L4: pharmacokinetics Flashcards
PK vs PD?
Pharmacokinetics (PK) vs Pharmacodynamics (PD)
Pharmacokinetics (PK): Describes what the body does to the drug. This includes the processes of Absorption, Distribution, Metabolism, and Excretion (ADME). Essentially, PK describes how a drug moves through the body.
Pharmacodynamics (PD): Describes what the drug does to the body. This is related to the mechanism of action, receptor interactions, and the physiological effect the drug produces.
PK/PD relationship: The relationship between pharmacokinetics and pharmacodynamics describes how the concentration of the drug over time (PK) affects the body’s response to the drug (PD). This relationship helps understand dosing, efficacy, and safety.
Example: Propranolol vs. Aspirin
Propranolol (Non-selective beta-blocker): It has a relatively longer half-life (around 2 hours) compared to Aspirin. This means it stays in the bloodstream longer and therefore has a prolonged effect. Its duration of action and clearance rate differ from other drugs.
Aspirin: Has a shorter half-life (~40 minutes). It is cleared from the body more quickly, which impacts its pharmacokinetics. Though it might be absorbed and distributed rapidly, it’s eliminated faster compared to propranolol.
Absorption and distribution?
Absorption: The process by which the drug is taken into the bloodstream. This varies depending on the route of administration (oral, intravenous, etc.). Some drugs are absorbed more efficiently than others, and the bioavailability (the amount of the drug that reaches systemic circulation) can vary significantly.
Distribution: After absorption, the drug moves from the systemic circulation to its site of action. Factors like lipid solubility, protein binding, and blood flow affect how well a drug distributes throughout the body and reaches its target tissues.
variability between drugs?
Different drugs behave differently in the body. For example:
Routes of administration: Some drugs are metabolized more quickly based on how they’re introduced into the body (oral vs. intravenous).
Drug characteristics: Factors like lipophilicity (fat solubility), protein binding, and clearance rate can significantly affect the distribution and elimination of drugs.
absorption?
Absoprtion: process by which drug moves from site of administration to site of action.
Quantified by the absorption rate constant (a first order process)
Oral absorption requires unique properties:
Water soluble in gut
Lipohillic for membrane permeation
Water soluble in plasma
Has to be resistant to acid in the stomach but soluble
Lipid soluble to cross intestinal membranes
Absorption can be solubility (dissolution rate) and ph (pka) dependent
Solubility is also ph dependent. Gi has diff ph as u move through. Becomes increasingly neutral and basic as you move from the stomach (ph 1-2)
If you have a drug want to go to colon, make less soluble or more soluble where you want or dont want it. Restrict drug to site of action and prevent absoprotion into the blood?
distribution?
Process by which a drug moves from bloodstream into peripheral tissues
Can be impacted by plasma protein binding.
Quantified by the Volume of Distribution (Vd)
“The ratio between the amount of drug in the body and the amount in the plasma”
Vd= total amount of drug dosed/ plasma concentration at tD
the bigger the vd the more it is distributing out of the blood
Greater Vd than blood volume: If the Vd is greater than the total blood volume (around 5L in an average adult), this suggests that the drug has distributed from the bloodstream (plasma) into the tissues of the body. The drug is no longer confined to the plasma, and a significant portion of it has moved into the body’s tissues or organs. This could be due to the drug’s ability to cross cell membranes and bind to tissue proteins, fat, or other components.#
Vd similar to blood volume: If the Vd is close to the blood volume (around 5L), it means the drug is mostly confined to the plasma or bloodstream. It might not be significantly distributed into tissues, and most of it stays circulating in the vascular system.
Vd less than 5L: If the Vd is less than the total blood volume (which is typically 5L), it suggests that the drug is highly concentrated in the plasma or vascular system and not distributed into tissues. This could happen for drugs that are protein-bound or highly polar, which makes it harder for them to cross cell membranes into tissues.
metabolism?
Metabolism
Drug Metabolism can happen in most organs and is covered by 2 Phases:
Phase 1 Reactions:
Introduces a new chemical group via:
Oxidation Reactions
Reduction Reactions
Hydrolysis Reactions
Aim: To produce Inactive metabolites
Phase 2 Conjugation Reactions:
Conjugates the molecule with charged chemical species via:
Glucouronidation
Acylation
Sulfation
Aim: To decrease lipophilicity and increase
solubility for enhanced excretion
4-hydroxypropranolol is an inactive metabolite- for proprsmo
Often give drugs in innactive form as they are more redily absorbed. Pro drug- innactive parent drug. In systemic circulation metabolised to prod inactive? Or active
Phase 2: bigger= more soluble? Readily excreted.
excretion
Excretion where both parent and metabolite are exrected.
Drug Excretion is predominantly made up of two main routes:
Renal Excretion – Into the Urine
Glomerular filtration of unbound drug
Active Secretion in the Kidney
Active & Passive reabsorption in the Kidney
This applies to both the Parent Drug and any Metabolites
Hepatic Excretion – Into the Bile (Faeces)
Trans-hepatocyte
Hepatic Drug transports
Sum of influx (OAT) and efflux (P-gp) pumps
This applies to both the Parent Drug and any Metabolites
Important to consider enterohepatic recirculation when looking at plasma profiles for orally administered drugs
However other Excretion Routes Include
Sweat
Milk
Saliva
Or some drugs can be eliminated without metabolism ? so secreted in its active form in the urine. E.g: antibioitics in uti.
All of these processes are limited by the blood flow to the orgn.
primary measures of drug
Primary measures of drugs
Clearance- irreversible elimination of bloood from plasma. compesi t of both metabolism and elimination.
The 2 major measures are
Clearance
Volume of distribution
Secondary measures:
Bioavailability: fraction of unchanged drug reaching the syetemic circulation
Half life- time taken for plasma drug levels to decline 50%
Ame: bioavailability
Dme: half life
Parts of adme
Volume of distribution 270 for propranolo. Volume od distribution increases half life for propranolol,
11#Calculating primary and secondary pk parameter
Clearance
Clearance (Cl) is the only parameter that determines the maintenance dose rate required to achieve a target plasma concentration (and therefore effect) at steady state
Volume of Distribution
Volume of distribution (Vd) is an essential determinant of drug half-life, as t1/2 = 0.693 * Vd/Cl. What this means is that for 2 drugs with the same clearance, but different voluymes of distribution, the bigger volume with have a longer half-life.
Iv dosing- 100%
Typical in vivo pk experiments:
Bioavailability
Fraction of unchanged drug reaching the systemic circulation (F). For intravenous dosing: F = 100%. For oral dosing: F depends on Absorption and Clearance
IV Bolus Dose
Administer a Fixed Dose
Take serial blood samples
Analyse drug plasma levels#
Oral Dose
Administer a Fixed Dose (Sometimes greater than IV)
Take serial blood samples
Analyse drug plasma levels
Iv sdosing- cmaxing starts at 0
Oral at 0- no drug in plasma blood
Key difference: iv dosing = immedaote onset of elimination no absorption,
calculating PK parameters: in vivo experiments?
intravenous (IV) bolus: directly administered into the plasma compartment, instantaneous distribution, elimination
oral dosing: dosed into the gi tract. inteoduces a first-order absorption rate constant (ka), absorption phase (absorption rate > elimination rate), cmax (absorption rate= elimination rate), elimination phase (elimination rate > absorption rate)
kinetics?
Oral dosing- cannot calculate volume of distribution
Describing an exponential: rates of reaction
Zero order- not related to conc so rate is fixed
First order kinetics. Proportional to the conc,
Most drugs follow first order kinetics = No Accumulation
Zero order Kinetics e.g. Phenytoin = Accumulation
what is half life?
the time taken for plasma concentration of a drug to decline by 50%
on a monoexponential decline curve the half life can be estimated anywhere on the curve
the rest is calculations
