Pharmacokinetics and principles of drug action Flashcards
Lecture 2-5
What does ADME stand for
Absorption, distribution, metabolism, and excretion
What is pharmacokinetics?
drug time in the body
What is pharmacodynamics?
Drug action binding to action site, or other sites
Describe the concept of bioavailability (F)
It is a parameter of absorption. It is a measure of the drug available to the systemic circulation over time after administration. for i.v -> F = 1
F= AUC oral/AUC i.v. x Dose i.v./Dose oral
Describe the concept of volume of distribution (Vd)
it is a parameter of the distribution. It refers to apparent volume of space into which a drug can distribute after dosing.
Describe the concept of clearance (CL)
volume of blood cleared of drug appearing in excrete per unit time.
CL(R) = urinary drug concentration (U) x volume of urine produced/time (V) / plasma drug concentration (C)
Describe the concept of elimination half-life (t1/2), and the elimination rate constant (ke)
It is a parameter of the metabolism and the excretion.
t1/2 refers to the time it takes for the plasma concentration to drop by 50%/
t1/2 = 0.693 x Vd/CL
ke = CL/Vd
What are the assumptions made about drug distribution pattern in the one-compartment model.
Assumes body is composed of a single, homogenous compartment (central), compartment usually comprises plasma and well-perfused tissues. This model applies to hydrophilic drugs eg. aminoglycosides
Describe the plasma level curve
It is plasma concentration as the x-axis, nd the time at the y-axis. There is a Cmax, with accordance to the tmax. Plasma concentration is the area under the curve.
What is the main site of drug absorption?
The small intestine. because of its large surface area, good blood flow, and long residence time ( approx 4 hrs)
What are the factors affecting drug absorption/bioavailability?
Drug factors: physicochemical properties, dosage form
Patient physiology: gastric emptying rate, GI motility, disease state
Other factors: interaction with other drugs or food
How do you calculate the Vd for i.v bolus injection?
Vd = amount of drug administered / drug concentration in plasma at time 0h
What protein binds to drugs usually?
Albumin
What benefits does plasma protein binding to drugs provide?
Prolongs duration of action
What benefits does tissue binding to drug provide?
slows elimination. (decrease metabolism and excretion rate of drug)
Warfarin binds to plasma proteins or tissues?
Plasma proteins
Chloroquine (malaria) binds to plasma proteins or tissues?
Tissues
Which has a higher distribution? Chloroquine or warfarin?
Chloroquine
What are the factors affecting Vd?
Body size, lipid solubility of drug, protein binding in tissues vs plasma. and disease state that alter physiology.
Phase I and Phase II of drug metabolism is known as?
Phase I preparatory
Phase II synthetic
Phase I converts drugs to?
Derivative
Phase II converts drugs to?
Conjugate
What is the main purpose of metabolism?
Converts drugs to be easier secreted out of the body. From lipophilic to hydrophilic
What are the common chemical processes of phase I drug metabolism?
Compounds are functionalised by oxidation, reduction or hydrolysis
What molecules are conjugated with products of phase I in phase II?
Endogenous molecules, like glucuronic acid
What is metabolic inactivation?
The overall effect of these processes is to convert a pharmacologically active, lipophilic drug to an inactive hydrophilic metabolite (conjugate), which is readily excreted in the urine. Eg. Phenobarbital
What is metabolic bioactivation?
Not all metabolic processes result in a diminution of pharmacological activity. Metabolism is used to convert drugs to prodrug, converting it from non-functional to functional drugs. Eg. L-DOPA to dopamine (anti-parkinson agent)
What is metabolic toxicity?
products of drug metabolism can be converted to toxic. Eg. derivative of paracetamol - NAPQI can lead to cell death
What is cytochrome P450?
It is responsible for biotransformation for most drugs, it is a family of enzymes that oxidise lipid soluble compounds (drugs, steroids). It is isozymes, and proteins, each has preferred sets of substrates.
What are the factors that affect drug metabolism?
Delayed entry into the liver caused by distribution (Vd), CYP enzyme inhibition by drugs egt. fluxetine inhibites CYP2D6 causing propranolol conc to increase, CYP enzyme induction of drugs eg. rifampicin induces CYP3A4, causing midazolam concentration of decrease, ethinicity/genetics, age and pathology (liver and general)
What are the m,ajor drug excretion and clearance
Urine (renal)
Bile (hepatobiliary)
Feces (fecal)
Expired air (pulmonary)
What are the minor drug excretion and clearance?
Sweat (dermal)
Saliva (salivary)
Milk (mammary)
Tears (lacrimal)
What is drug excretion?
Drug excretion is defined as the transfer of drugs from body tissues to the external environment. Excretion is a principal mode of terminations of drug effects.
What are the pathways of kidney excretion?
1) Passive glomerular filtration
2) Active secretion
3) passive reabsorption
What drugs do glomerular filtration target?
Small molecular weight and unbounded drugs
Describe the active tubular secretion in kidneys?
active transport by carrier mediated transport (eg. penicillin) can be competitively inhibited by other drugs of the same chemical class (eg. probenecid inhibits penicillin transport)
What drugs can be passively reabsorb?
Non-ionised forms of drugs, polar drugs metabolites are not readily reabsorbed
What is pharmacodynamics?
Refers to the relationship between drug concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects.
What is an agonist?
Agonist refers to the interaction with receptor and elicits a direct response. eg. adrenaline
What is an antagonist?
It refers to a drug that interacts with receptor without eliciting a direct response. eg. beta-blockers blocks adrenaline
What is the drug receptor theory?
Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects (PK - PD)
What is affinity?
Refers to drug + receptor to DR complex. It is the measure of the probability that a drug molecule will interact with its receptor to form a DR complex. It is also the extent or fraction to which a drug binds to receptors at any given drug concentration - strength.
It follows the law of mass action.
Both antagonist and agonist must have affinity for the receptor.
What is potency?
Potency is related to the dose required to produce a given degree of response Eg. EC50.
The lower dose required, the higher the potency.
Agonist potency depends on affinity and efficacy.
What is efficacy (alpha)?
Refers to DR complex to effector. It is the intrinsic activity: the ability of bound ligand to activate the receptor.
It is a measure of the biological effectiveness of the DR complex the drug forms with its receptor: induced fit, conformation change.
Full response alpha = 1
Partial agonist = 0< a < 1
Antagonist a = 0
The higher the a, the higher Emax (response)
What is the dose-response relationship?
efficacy
What are the types of antagonism?
Chemical, physiological and pharmacological.
What is the difference between graded and quantal drug response?
A graded response is a response that varies in magnitude in a dose-dependent manner, ie. the response increase with dose under the maximum response is reached.
Quantal response is a all-or-none response, ie. yes or no response. The number of subject responding to the drug varies in a dose-dependent manner.
What is a receptor?
A receptor is any component of a biological system that interacts with a drug and thereby leads to the drug effect.
What are the potential response of ion channels? (antagonist or agonist)
Increase or decrease opening probability. Permeation blocked.
What could be potential substrates to enzymes?
Inhibitor, false substrate, or prodrugs
What are the transduction mechanisms for receptors?
Enzyme activation, inhibition
Ion channel modulation
DNA transcription
Antitumor drugs target?
DNA eg. cisplatin targets to inhibit replication or transcription
Antibiotics target which molecule?
RNA eg. tetracyclines/streptomycin targets RNA to inhibit protein synthesis, which is essential for bacterial reproduction
What determines the the affinity?
drug size
Drug-receptor interactions (electrostatic bond: ionic bonds, hydrophobic bond, van der waals covalent bond
Drug shape
What is the law of mass action?
The rate of chemical reaction is proportional to the products of the concentration of reactants.
What is the equation of the dissociation constant (KD) for affinity?
K = rate constant of forward reaction / rate constant reverse reaction
= [D][R]/[DR]
This assumes that the drug binds to receptor reversibly.
Why are there spare receptors?
Maximum response is often obtained before 100% receptor occupancy is reached
What ar chemical antagonist?
Drug level interaction that inhibits the agonist drug itself. eg. chelating agents and heavy metals, activated charcoals and toxins
What are physiological antagonism?
2 drugs causing opposing effects that arise through different mechanisms
. eg. Histamine (H1- decrease in BP) vs adrenaline (alpha 1 - increase BP)
Acetylcholine (M2 - decrease HR) vs noradrenaline (beta 1 - increase HR)
What are pharmacological antagonism?
Antagonism at the receptor level, where one drug binding to the receptor and prevent the active drug from binding.
Competitive (surmountable) antagonism
Non-competitive (insurmountable) antagonism.
Where does the log-response curve shift to for competitive inhibition?
Shifts right, increasing EC50
Where does the log-response curve shift to for non-competitive inhibition?
shifts downwards with the same EC50, but differing response
What is the difference between potency at the receptor vs clinical potency?
Clinical potency, on the other hand, reflects the drug’s effectiveness in producing a therapeutic outcome in patients. It accounts for factors beyond just receptor binding, including pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics (how the drug interacts with the body).
This refers to the drug’s ability to activate or inhibit a specific receptor at the molecular level, often measured by the concentration (EC50 or IC50) required to achieve a certain effect (typically 50% of the maximum effect) in a controlled, in vitro environment.
