pharmacokinetics Flashcards
define pharmacodynamics
The biochemical, physiological and molecular effects of a drug on the body
- what does the drug do to the body
define pharmacokinetics
the fate of a chemical substance administered to a living organism
- what the body does to the drug
what are the 4 stages of pharmacokinetic processes
- absorption - Transfer of a drug molecule from site of administration to systemic circulation
- distribution
- metabolism
- excretion
name routes of absorbtion
- IV - intravenous
- IA - intra-arterial
- IM - intramuscular
- SC - subcutaneous
- PO - oral
- SL - sublingual
- INH - inhaled
- PR - rectal
- PV - vaginal
- TOP - topical
- TD transdermal
- IT intrathecal
what are the % absorption into blood for each method of adminiteration
- IV and IA - 100% reaches systemic circulation
- all other routes must pass at least one membrane
Mechanisms for drug permeation across cell membranes can occur by:
Passive diffusion through hydrophobic membrane
for Lipid soluble molecules
Passive diffusion aqueous pores for Very small water soluble drugs (eg lithium)
Most drug molecules are too big
Carrier mediated transport for proteins which transport sugars, amino acids, neurotransmitters and trace metals (and some drugs)
what are the factors affecting drug absorption
- drug lipid solubility
- drug ionisation
how does drug ionisation affect drug absorption?
- unionised drug - lipid soluble - can cross membrane barriers
- Ionised drug - poor lipid solubility - poorly absorbed
- Most drugs are weak acids or weak bases with ionisable groups
how does drug lipid solubility affect drug absorption?
Lipid soluble molecules can diffuse through cell membranes (along concentration gradient)
Water soluble molecules cannot diffuse and must be transported via alternative mechanisms
what are the 2 major sites of drug absorption which can prevent it from reaching target
- small intestine
- stomach
give some patient and drug factors of oral drugs which affect absorption in the stomach
Patient factors
Food (full stomach will generally slow absorption)
Gastric motility (altered by drugs and disease state)
Previous surgery (eg gastrectomy)
Drug factors
Drug molecule may be digested by gastric enzymes (peptides, proteins)
Eg. insulin and biologicals (‘mab’ drugs)
Drug molecule may be degraded by low pH of stomach (benzylpenicillin)
Drug molecule pKa will alter proportion of ionised drug vs unionised drug
Weak acids are best absorbed in the stomach (weak bases are best absorbed in the intestine), explain why
- in acidic environments, weak acids remain unionised because the high conc of H+ drives equalibrium towards the unionised form - lipid soluble to cross the gastric mucosa
- weak bases would be poorly absorbed in the stomach because weak bases in acidic environemnts will be pushed towards being ionised as they accept H+ ions, this makes it non-lipid soluble meaning it cant cross the membrane
- in alkaline environements, weak bases become ionised so lipid soluble so it can travel over the membrane easier
- weak acids will become more unionised so less lipid soluble, making it harder to cross the membrane
outline some patient and drug factors affecting the absorption of oral medications in the small intestine.
Patient factors
Intestinal motility (altered by drugs and disease state)
Previous surgery (eg short bowel, ileostomy)
Malabsorption (cystic fibrosis, coeliac disease)
Drug factors
Lipid solubility (lipid soluble molecules readily absorbed)
Molecule size: very large molecules cannot be absorbed
Medicine formulation:
Tablet/capsule coating can delay time between administration and drug release
Modified release formulations slows rate of absorption (allowing less frequent dosing)
Substrate for p-glycoprotein
Subject to first pass metabolism
outline the role of P-glycoproteins and its role in drug absorption inhibition.
P-glycoproteins (P-gp) are drug transporter proteins widely distributed in body
Excretory function to remove toxic substances (incl drugs) out of cells
Situated in intestinal lumen to reduce absorption of exogenous substances from the GI tract
Mediate the efflux of drugs/toxins from intestinal mucosa into intestinal lumen
not all drugs are substarates for P-gp
examples include rivaroxaban, digoxin, taclimus
define bioavailability
Proportion of administered dose which reaches the systemic circulation:
explain bioavailability
Biologic activity near the site of absorption limiting the proportion of drug reaching the systemic circulation
Degradation by enzymes in intestinal wall
Absorption from intestine into hepatic portal vein and metabolism via liver enzymes
Degree of first pass metabolism can vary between individuals
Avoid by giving via routes that avoid sphlanchnic circulation (eg rectal, sublingual)
what factors affect the degree of bioavailability across different drugs
- how much the drug is absorbed and extent of first pass metabolism
- Varies with route of administration
- Variation between individuals (genetic, disease states)
- Can be variation between drugs (e.g. branded vs non branded antiepileptic drugs)
NOT EFFECTED BY RATE OF ABSORPTION
From the systemic circulation, drugs can distribute to four compartments in the body, what are these?
- plamsa
- fat
- interstitial fluid
- intracellular fluid
Drug properties will influence ability to move between compartments, what are these?
- molecular size - the smaller the molecule, the more the distrobution
- lipid solubility - the more lipophillic, the higher the distribution
- protein binding - if it is poorly bound to proteins, the higher the distribution
define drug volume of distribution
Theoretical volume a drug will be distributed in the body (apparent volume of distribution)
Volume of plasma required to contain the total administered dose
Drugs that are well distributed will have high Vd
Drugs that are poorly distributed will have low Vd
outline the ways which drugs can reach the CNS.
- High lipid solubility
- Intrathecal administration (e.g. baclofen in MS and spinal cord injury, chemotherapy) - by needle to bypass the BBB
- Inflammation (causes barrier to become leaky)
when is volume of distibution considered when prescribing drugs
Caution dosing drugs with a small Vd using Actual Body Weight in obese patients
Changes in distribution caused by disease states
Sepsis: leaky blood vessels ↑ distribution, greater penetration of BBB
Liver impairment: hypoalbuminaemia
Age related changes in body composition leads to smaller Vd of water soluble drugs, therefore higher plasma concentrations. Caution required in elderly patients
Drugs able to cross BBB are more likely to cause CNS side-effects
define drug elimination
‘the process by which the drug becomes no longer available to exert its effect on the body’
can be because:
- its been metabolised into a different state
- excreted
outline the 2 ways of drug elimination
metabolism:
modification of chemical structure to form new chemical entity (metabolite)
excretion:
of unchanged drug (hydrophillic, polar molecules)
outline the 2 steps in metabolism for drug excretion
Phase 1: Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure
Phase 2: Conjugation of functional group to produce hydrophilic, inert molecule
what enzyme is responsible for phase 1 metabolisms, outline where thye are located and their mechanism
Cytochrome P450 (CYP450) enzymes
name the most significant CYP enzymes for drug metabolism and an example of the drug they eliminate.
3A4
2C9
2C19
1A2
2D6
outline the mechanism of phase 11 metabolism.
Conjugation of an endogenous functional group (glycine, sulfate, glucuronic acid) to produce a non-reactive polar (therefore hydrophilic) molecule
Hydrophyllic metabolite can then be renally excreted
outline a pro-drug
A drug which is pharmacologically inactive, but converted to an active compound in vivo by an enzymatic or chemical transformation
give the benefits of a pro-drug
Pro-drugs can be beneficial in the following ways:
- improved pharmacokinetic profile
- deliver pharmacologically active drug to intended site of action
- minimise side effects
how can ethnicity affect the metabolism of a drug?
- there can be variations in the CYP450 coding genes
- can therefore effect their activity
what are considerations regarding the metabolism of a drug which should be considered when presccribing?
In severe liver impairment, will the metabolism of this drug be reduced?
Reduced dose/frequency needed?
Additional monitoring required?
Avoid?
CYP450 enzyme induction/inhibition drug interactions (to be discussed in detail in Drug Interactions lecture)
Saturation of metabolic pathways can lead to accumulation/toxicity of drug and or metabolites
in which forms can drugs and metabolites be excreted
Liquids (small, polar molecules): urine, bile, sweat, tears, breast milk
Solids (large molecules): faeces (through biliary excretion)
Gases (volatiles): expired air
The most significant route of excretion is in the urine via the kidneys
name the 3 processes for renal excretion of drugs.
- glomerular filtration
- active tubular secretion
- passive reabsorption
explain the process of glomerular filtration during the renal excretion for drugs
20% of plasma filtered
Free/unbound drug molecules
Very large molecules excluded
explain the process of active tubular secretion during the renal excretion for drugs
80% of renal blood flow passes on to peritubular capillaries
Drug molecules transported by carrier systems:
Organic anion transporter (OAT)
Organic cation transporter (OCT)
Can clear protein bound drug
Most effective renal clearance mechanism
explain the process of passive reabsorption during the renal excretion for drugs
Diffusion down the concentration gradient from tubule into peritubular capillaries
Hydrophobic drugs will diffuse easily
Highly polar drugs will be excreted
what are considerations regarding the elimination of a drug which should be considered when presccribing?
Kidneys excrete drugs and drug metabolites (active and inactive)
Reduced kidney function can lead to accumulation and toxicity of renally cleared drugs
define first-pass metabolism
First-pass metabolism (also called first-pass effect or presystemic metabolism) is the process by which a drug or substance is significantly metabolized before it reaches the systemic circulation. It occurs primarily in the liver and, to a lesser extent, in the gut wall after oral administration of the drug.
where in the body does distribution take place and how do they travel to each place?
interstitial fluid into and from fat, plasma, intracellular fluid
always from interstitial fluid
name the transporters used in drug excretion in the tubular secretion stage.
- organic anion transporters
- organic cation transporters
