - Oxidation
Microsomal ??? Oxidase (MFOs):
1. Flavoprotein, aka NADPH-cytochrome c reductase: Flavin mononucleotide (FMN) and Flavin adenine dinucletotide (FAD);
2. Cytochrome P450: located in most cells (primarily liver and GI tract) light absorption at 450 nm when complexed with CO; hemoprotein: an iron atom alternating between Ferrous (Fe2+) and Ferric (Fe3+) states;
Mixed Function
Most common inhibition of Cytochrome P450 is through competition for the same ???
= serious adverse events.
isozyme
TRUE or FALSE: Numerous drugs have shown to inhibit one or more of the CYP dependent transformation pathways of warfarin (anticoagulant). e.g. omeprazole (gastroesophageal reflux etc)
TRUE
if metabolite from Phase I is sufficiently polar, drug can be excreted by kidney. Usually NOT the case and metabolites are ??? hence phase II
lipophilic
Phase II of drug metabolism: a subsequent conjugation reaction with an endogenous substrate = polar, usually more water soluble compounds that are often therapeutically ACTIVE or INACTIVE?
inactive
what type of phase II conjugation reaction is most important and products are often excreted in bile, requires enzyme UDP-glucuronosyltransferase?
glucuronidation (conjugation to α-d-glucuronic acid)
the sole determinant of the rate that a drug reaches the steady-state is ???
t1/2 (half life)
Empirical PK-Lipinski’s Rule of Five: describes molecular properties important for a drug’s pharmacokinetics in human body. However, the rule does not predict if a compound is pharmacologically ???
active.
Empirical PK-Lipinski’s Rule of Five
- 5 hydrogen bond donors (N or O atoms with one or more hydrogen atoms)
- 10 hydrogen bond acceptors (N or O atoms)
- ??? 500 daltons
- An octanol-water partition coefficient log P not greater than 5
Molecular weight
Pharmacogenomics: the whole genome application of pharmacogenetics, which deals with SINGLE or MULTIPLE (?) gene interactions with drugs
single
