Basics of Clinical Pharmacology
"what the body does to the drug" pharmacokinetics
Pharmacokinetic processes fundmental to all drugs • Absorption
• Distribution
• Metabolism
• Elimination
Are pharmacokinetic processes common to all drugs? Yes
Systemic absorption into circulation depends on: • Drug's solubility
• Blood flow to the site of absorption
• Area of absorbing surface available
Definition of bioavailability Relative amount of drug that reaches systemic circulation
parenteral route of administration IV or IM
bioavailability for parenteral route of administration 1 (100%)
What does a bioavailability of 1 mean Drugs are 100% absorbed into systemic circulation
Enteral route oral and rectal
Bioavailability of enteral route of administration usually much less than due to first-pass metabolism by the liver
In the field of anesthesia, most drugs we use are IV → 1. instantly
____ reach systemic circulation (i.e have ___% 2. 100%
bioavailability)
In anesthesia, why do most drugs have 100% Because they are given IV and instantly reach systemic circulation
bioavailability?
Metabolism that occurs before a drug reaches systemic First-pass metabolism
circulation or its target site
First pass metabolism does what to bioavailability? Significantly reduces bioavailability of drugs, especially when orally administered
First-pass metabolism can be caused by liver
lungs
plasma esterase / pseudocholinesterase
, Basics of Clinical Pharmacology
Most significant first-pass metabolism for enteral liver
administration
technically, fentanyl uptake/metabolism occurs in _____ lungs
prior to reaching arterial circulation/target site
Example of a drug that undergoes first-pass metabolism by succinylcholine
Plasma esterase / Pseudocholinesterase
group that gets most cardiac output despite being a small vessel-rich group
percentage of body weight
group that gets almost no cardiac output vessel-poor group
Examples of VPG 1. Bones
2. Ligaments
3. Cartilage
Vessel-rich group composition brain, heart, liver, kidney, endocrine glands
Body mass (%) vs Cardiac Output (%) VRG: 10% vs 75%
- VRG Muscle: 50% vs 19%
- Muscle Fat: 20% vs 6%
- Fat Vessel-poor: 20% vs 0%
- Vessel Poor
Following an injection, a drug will initially go to VRG tissues as CO is mostly distributed there
Lipophilic drugs will rapidly equilibrate into CNS tissue (but also be avidly taken up in Fat)
The movement of a drug from vessel-rich tissues (Ex: Redistribution
Brain/CNS) into less perfused tissues (Ex: Fat or muscle),
reducing its clinical effect
For lipophilic drugs, Fat will gradually absorb the drug over redistribution
time
Why does redistribution cause drug effects to wear off? Because drug concentration in the target organ falls as it moves into fat and muscle,
even though the drug is still present in the body
What acts as a reservoir for drugs fat
What is redistribution in pharmacology? It accounts for a substantial part of offsetting the drug effect.
, Basics of Clinical Pharmacology
What happens to peripheral tissue concentration with It increases due to accumulation.
multiple doses of a drug?
What happens with repeated doses of lipophilic drugs? Peripheral tissues accumulate the drug
→ Impact of redistribution is reduced, leading to prolonged drug effects
After redistribution has occurred, what mainly determines Elimination by metabolism and excretion
the fall in plasma drug concentration?
What causes the major initial drop in plasma drug Rapid distribution of the drug into vessel-rich group (VRG) tissues
concentration after injection?
Most drugs are bound to plasma proteins
If drugs are bound to plasma proteins can they be NO - unavailable
excreted or uptaken?
Plasma proteins that bind drugs albumin
𝜶1-acid Glycoprotein
Albumin binds most acidic/neutral drugs
𝜶1-acid Glycoprotein binds most basic drugs
low protein levels means what for free-drugs in serum more free-drug
→ Higher amount of free drug in serum, since less is bound to proteins
What can cause low protein levels (6) 1. Age
2. Hepatic disease
3. Renal failure
4. CHF
5. Major burns
6. Pregnancy
do low protein levels impact propofol Does not particularly effect propofol as it is administered in its own binding
molecules
(lipid emulsion)
In theory, how should higher free drug levels affect drug Increase the drug's effect
action? → However, in practice, this relationship is unclear
Do plasma proteins account for most drug binding in the No
body? → Plasma proteins only account for small portion of total binding sites for a drug in
the body
"what the body does to the drug" pharmacokinetics
Pharmacokinetic processes fundmental to all drugs • Absorption
• Distribution
• Metabolism
• Elimination
Are pharmacokinetic processes common to all drugs? Yes
Systemic absorption into circulation depends on: • Drug's solubility
• Blood flow to the site of absorption
• Area of absorbing surface available
Definition of bioavailability Relative amount of drug that reaches systemic circulation
parenteral route of administration IV or IM
bioavailability for parenteral route of administration 1 (100%)
What does a bioavailability of 1 mean Drugs are 100% absorbed into systemic circulation
Enteral route oral and rectal
Bioavailability of enteral route of administration usually much less than due to first-pass metabolism by the liver
In the field of anesthesia, most drugs we use are IV → 1. instantly
____ reach systemic circulation (i.e have ___% 2. 100%
bioavailability)
In anesthesia, why do most drugs have 100% Because they are given IV and instantly reach systemic circulation
bioavailability?
Metabolism that occurs before a drug reaches systemic First-pass metabolism
circulation or its target site
First pass metabolism does what to bioavailability? Significantly reduces bioavailability of drugs, especially when orally administered
First-pass metabolism can be caused by liver
lungs
plasma esterase / pseudocholinesterase
, Basics of Clinical Pharmacology
Most significant first-pass metabolism for enteral liver
administration
technically, fentanyl uptake/metabolism occurs in _____ lungs
prior to reaching arterial circulation/target site
Example of a drug that undergoes first-pass metabolism by succinylcholine
Plasma esterase / Pseudocholinesterase
group that gets most cardiac output despite being a small vessel-rich group
percentage of body weight
group that gets almost no cardiac output vessel-poor group
Examples of VPG 1. Bones
2. Ligaments
3. Cartilage
Vessel-rich group composition brain, heart, liver, kidney, endocrine glands
Body mass (%) vs Cardiac Output (%) VRG: 10% vs 75%
- VRG Muscle: 50% vs 19%
- Muscle Fat: 20% vs 6%
- Fat Vessel-poor: 20% vs 0%
- Vessel Poor
Following an injection, a drug will initially go to VRG tissues as CO is mostly distributed there
Lipophilic drugs will rapidly equilibrate into CNS tissue (but also be avidly taken up in Fat)
The movement of a drug from vessel-rich tissues (Ex: Redistribution
Brain/CNS) into less perfused tissues (Ex: Fat or muscle),
reducing its clinical effect
For lipophilic drugs, Fat will gradually absorb the drug over redistribution
time
Why does redistribution cause drug effects to wear off? Because drug concentration in the target organ falls as it moves into fat and muscle,
even though the drug is still present in the body
What acts as a reservoir for drugs fat
What is redistribution in pharmacology? It accounts for a substantial part of offsetting the drug effect.
, Basics of Clinical Pharmacology
What happens to peripheral tissue concentration with It increases due to accumulation.
multiple doses of a drug?
What happens with repeated doses of lipophilic drugs? Peripheral tissues accumulate the drug
→ Impact of redistribution is reduced, leading to prolonged drug effects
After redistribution has occurred, what mainly determines Elimination by metabolism and excretion
the fall in plasma drug concentration?
What causes the major initial drop in plasma drug Rapid distribution of the drug into vessel-rich group (VRG) tissues
concentration after injection?
Most drugs are bound to plasma proteins
If drugs are bound to plasma proteins can they be NO - unavailable
excreted or uptaken?
Plasma proteins that bind drugs albumin
𝜶1-acid Glycoprotein
Albumin binds most acidic/neutral drugs
𝜶1-acid Glycoprotein binds most basic drugs
low protein levels means what for free-drugs in serum more free-drug
→ Higher amount of free drug in serum, since less is bound to proteins
What can cause low protein levels (6) 1. Age
2. Hepatic disease
3. Renal failure
4. CHF
5. Major burns
6. Pregnancy
do low protein levels impact propofol Does not particularly effect propofol as it is administered in its own binding
molecules
(lipid emulsion)
In theory, how should higher free drug levels affect drug Increase the drug's effect
action? → However, in practice, this relationship is unclear
Do plasma proteins account for most drug binding in the No
body? → Plasma proteins only account for small portion of total binding sites for a drug in
the body
