Pharmacology: Pharmacokinetics Flashcards
What are the enteral methods of drug administration?
Sublingual, swallowing and rectal (which bypasses the liver)
How are enteral drugs designed to be absorbed along the acidic part (stomach) of the GI tract or neutral part (intestine)?
Drugs are designed to dissolve at high or low pH
How does age effect enteral drug absorption?
Elderly: Less proteins & water in the body
Infant (human): >77% of water (human adult average ~70%)
pH of the GI-tract may change with age
In general, compounds that are rapidly absorbed by the enteral route have…
a. Low degree of ionization
b. High lipid/water partition in the non ionized form
c. Relatively low MW < 1000
d. A biological affinity with transporters/facilitated diffusion (e.g. cephalporins are absorbed by a transporter for dipeptides).
(NB. a/b/c = Lipinski’s rules)
In general compounds that are not rapidly absorbed by the enteral route have…
a. High degree of ionization (ions need specific channels/transporters: Na vs. Mg): Must be neutral to cross the membrane
b. Low lipid/water partition in the non ionized form (flows with the peristaltic mvt & eliminated or needs transporter e.g. glucose)
c. Too large (e.g. chemicals forming precipitate flows with the peristaltic mvt & eliminated).
d. Degraded by specific enzymes (e.g. insulin, epinephrine, histamine,…)
Weak acids ……………. a proton (H+) to form …………….
Weak acids (HA) donate (H+) to form anions: HA↔H++A-
Weak bases ……………. a proton (H+) to form …………….
Weak bases (B) accept a proton (H+) to form cations: BH+ ↔B+ H+
What is first pass metabolism?
If a drug is metabolised BEFORE it reaches the systemic circulation
Oxidation & Conjugation to make compounds water soluble. Many drugs are “inactivated” and excreted this way by the liver
What happens to lipophilic drugs that undergo first pass metabolism?
Phase 1 (catabolic): Oxidation, reduction and/or hydrolysis Phase 2 (anabolic): synthetic conjugation
The drug is then water soluble and usually inactive
What happens to lipophilic drugs that undergo first pass metabolism?
Phase 1 (catabolic): Oxidation, reduction and/or hydrolysis Phase 2 (anabolic): synthetic conjugation
The drug is then water soluble and usually inactive
Where do the enzymes for first pass metabolism live?
In the smooth endoplasmic reticulum of the hepatocytes
What is enterohepatic circulation?
Drugs metabolized may recycle several times before entering the systemic circulation (the drug follows bile salts)
When a drug is metabolised what can happen to the metabolite?
Detoxified (inactivated) eg Phenol
Similar activity to the drug eg. Diazepam
Have a different activity eg Ipronazid (anti-depressant) to Isoniazid (anti-tuberculosis)
Form toxic metabolites eg. Phenacetin
How does CYP P450 work?
Drug-R + O2 —–(NADPH to NADP by CYP)—-> Drug-OR +H2O
Where are CYP enzymes found?
The majority are in the liver but some are found in the walls of the intestine
In mammals CYP is bound to the endoplasmic reticulum
What is the most important CYP enzyme?
CYP 2D6 only represents 2% of enzymes in the liver but carries out 1/3 of metabolism of drugs in the liver
What are the topical drug administration methods?
Skin: Local slow & sustained effects (hours to weeks, e.g. patches).
Eye drops: local effect to renew frequently (washed away rapidly).
Nasal instillation local systemic effect.
What is the benefit/drawback of intradermal administration?
Slow absorption
What are the advantages and disadvantages of subcutaneous administration?
Faster absorption but fat layer may trap lipid soluble compounds
Massage increases blood flow and absorption.
What are the advantages and disadvantages of IM administration?
Very fast absorption
Physical activity/massage increases absorption.
Absorption: liquid>suspension>emulsion
When is intravascular administration used?
Mostly used when need to accurately control the body concentration of drugs. Typically used when compounds have narrow margins of safety between therapeutic and toxic index
What is the drawback with IV administration?
Drug injected cannot be recalled (whereas stomach pump or emetics can be used for enteral routes & other means exist to delay dermal/muscular injections).
A slow administration is needed to avoid side effects
What are the advantages and disadvantages of inhalation administration?
Gas and aerosols have a rapid systemic effect but dependent on:
1- the tidal volume
2- the size of the aerosol particle (not true for gas). The smaller the more likely to reach alveolar ducts and sacs. Otherwise get stacked in bronchi
What are the advantages and disadvantages of inhalation administration?
Gas and aerosols have a rapid systemic effect but dependent on:
1- the tidal volume
2- the size of the aerosol particle (not true for gas). The smaller the more likely to reach alveolar ducts and sacs. Otherwise get stacked in bronchi
What are the main and secondary routes of drug excretion?
GA)
Secondary routes: Milk, sweat
When the pH of the urine < pH of blood what happens to drug excretion?
a) Trapping of basic drug in urine therefore increased renal excretion
(b) Greater reabsorption of acid drug therefore reduced renal excretion
When the pH of the urine > pH of blood what happens to drug excretion?
(a) Trapping of acid drug in urine therefore increased renal excretion
(b) Greater reabsorption of basic drug therefore reduced renal excretion
Define Quantitative Pharmacokinetics (PK)
Changes in plasma/tissue drug concentration with time
Define Quantitative Pharmacodynamics (PD)
Changes in biological response with time
Define drug absorption rate
The Amount of Drug Absorbed from Administration Site to Measurement Site per Unit Time
Units: Mass or Moles per time
Absorption rate from bolus intravenous administration can be considered…
instant
Absorption rate from infusion administrations eg intravenous infusion, transdermal patch etc follows….
zero order kinetics
Absorption rate from diffusion type administrations eg oral, intramuscular etc tend to follow….
first order kinetics
What is the infusion rate (IR)?
Absorption rate from infusion administration = Infusion Rate (IR) and rate is independent of the Amount of drug (zero order)
Absorption rate from oral administration tends to be proportional to….
….amount of drug (first order)
Amount of drug at administration site decreases with time therefore, rate of absorption decreases
Define drug elimination rate
The Amount of Parent Drug Eliminated from the Body per Unit Time
Units: Mass or Moles per time
Elimination rate is defined with respect to irreversible removal of parent drug and does not include metabolites
Define volume distribution
The volume into which a drug appears to be distributed with a concentration equal to that of plasma OR A proportionality constant relating the Blood/plasma concentration to the amount of drug in the body
If Vd is in the order of 0.1-0.3L/Kg then the drug is most likely…
water soluble and distributes to the ECF
If Vd is in the order of 0.6L/Kg then the drug most likely ……
distributes to the ECF and ICF
If Vd is high (in the order of 2L/Kg) then the drug is probably….
accumulating in a particular site
What is total body (blood) clearance?
The volume of blood/plasma cleared of parent drug per unit time OR A constant relating the rate of elimination to the blood/plasma concentration
Rate of elimination =
Blood/plasma clearance x Blood/plasma conc
Cl total =
Cl(hepatic) +Cl(renal) + Cl(Pulmonary)
Rate of elimination cannot exceed the….
Rate of flow to the organ
How do we determine Total body clearance (CL)?
Blood/Plasma clearance is determined from the area under the blood/plasma concentration versus time curve (AUC) from an IV administration
CL = Dose/AUC for IV or = FDose/AUC
where oral availability = F
What is bioavailability (F)?
the fraction or percentage of administered dose that reaches the plasma
How do we determine bioavailability (F)?
F = ( Dose IV/ Dose oral) x (AUC IV/AUC oral)
What is the elimination rate constant (k)?
A constant relating the rate of elimination to the amount of drug in the body
k = clearance/ vd
