M1 Lecture 2: Pharmacokinetics Flashcards
ADME
Absorption: Ingestion → blood
Distribution: Blood → organ tissues
Metabolism: Drug converted into chemical compounds for use
Excretion: Elimination out of the body
common routes of administration
orally (most common)
intravenous (straight into the blood, most effective)
injections
sublingual (under tongue)
buccal route (above tongue)
topical (skin, eye, ear drops)
rectal and vaginal
bioavaliability
% of drug that reaches systematic circulation
which route of administration skips absorption step
IV route
factors affecting drug absorption
lipid solubility, pH, transit time, enzymatic and chemical stability, food, dosage form
Lipid soluble drugs…
CAN cross cell membranes (bc cell membrane mainly made up of lipids)
Water soluble drugs…
CANNOT cross cell membranes
most drugs… (in relation to drug and lipid solubility)
weak acids and bases
exist in ionized (charged) (H2O soluble, polar) and unionized (uncharged) (lipid soluble, unpolar) form
degree of ionization depends on…
1. pH of enviro
2. pKa of drug (where 50% is ionized and unionized)
what is aspirin (acetylsalicylic acid)
weak acid
noreepinephrine
weak base
Drug ph: Weak Acid
ph: Acidic
protons (H+):
drug state:
liquid soluble:
rate of absorption:
Drug ph: Weak Acid
ph: Acidic
protons (H+): Excess
drug state: unionized>ionized
liquid soluble: yes
rate of absorption: high
Drug ph: weak acid
ph: basic
protons (H+)
drug state:
liquid soluble:
rate of absorption:
Drug ph: weak acid
ph: basic
protons (H+): few
drug state: ionized>unionized
liquid soluble: no
rate of absorption: low
Drug ph: weak base
ph: acidic
protons (H+)
drug state:
liquid soluble:
rate of absorption:
Drug ph: weak base
ph: acidic
protons (H+): excess
drug state: ionized>unionized
liquid soluble: no
rate of absorption: low
Drug ph: weak base
ph: basic
protons (H+):
drug state:
liquid soluble:
rate of absorption:
Drug ph: weak base
ph: basic
protons (H+): few
drug state: unionized>ionized
liquid soluble: yes
rate of absorption: high
stops of absorption along the GI
- stomach: drug reaches and disintegrates + dissolves
- small intestine: high permeability, large surface area, high blood flow (primary site for drug absorption)
- large intestine: low permeability and small surface area, poor site for drug absorption, some drugs are absorbed bc long transit period (24-48hrs)
distribution
along concentration gradient between blood and tissue (onset, duration, intensity of action)
physiological factors affecting drug distribution
- blood concentration
- cardiac output
- organ vascularity and blood flow
- capillary permeability
- tissue perfusion
drug properties affecting drug distribution
- degree of ionization
- liquid solubility
- binding to plasma and tissue proteins
- pH
volume of distribution what is it + what is the eqtn
measure of space able to contain drug
Vd = (total amount of drug in body / drug concentration in plasma) L/70kg
4 drug reservoirs
- plasma proteins
- intracellular space
- fat
- bones
Compartment: Total body water
Vd (L/70kg):
Drug:
Ex:
Compartment: Total body water
Vd (L/70kg): 42
Drug: small water soluble molecules
Ex: ethanol
Compartment: Extracellular water
Vd (L/70kg):
Drug:
Ex:
Compartment: Extracellular water
Vd (L/70kg): 14
Drug: large water soluble molecules
Ex: Gentamicin
Compartment: Plasma
Vd (L/70kg):
Drug:
Ex:
Compartment: Plasma
Vd (L/70kg): 3
Drug: large protein molecules
Ex: antibodies
Compartment: Fat
Vd (L/70kg):
Drug:
Ex:
Compartment: Fat
Vd (L/70kg): >42
Drug: lipid soluble molecules
Ex: diazepam
3 results of metabolism
- bioactivation
- deactivation
- detoxification
Purpose of metabolism
- increased drug’s water solubility
- helps elimination
sites of drug biotransformation (main one, and subsections)
- Liver (primary site)
- high concentration of metabolizing enzymes
- high blood flow
- receives blood from GI tract - kidneys, intestine, lungs, skin
Phase 1 Reaction of Drug Metabolism Overview
reactions add or unmask a functional group
modifies product thru oxidation, hydrolysis, or reduction
Oxidation: give o2 to drug and gain elections
Reduction: give (H) hydrogen or take o2, give electron
Hydrolysis: adds water, ex: carboxyl esterases
Phase 1 Reactions: Oxidation Reaction
- add O2/lose an electron
- main enzyme system for this process is the cytochrome P450 (CYPs) enzyme (REMEMBER CYP 3A4 METABOLIZES MOST DRUGS**)
- other than that enzyme:
alcohol + alcohol dehydrogenase = aldehyde
norepinephrine + monoamine oxidase = inactivation
Phase 2 Reaction of Drug Metabolism Overview
reactions add a large water soluble component to allow excretion by the kidney
Addition of a water-soluble component to facilitate excretion
Glucuronidation, Sulfation, Glutathione conjugation, Acetylation
Phase 2 Reactions: Conjunction Reaction
adding a water-soluble moiety to phase 1 product - water soluble - easy to excrete
Main Conjunction Reaction: Glucuronidation
(Of phase 2 drug metabolism)
Enzyme:
Added Molecules:
Enzyme: UDP-glucuronosyltransferase (UGT)
Added Molecules: Glucoronates
Main Conjunction Reaction: Sulfation
(Of phase 2 drug metabolism)
Enzyme:
Added Molecules:
Enzyme: Sulfotransferase (SULT)
Added Molecules: Sulfates
Main Conjunction Reaction: Glutathione conjugation
(Of phase 2 drug metabolism)
Enzyme:
Added Molecules:
Enzyme: Glutathione transferase (GST)
Added Molecules: Glutathiones
Main Conjunction Reaction: Acetylation
(Of phase 2 drug metabolism)
Enzyme:
Added Molecules:
Enzyme: N-acetyl transferase (NAT)
Added Molecules: Acetates
1st pass metabolism
- inactivation of orally administered drugs before reaching the systemic circulation
- before absorption = intestine
- after absorption = liver
- result: decreased amount of active drug reaching blood and site of action
- how to avoid: change route of administration
factors affecting biotransformation: intra-individual differences
- diseases (especially liver)
- drug-drug interactions (DDI)
- diet
- gut microbiota
factors affecting biotransformation: inter-individual differences
- age
- sex
- genetic factors
routes of excretion
- kidney (primary)
- GI tract
- lungs
- bodily fluids (sweat, saliva, milk)
all meds excreted diff
renal excretion
glomerular function
- filtration (filtrate = plasma - plasma proteins)
tubular function
- reabsorption (water and useful materials - back to blood)
- secretion (waste products - urine)
excretion =
filtration - reabsorption + secretion
drug and renal excretion
- drugs must b water soluble (ionized) to be excreted thru kidney
- RBF (renal blood flow) = +/- 1200ml (20-25% of CO)
- GRF (glomerular filtration rate) = 125ml/min (decreased GRF, decreased excretion)
- active transporters in renal tubule can move drugs from blood - urine - excretion (ex: penicillin)
effect of urine pH on drug excretion (for acidic and basic)
acidic urine: increased excretion of basic drugs (ex: opioids)
basic urine: increased excretion of acidic drugs (ex: aspirin)
what drugs can be reabsorbed back into the blood
lipid soluble drugs
what happens to penicillin during active secretion?
how can we solve this problem?
+/- 80% of penicillin dose is cleared from the body within 3-4 hrs after administration = lower concentration and effect
to solve: combine drug w drug probenecid (competitively blocks penicillin excretion)
methods of excretion
- lack of absorption thru intestine: drugs w low bioavailability, protein-bound drugs in intestine
- excretion via bile: excreted by hepatocytes into bile, eliminated thru GI in feces
enterohepatic cycle
process where drug after being absorbed into bloodstream from GI tract is taken by the liver, and a portion is excreted into small intestine through bile. in small intestine, some drug can be reabsorbed into bloodstream basically recycling it. can prolong a drug’s presence in body and affect its effectiveness or duration.
Glucuronidation
Adds: Glucuronate
Enzyme: UDP-glucuronosyltransferase
Sulfation
Adds: Sulfate
Enzyme: Sulfotransferase
Glutathione conjugation
Adds: Glutathione
Enzyme: Glutathione transferase
Acetylation
Adds: Acetate
Enzyme: N-acetyl transferase
