PGI Bat-og, Jose Allen Roncel C.

Daily Learning Report 10/20/2022

Chapter 11 – Basic Principles of Clinical Pharmacology

Pharmacokinetics

 In order for drugs to work, they must be able to reach the site wherein it takes effect,

and to do so, it must be able to penetrate through the cell membranes. Drugs that are

lipophilic in nature must be able to cross the layers which are hydrophilic in order to

reach the lipophilic cores. One way to achieve this is through passive diffusion

wherein they could go by traveling down the concentration gradient; however it

would only work if they are small.

 Hydrophilic drugs on the other hand require channels that arise from transmembrane

proteins in order for them to go down their concentration gradients; these said

hydrophilic channels can be seen throughout all the organ systems in the body except

the CNS. This means that hydrophilic drugs would require drug-specific

transmembrane proteins for them to be able to enter the CNS.

 In contrast to passive transport, active transport works by utilizing energy to transport

substances through the membranes against the concentration gradient with the help of

transmembrane carrier proteins. Facilitated diffusion is another process and is similar

to active transport; however it does not require energy in order to transport drugs.

These two processes are saturable meaning that it would cease to transfer drugs when

the carrier proteins are all occupied.

 Again, lipophilic drugs can pass through the concentration gradient without the aid of

transporters; however, they can still benefit from those since they have an effect

towards the concentration gradients.

 Drugs only work when they reach their respective sites of action and one way for it to

happen is by going through the blood supply or the circulatory pathway. Drugs given

intravenously results in the rapid supplement of the drug and would present with a

100% bioavailability.

 Bioavailability is the fraction of the uncharged drug that reaches the systemic

circulation administered by any route.

 An important thing to watch out for in giving drugs intravenously is the immediate

increase in concentration of the drug in the system. Since drugs are also known to

have side effects, its rapid infusion may pose a huge risk and display toxic effects

especially if it has a low therapeutic index.

 Therapeutic index is the ratio of blood concentration at which the drug is toxic in

50% of population vs the concentration at which the drug produces therapeutic

effects.

 Although the other routes of administration are not as fast as through intravenous

route, they can still provide therapeutic effects since they would only differ in the rate

at which the drug is absorbed into the systemic circulation. The drug effects can be

seen when the minimum effective plasma concentration is achieved or exceeded.

 Out of all the different routes of drug administration, the oral route has been regarded

as the safest and most convenient route. In anesthesia, however, this is not given

much concern since this route offers a high degree of variability and is affected by

many factors partly due to the fact that the drugs must first reach the small intestines

wherein the highest level of absorption in the gastrointestinal tract occurs. It should

also be considered that the mucosa of the small intestine acts on the drug themselves

and actively metabolizes them causing the bioavailability of the drug to be decreased.
 First pass metabolism – drugs administered orally undergo metabolism in the gut and

additionally in the liver before it reaches the systemic circulation.

 In order to reach therapeutic levels, drugs given orally should be at a higher dose

when compared to the intravenous counterpart.

 In the field of anesthesia, oral route is not given the spotlight since there is a lot of

variability and it takes a lot of time for the drug to take effect.

 There are also drugs given intranasally or orally and take effect upon direct,

prolonged contact with the mucosa. Additionally, there is the sublingual route which

directs the drug towards the systemic circulation without having to be metabolized by

the gastrointestinal tract and the liver’s first pass metabolism. In comparison with

oral route, these results in a higher bioavailability and a more rapid onset of

therapeutic effect.

 Drug preparations that are given through the skin also exist, these falls under the

transcutaneous administration route. The downside of this route is that it takes much

longer for the drugs to take effect.

 Another rapid way of giving drugs is through the subcutaneous or intramuscular

route. The drugs reach therapeutic levels fast since these tissues are highly vascular

and the absorption is enhanced due to the high blood flow.

 A common way of giving anesthesia that is regularly seen in the hospital is through

spinal anesthesia. The anesthetics given intrathecally work on the spinal cord which

is their primary site of action making it have a rapid onset since it reaches the site

directly. On the other hand, epidural anesthesia although similar in preparation,

differs and takes more time to take effect because anatomy-wise, it has to travel first

through the nerve sheaths before reaching the primary site of action.
 Inhalational anesthetics such as isoflurane or sevoflurane exert its effects by going

through the pulmonary alveoli which not only has a large surface area, but also a

considerable amount of volumetric blood flow.

 The next step after the drug reaches the systemic circulation is the distribution of its

concentration throughout the organs of the body initially going into the brains, lungs,

heart, and kidneys first which are the core circulatory components with the highest

degree of perfusion. This is because in terms of physiology, bulk of the cardiac

output goes to them. After these core organs, the muscles, liver, splanchnic organs,

adipose tissue, and bones would follow. The amount of drug that these organs receive

depends on the amount of blood flow since the capillaries do not get saturated as

much.

 Redistribution occurs when the organ to be perfused with the drug reaches

equilibrium with the concentration present in the blood. An example would be the

brain which has a high degree of perfusion but has a low tissue volume. Once the

brain reaches drug concentration that is higher than that of the blood, the drug would

then diffuse back into the blood due to the concentration gradient and then proceed to

perfuse the other organs of the body which are not yet completely concentrated.

 Drug is eliminated through excretion from the body or metabolized first before being

eliminated. Both of these processes contribute to the decrease in the drug

concentration and loss of the effects of the drug. Elimination then is considered as the

irreversible loss of the drug from the site of measurement. Drug clearance or

elimination clearance on the other hand quantifies elimination, it is the volume of

blood from which all the drug would be removed per unit time.

 Hydrophilic drugs are those that can be eliminated from the body through urine or

stool and remain unchanged, they do not require processes to convert their
 components. In contrast, if the drugs are not hydrophilic enough, they need to first be

modified into something more hydrophilic so as to be eliminated from the body. The

processes that involve this are the biotransformation reactions. Phase 1

biotransformation reactions turn the drug into a more polar one through hydrolysis,

oxidation, or reductive reactions. The enzymes responsible for this biotransformation

are the cytochrome p450, wherein CYP3A4 is the most frequently occurring. They

are prominent in the liver cells and intestinal enterocytes with minimal numbers in

lungs, kidneys, and skin. They work on the drugs by oxidizing them meaning an

oxygen atom would be inserted. Phase 2 involve the transformation by combining it

with different compounds to make it hydrophilic in a process called conjugation. In

order for a drug to be conjugated, it must have a polar group that would serve as the

attachment site for conjugation so in some drugs, a phase 1 reaction is required first

in order for phase 2 to occur. The products of phase 2 reactions are polar compounds

that are water soluble; these are then removed through the kidneys or liver.

 In renal drug clearance, elimination is through the passage of urine wherein it

contains the hydrophilic drugs as well as the conjugated, metabolites of lipophilic

drugs that resulted from the phase 1 and 2 reactions.

 Hepatic clearance involves the liver’s capacity to be able to metabolize drugs as well

as the drugs that have diffused into it. The hepatic clearance is has a direct correlation

to the hepatic blood flow.

 The volume of distribution is the measurement of the fluid volume required to

contain all of the drug in the body at the same concentration in the blood. It is used

for the estimation of the plasma concentration when we know the amount of drug is

in the body as well as estimating the dose required to obtain the given plasma

concentration.
  Drug clearance is the parameter used when quantifying the amount of elimination, it

corresponds to the volume of blood from which all the drug appear to be removed per

unit time and is also the proportionality factor relating the rate of drug elimination to

the plasma drug concentration.

 Elimination half-life corresponds to the time it takes for the plasma concentration as

well as the amount of drug in the body to decrease by half of its concentration. Its

value would be dependent on the amount of drug present in the body.

Pharmacodynamics

 Drug receptor interactions – the binding of drugs to their receptors follow the law of

mass action wherein the rate of chemical reaction is proportional to the product of the

concentrations of the reactants.

 Agonist effect involves the binding of the drug to the receptor which alters the

function of the receptor while the antagonist effect indicates that the binding of the

receptor does not affect its function but prevents the subsequent binding of the

agonists.

 Agonists are drugs which interact and activate receptors having both an affinity and

efficacy. They are classified as either full agonist having a maximal response with

high affinity and intrinsic activity or partial agonist which are agonists with

submaximal efficacy even though there is full occupation of the receptors (high

affinity, low intrinsic activity).

 Antagonists are drugs which have a high affinity but without intrinsic activity. These

may be either competitive or noncompetitive. In competitive antagonists, affinity

binds reversibly at the receptor site. In its presence, the agonist log concentration

effect curve is shifted to the right without change in slope. In noncompetitive

 antagonists, there is irreversible interaction of the antagonist at any site of the receptor

preventing the binding of agonists, this is shown by the flattening of the agonist in the

concentration-effect curve.

 In the dose-response relationship, the concentration-effect curve shows that responses

to low doses of a drug usually increase in direct proportion to the dose. However, the

incremental response diminishes until there is ultimately no more increase in the

response. Based on the receptor occupancy theory, the magnitude of the response is

proportional to the fraction of total receptor sites occupied.

 The therapeutic threshold of the drug is the minimum concentration of the drug that

produces its therapeutic effect.

 Drug interactions involve any reactions between a drug and a second substance which

includes other drugs, food, or chemicals. It may result in the increase or decrease of

the drug effect and as such must be observed carefully since they may either have

beneficial or detrimental effects.

In this chapter, I was able to review the topics that I studied back in 2nd year of med school;

topics that I almost completely forgot. I have learned how the drugs work and exert their

effects as well as the differences they have through various routes of administration. An

important topic I learned is regarding the clearance of drugs, such that it is important to

properly assess the patient’s kidney and liver function since it is through these organs that

these are eliminated by the body. For example, in patients with kidney problems, inhalational

anesthetics should be preferred since they don’t depend on the kidneys to be eliminated.