Pharmacology: ADME

Pharmacology
The study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal processes

Pharmacokinetics
“the body’s effects on the drug”
Changes in plasma drug concentration over time

What are the 4 pharmacokinetic processes?
1. Absorption
2. Distribution
3. Metabolism
4. Elimination

Absorption
The movement of a drug from its site of administration into the bloodstream

Distribution
The movement of a drug from the bloodstream to the various tissues of the body

Metabolism
The biotransformation of a drug into inactive or active metabolites

Elimination
The removal of a drug from the body

What are the 4 pharmacokinetic parameters?
1. Bioavailability
2. Volume of distribution
3. Elimination half-life
4. Clearance

Bioavailability
The fractional extent to which a dose of drug reaches the systemic circulation

Volume of the distribution
The apparent space in the body available to contain the drug

Elimination half-life
A measure of the rate of removal of drug from the body

Clearance
A measure of the body’s efficiency in eliminating the drug

Pharmacodynamics
“The drug’s effects on the body”
The relationship between drug concentration and effect

Mechanism of drug action
The drug interaction with macromolecular components responsible for the biochemical and physiologic effects in the body

Receptors
The component of the organism with which the drug is presumed to interact

Intrinsic activity
The drug effect on receptor function (e.g. agonist, antagonist)

Affinity
The strength of the interaction between a drug and its receptor

Potency
A measure of the concentration of drug required to elicit a particular response

Efficacy
A measure of the degree of response elicited by a particular drug

Pharmacogenetics
The study of the genetic basis for variation in drug response

Disease
Variability in the underlying disease that may affect treatment response or adverse drug effects

Elimination vs. excretion?
Elimination can be a combination of processes — part of elimination process should involved metabolizing it into an excretable form

How do tissue blood flow and absorptive surface area impact the rate and degree of absorption?
The more the blood flow to the area, and the greater the surface area, the greater the degree of absorption

What factors affect diffusion?
Concentration gradient, polarity (highly charged won’t pass easily), size can play a role, lipid solubility (very important)

What factors affect paracellular transport?
Water solubility

What factors affect facilitated diffusion?
Specific molecules that can help transport a drug across a membrane

What 3 processes are passive?
Paracellular transport, diffusion, facilitated diffusion

What process is active?
Drug transporter, requires energy (either primary or secondary)

Oftentimes, but not always, drug transporters are involved in what process for drugs?
Excretion of drugs

What form of drugs is more lipid-soluble and able to cross the cell membrane?
The un-ionized forms

What form of drug is often the active form?
Ionized forms

Weak acids are uncharged in what environment?
Acidic environment

Weak bases are uncharged in what environment?
Basic environment

What is the key point of absorption?
The route of administration and rate and degree of absorption are important contributors in achieving therapeutic tissue drug concentrations

What may affect compartment volumes?
Age, gender, habitus, and disease

Describe lipid accumulation in drug distribution
Sometimes, you’ll find that someone with larger fat capacity may have situation where (even after drugs no longer taken) fat serves as depot and can potentially maintain a higher degree of plasma concentration of the drug
– Larger fat compartment may play into termination effect of drugs –> shorter course of action, may need to increase dose of drug

What is the rapid initial phase of distribution?
Most highly perfused organs (e.g. liver, kidney, brain, heart)

What is the slower secondary phase of distribution?
Occurs over minutes to hours and involves larger fraction of body mass (e.g. muscle, viscera, skin, fat)

Weak acids bind to what proteins?
albumin or lipoprotein

Weak bases bind to what protein?
alpha-1 acid glycoprotein

Describe protein binding in drug distribution
– protein binding may occur in plasma or tissue
– bonds are typically non-covalent and reversible
– binding may impair membrane permeation
– tissue-binding creates drug reservoirs that may have toxic or therapeutic implications
– drugs with high degrees of protein binding and low therapeutic indices may be sources of adverse drug effects

What are the key points about distribution?
– drug distribution is dependent on regional blood flow and membrane permeation
– membrane permeation and protein binding are reversible
– drug storage depots resulting from lipid accumulation or protein binding may shorten or prolong drug effects

What is the major site of drug metabolism?
Liver

Metabolism results in drug activation or inactivation that can do what?
– promote drug excretion by enhancing water solubility and/or suitability for renal excretion
– diminish therapeutic effect, enhance therapeutic effect, cause toxic or other effects

If you take drug in inactive form, what happens?
It must be activated (open in liver)

Liver can also inactivate drugs. What will this do?
Diminish drug effects so it can be excreted easily by kidneys

What is the potential implication of liver metabolism on orally administered drugs?
That drug may be subject to “first pass” effects — so it may be a drug that needs to be activated in the liver first
– Does not mean first pass drugs are the only ones given orally. It may mean you just need to a higher dose to make it through the liver

Conjugation
Putting molecules onto the drug (sulfation, etc.)

CYP2D6
accounts for 2% of the CYP P450 in the liver
– bottleneck, can be saturated easily

CYP3A4/5
accounts for 40% of CYP P450 in the liver
– workhorse, so much of it in the liver

URM
ultrarapid metabolizer

EM
extensive metabolizer

PM
poor metabolizer

What happens in phase 1 metabolism?
Transformations (redox, hydrolysis)
– generate OH, NH2, and COOH functional groups that can undergo phase II conjugation
– CYP2D6: bottleneck
-CYP3A4/5: workhorse
– might turn into an active form (not always)

What happens in phase 2 metabolism?
Conjugations (sulfation, methylation, glucoronidation, acetylation)
– Typically enhances water solubility and/or promotes transporter secretion
– usually turns drug into an inactive compound (but not always)

What is the major route of excretion?
Kidney is major route of drug excretion
– biliary excretion is less important but still a clinically relevant mechanism of drug excretion

What will happen to most drugs before they’re excreted?
Most drugs will be metabolized before excreted, but not all

Where does filtration occur in the kidney?
Glomerulus

Describe filtration in renal excretion
– glomerulus
– passive
– pressure and flow dependent
– protein bound drugs remain in the plasma

Describe secretion in renal excretion
– proximal convoluted tubule
– active and passive
– energy-dependent drug transporters
– protein-bound drugs can be secreted

Describe failure of reabsorption in renal excretion
– distal convoluted tubule
– passive
– pH = 5.4
– basic drugs excreted (charged, so can’t pass through)
– acidic drugs reabsorbed (uncharged in acidic environment)
– lipid soluble drugs reabsorbed

Urine pH can be manipulated to alter what?
Drug excretion

The pH of the urine is acidic in the distal convoluted tubule. What does this mean about excretion?
Charged (basic) drugs can’t passively move past the membrane and into the blood so they are excreted
Uncharged (acidic) drugs can passively move past the membrane and into the blood so they are reabsorbed

Drug transporters are involved in what renal processes?
Absorption, distribution, and excretion

Transporters can be involved in the distribution of drugs to where?
To different organs

ATP binding cassette (ABC)
– active transport
– ex: P-glycoprotein

Solute carrier (SLC)
– facilitated and secondary transport
– ex: organic anion/cation transporters (OATs/OCTs)

What are the key points of excretion?
– kidney is primary organ of drug excretion
– filtration, secretion and failed reabsorption are important renal excretory mechanisms
– secretion relies on drug transporters

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