Ep 21 Pharmacology Basics

Pharmacology Basics

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An overview of pharmacology concepts. If you are interested in taking a pharmacology course stop by https://www.memorizingpharm.com/

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Auto Generated Transcript:

Hey, welcome to the Memorizing Pharmacology podcast. What I wanted to start with was a pharmacology basics just an overview of many of the concepts that you’ll need to know and it’s set up as a fill in the blank. So starts with an introduction then we’ll talk a little bit about drug regulation and development a little bit about trials and how drug makes it to market about drug names and difference between generic and brand then we’ll go into a little bit of depth of pharmacokinetics which is the four basic principles the absorption.

The distribution the metabolism the excretion then pharmacodynamics how these drugs interact with receptors and things like that then some kind of drug interactions that we can have and then some adverse drug effects and then how individually we react to medicines but again it’s just a 45 minute brief overview of pharmacology I hope you enjoy.

Hello today we’re going to talk about some fundamental concepts of pharmacology we’re going to talk about the history of drug development and drug regulation the different names of drugs. We’ll introduce the concepts of pharmacokinetics and pharmacodynamics we’ll talk about how drugs can interact with each other and the adverse effects they can have and finally the individual responses to medications.

Before we get started I want you to think of these three terms we’ll talk about each of these concepts in more detail as we move along there are three important characteristics of every drug. The first is effectiveness effectiveness is whether or not a drug has its response that it is intended to or how well the drug works it is considered the most important cons characteristic of a drug because if it doesn’t do the job it’s supposed to what is the point in giving it.

The next characteristic is safety whether or not a drug produces harmful adverse effects it’s impossible to eliminate all adverse effects of a drug so drugs are considered in terms of risks and benefits chemotherapy for example always comes with an increased risk of infection when given in high doses and a drug even as safe as aspirin also has its own adverse effects long term it has the risks of gastric bleeding in ulcers.

And finally selectivity selectivity means that a drug only has the effect that it is intended to or it only acts on its target it’s important to remember that all drugs can cause side effects and none are completely selective.

To get started I would like to talk about some history of drug regulation and development in 1906 the first law regarding drug regulation was passed the federal pure food and drug act of 1906 set quality and purity standards. And then in 1938 the food drug and cosmetic act regulated drugs based on their safety diethylene glycol the ingredient in antifreeze was used as a solubility agent in an antibiotic and more than 100 people died so the fda decided that drugs must be deemed safe before they would gain approval from the fda.

Then in 1962 the harris keffer amendment was passed stating that drugs must be proven effective as well as safe. The events leading up to this happened mostly in europe where thalidomide a sedative was being used by many women to treat morning sickness. The drug ended up causing birth defects and fetal deaths. Thalidomide was never approved in the u.s but it did spur the fda to want stricter requirements for drug approval.

In 1970 the controlled substances act created rules for drugs that have a potential for abuse. The next law I’d like to talk about is the 1992 prescription drug user fee act it allowed for accelerated approval of new drugs for aids and cancer. The fda takes a very long time to approve drugs and medications were needed quicker than that process allowed for these serious illnesses.

In 1997, the fda modernization acts act expanded this to cover other serious illnesses and created other rules regarding clinical drug trials. Drug companies test their new medications through randomized control trials. The use of controls help researchers determine how new drugs compare to either existing treatments or no treatment this is done by comparing the new drug to a placebo or to another existing medication randomization prevents allocation or selection bias."

"This keeps researchers from putting sicker people in the placebo group and trying to purposely assign people to make the groups appear the same. Still has challenges due to unknown factors. Randomization controls for both known and unknown factors. This helps ensure members of each group are similar and that the outcome will more likely be the result of the treatment instead of the differences between the groups.

To minimize personal bias, subjects are blinded. By being blinded, the people involved in the trial can’t use their own biases or judgments to determine how they think the treatment affected them. A double-blind experiment is when both the subjects and the researchers do not who know who received the treatment or the placebo. Groups are treated the same and the placebo is usually matched so that it appears identical to the treatment. It’s revealed at the end of the trial who was in each group.

There are different stages to drug testing before new drugs can be tested on humans pre-clinical testing must be done. Pre-clinical testing looks at the potential useful effects, the toxicities in the pharmacokinetics of new medications. Only after pre-clinical testing has been done will the FDA award a drug with an investigational new drug status.

Once a drug enters clinical trials there are different phases that it must go through first in phase one healthy volunteers are used to test the drug’s metabolism pharmacokinetics and potential effects then a drug moves into phase two where the patients who have the condition that is being treated are used to test to determine the best dose and therapeutic uses for the drug.

In phase 3 patients with these conditions are used to test the drug for safety and effectiveness. The drug then is approved and goes to market but it is not done with its testing phase four post marketing research is done to continue to monitor for safety and effectiveness in general population some adverse effects may not be seen in clinical trial populations so post-marketing research continues to monitor drug over time as it is used in a greater larger group of people.

Next I want to talk about different names that drugs can have each drug has a chemical name generic name and trade or brand name. The chemical name tells you about drug’s chemistry for example chemical name for Tylenol is N-acetyl para-aminophenol which is long and complicated.

The trade or brand name is owned by drug manufacturer and is used for marketing sometimes drugs are referred to as their brand names because they are easier to pronounce but best name to use for a drug is its generic name a drug’s generic name often contains a stem to tell you which class it belongs to generic name for Tylenol is Acetaminophen a generic drug for low pressure is Metoprolol and it contains ending olal which gives you clue that it is beta blocker used for hypertension.

In order for a generic to be considered equivalent to brand name, drug and dose must be exactly same however inactive ingredients may differ which can have effect on drug’s absorption for some medications this little difference can have big effect for some medications slight increase in absorption can lead to drug being toxic or not safe and slight decrease in absorption can make it so that drug no longer as effective an example of medication that we should be cautious with when switching between brand and generic or even between two different generic manufacturers is Synthroid or Levothyroxine.

Next I want to talk about pharmacokinetics as you may guess by ending kinetics pharmacokinetics talks about how drugs move throughout body there are four basic principles of pharmacokinetics and they can be remembered by acronym admin A for absorption D for distribution M for metabolism and E for excretion.

Absorption is how a drug moves from site of administration into blood sites of administration could be orally or intravenously or other administration modes which we will talk about later distribution then is how drug moves throughout body how it gets its intended target metabolism is biotransformation of drug or how it is changed excretion is how drug exits body."

"When talking about routes of medication administration, there are two broad categories it can fall into: Enteral or using the gastrointestinal tract or giving medications orally and Parenteral or going outside of the GI tract which usually refers to medications that are given by injection. Parenteral routes of administration include intravenously or IV, intramuscularly or IM, or Sub Q subcutaneously or under the skin.

When a drug is given intravenously or by IV, the absorption is almost instantaneous because if you remember from above absorption refers to how the drug moves from the site of administration into the blood and IV administration injects the medication directly into the vein or into the blood. Because the absorption is 100 percent, IV administration is best for use in emergency situations when drugs have to work quickly. However, IV medications can be expensive and they’re inconvenient for the patient to treat themselves at home because IV medications must be given by trained medical professionals.

The route of administration that is most convenient for the patient and usually the least expensive is Enteral or oral or PO. However, some medications can be inactivated by oral administration and oral medications have variable absorption. Enteral medications usually come in tablet or capsule form. There are some preparations that can be made to give the drug different properties.

Enteric coatings are used to allow a drug to pass through the stomach and into the intestines. Enteric coatings have two different intended effects. Enterocodings can be used to protect the drug from the stomach so that it doesn’t dissolve or become inactivated before it reaches the intestine and they can also be used to protect the stomach from the drug as is the case for enteric coated aspirin to help prevent against gastric ulcers.

To allow a drug to achieve more steady levels over time, sustained release preparations are used. Sustained released or extended released preparations have an advantage in that this allows medications that may have needed to be taken many times throughout the day to only be taken once or twice daily with a sustained release preparation.

Once a drug has gotten into the blood it must be able to exit the blood and reach its intended target. Medications need to move through the blood to tissues, exit vasculature and then enter intended cells. Some medications need to get into brain or into CNS system in order to enter CNS system medications must be able to move through blood brain barrier drugs that are lipid soluble can more readily cross blood-brain barrier also drugs that are lipid-soluble are more likely to enter placenta some medications are harmful to growing fetus and this lipid solubility would be a bad factor in regards its ability to cross placenta.

The next two pharmacokinetic principles are metabolism and excretion. The liver is most often responsible for drug metabolism and most excretion is done by kidneys. When drugs are administered orally they are absorbed from gastrointestinal tract and transported to liver some medications are rapidly metabolized by liver and can undergo what is known as first pass effect drugs that are rapidly metabolized can be inactivated and then have no therapeutic effect."

"To bypass the first pass effect, medications are often administered parentally so that they are not transported to the liver. Another way, another example of a medication that avoids the first pass effect is sublingual nitroglycerin. When nitroglycerin is administered sublingually or under the tongue, it is readily absorbed into the bloodstream and carried to the site of action instead of through the gastrointestinal tract and into the kidney in the liver.

Many drugs are metabolized by cytochrome P450 enzymes. Medications can be either SIP or cytochrome P450 substrates, inhibitors or inducers. Drugs that increase the rate of metabolism are called inducers and drugs that slow the rate of metabolism are called inhibitors. If the metabolism of a drug is induced, it means it’ll be broken down quicker and the dose would need to be increased to have the same effect. If the metabolism is inhibited or slowed down that can lead to drug accumulation which can increase toxicity in adverse effects.

Most drugs are excreted or exit the body by the kidneys through urine but there are other ways that drugs can be excreted from the body. A drug can leave the body through sweat, saliva, bile, breast milk and even by exhaling air. These four principles absorption distribution metabolism and excretion all play a part in determining how long a medication will meet will be at its intended target.

It’s nearly impossible to measure the concentration of a medication at the intended target so plasma drug levels are drawn to determine whether or not a medication falls within the therapeutic range. There is a direct correlation between toxicity and effect and plasma concentration. The therapeutic range refers to range of plasma levels that are present when a drug is effective without producing toxic effects.

Most medications are not given in a single dose instead multiple doses are given over time so one important concept that we must look at is half-life. The half-life is time it takes for half or fifty percent of drug concentration to leave body. The half-life is used to determine how frequently a drug is dosed also half-life is important in determining how long it takes medications to reach steady state or plateau in blood.

Drug concentrations will reach steady state after approximately four half-lives. One way to help a drug reach study levels faster is to give loading dose or larger dose of medication. The loading dose does not have different half-life there’s just more of it so when half of original dose is gone concentrations are still higher in blood.

Now that we’ve talked about pharmacokinetics let’s move on to pharmacodynamics. Pharmacokinetics is concept of what body does to drugs whereas pharmacodynamics is what drugs do to body or effects that they have there is dose response relationship that allows us to individualize medications for patients based on desired response.

Two concepts related to dose response relationship are maximal efficacy and relative potency. Maximal efficacy refers to greatest effect a drug can produce for example morphine has greater efficacy in treating pain than acetaminophen that means it can treat more intense pain than acetaminophen can.

Relative potency is measurement of how much of drug is needed to have desired effect one example of this is two different diuretics Bumetanide which is dosed in one or two milligram doses versus Furosamide with normal dose between 20 and 40 milligrams. The important thing to remember with potency means that is drug more potent doesn’t necessarily mean it’s more effective it just means you need less of dose to have same effect."

"I’ve talked a lot about drugs needing to reach their intended target. Oftentimes that target is a receptor. A receptor is a special chemical binding site where a drug acts. Think of receptors and drugs as a lock-in key or puzzle pieces where only certain drugs or substances will have the correct properties or characteristics to bind with certain receptors. Receptors also act with endogenous substances in our body. These are things like neurotransmitters and hormones that are already endogenous or living in our system.

Drugs are selective for certain receptors and if a drug is more selective it will have fewer side effects. Drugs can have one of two different effects at a binding site or a receptor. They can either be an agonist where they mimic the actions of endogenous substances or an antagonist where they block the receptor and prevent their activation. So these antagonists block the action of the endogenous substances in our body like neurotransmitters and hormones.

Agonists have a high affinity for receptors and have intrinsic activity whereas antagonists have no intrinsic activity they are only blocking the activity of other substances. Affinity is the strength of attraction between the receptor and the drug or endogenous substance. Intrinsic activity refers to the drug’s ability to activate the receptor. This is why antagonists have no intrinsic activity.

In addition to being an antagonist or an agonist, drugs can also be partial agonists. This means that they do not have as strong of an effect as a full agonist. Drugs that are partial agonists can also have some agonist and some antagonist activity.

It is also important to note that some medications do not act through receptors but rather produce their effects through physical or chemical properties. One example of this is antacids that work to neutralize stomach acid rather than on certain receptors.

Earlier we talked about the therapeutic range, a similar concept in pharmacodynamics is the therapeutic index during clinical testing the ED50 and the TD50 are determined. The ED50 or effective dosed 50 is the dose where 50 percent of patients achieve the desired or therapeutic effect. The TD 50 or toxic dose 50 is the dose where 50 of the patients had an undesired toxic or side effect.

The therapeutic index is the range in between the ED50 and the TD50 it’s defined by the top, the TD50 over the ED50. The image to right shows two different dose response curves to represent therapeutic index on left you’ll see bell curve where number of patients who achieved therapeutic effect and number of patients who had toxic effects at different doses green line in between represents therapeutic index on right there is another way to look at it where percentage of patients are plotted against dose and you can see ED50 and TD50 where 50 percent of patients achieved either therapeutic response or toxic response.

In row A we see medication that has more wide therapeutic index compared to row B where medication has narrow therapeutic index we can see in row B that therapeutic effects and toxic effects can overlap in drugs that have narrow therapeutic index this is why drugs with narrow therapeutic index are more dangerous and levels need to be monitored more closely.

Let’s take moment to look at hypothetical example to help illustrate therapeutic index let’s imagine that Drug A represents analgesic where ED50 is equal to 200 milligrams and TD50 is equal to 2000 milligrams 2000 divided by 20 would give us therapeutic index of 10.

On other hand let’s imagine that Drug B represents blood thinner where ED50 is 5 milligrams and TD 50 is 20 milligrams 20 divided by 5 would give us therapeutic index of 4. Drug B has more narrow therapeutic index than Drug A up until this point we’ve talked about effects of drugs and how they act individually."

Patients are rarely on only one drug at a time and drug interactions is an important concept that we must talk about. There are three ways drugs can interact with each other. They can intensify the effects of each other, one drug can reduce the effects of another, or the two drugs when taken together can produce a brand new response.

When two medications intensify their effects, this is known as a potentiative interaction. Potentiative interactions can be either good or bad that is beneficial or detrimental. An example of a beneficial potentiative interaction is the use of Clavulonic acid with Amoxicillin in the antibiotic Augmentin. The Clavulonic acid increases the effects of Amoxicillin so this is a beneficial or good potentiative interaction. The two medications work together to intensify their effects.

An example of a detrimental potentiative interaction on the other hand is when a patient takes both Warfarin and Aspirin both of these medications have a risk of bleeding and taking them together increases that risk so it potentiates the risk and since we’re talking about adverse effects this is detrimental.

When two medications interact to reduce the effects of one or another medication this is an inhibitory interaction like potentiative interactions inhibitory interactions can be either beneficial or detrimental. An example of a detrimental inhibitory interaction is when a patient who has asthma and is taking Albuterol starts taking Propranolol. Propranolol is a beta blocker and it can interact with receptors in lungs which is where Albuterol works so Propranolol inhibits effects of Albuterol.

On other hand a beneficial inhibitory interaction could be when Naloxone is used to reverse respiratory depression in an opioid overdose. The Naloxone is used to inhibit opioid and stop overdose symptoms.

An example of an interaction that produces new response is when Metronidazole an antibiotic is taken with Disulfiram. Disulfiram or Antabuse is used to treat alcohol abuse when patient drinks alcohol while taking Disulfiram they become violently sick. A patient who is taking Metronidazole who drinks alcohol would have that same Disulfiram like effect.

While those two medications typically would not produce that response on their own when alcohol is taken with Metronidazole they will become violently ill. Another way that some medications can interact with each other is through chelation some medications like Ciprofloxacin can bind to metal irons such as iron calcium and magnesium when Ciprofloxacin binds to these heavy metals that is called chelation and that is why some antibiotics should not be given within few hours of multivitamins or antacids especially those that contain magnesium calcium or aluminum.

Drugs not only interact with other drugs but they can also interact with food so does food increase or decrease drug absorption the answer is either it depends some medications are best taken on empty stomach for example Alendronate a drug used for osteoporosis is almost completely non-absorbed when taken with food.

 

"Other medications such as Metoprolol are best taken with food to increase drug absorption. An important drug food interaction is grapefruit juice. Grapefruit juice is an inhibitor of SIP 3A4 and can slow down the metabolism of many drugs including Simvastatin and Amlodipine. Because metabolism is inhibited, the peak effects of these drugs will increase which could lead to increased adverse effects.

Now we will move on to adverse drug reactions and medication errors. An adverse drug reaction is an unintended undesired effect when a drug is given at normal doses. We’re going to define some terms related to adverse drug reactions. First, we’ll start with the most commonly known, the side effect. A side effect is a virtually unavoidable effect at intended doses.

An allergic reaction is an immune response that occurs after the body has been re-exposed to a drug. Toxicity is the harmful physiological effects at excessive doses. An example of toxicity is when a patient has life-threatening hypoglycemia or low blood sugar after an overdose on insulin.

Iatrogenic disease may be a new term for you. Iatrogenic disease is a disease caused by drugs or medical treatment. An example of this is patients who are taking antipsychotic medications may develop Parkinson’s disease like symptoms due to the medications that they have been taking.

Side effects are usually predictable but an idiosyncratic effect is unpredictable. An idiosyncratic effect is an uncommon uncommon reaction that is due to a person’s genetics.

Two very specific types of effects are carcinogenic effects and teratogenic effects. Carcinogenic effects are cancer-causing effects of drugs or chemicals. Teratogenic effects refer to birth defects caused by medications.

Lastly, a paradoxical effect is a response that is opposite of what is intended or expected. An example of this is when Benadryl Diphenhydramine is given to young children. Diphenhydramine typically has a side effect of causing drowsiness but when it’s given to young children it’ll have a paradoxical effect of causing excitement or hyperactivity.

Adverse drug reactions can also be organ specific. One important organ due to its relationship with drug metabolism is the liver so we should be aware of medications that can cause hepatotoxicity or liver toxicity.

Another important adverse drug reaction that we need to discuss is QT prolongation. The QT interval on an electrocardiogram measures the time it takes for the ventricle of the heart to repolarize after each contraction. QT prolongation can cause fatal dysrhythmias specifically Torsades to point.

The FDA requires that all new drugs be tested to see if they cause QT prolongation. Currently over 100 drugs are known to cause QT prolongation. When two medications that can both cause QT prolongation are given together this needs to be addressed.

An example of this is when Levoquin or Levofloxacin is given to a patient who is on a Cytalopram, an SSRI used to treat depression. In this case, we would discuss with the patient’s doctor about changing the antibiotic to one that is not known to cause QT prolongation. We would not want to change the patient’s antidepressant therapy and the antibiotic is only given for a short time so that is the medication that we would want to have changed.

Medication errors are a major cause of patient injury and cost billions of dollars each year. Medication error is defined as any preventable event that may cause or lead to inappropriate medication use or patient harm.

Anyone involved at any step of patient care can potentially make a medication error. The Institute of Medicine has identified three main categories as causing 90 percent of all medication errors these are human error, communication mistakes and drug name confusion.

All health care providers must be aware of types of medication errors that can occur in events that lead up to them so that everyone can be vigilant in preventing medication errors.

It’s important for all hospitals and other institutions to adopt a culture of safety other measures that have been taken to reduce medication errors include using bar coding systems to scan patients and medications also replacing handwritten medication orders with computerized order entry.

Another measure that has been taken to reduce medication errors and prevent adverse reactions is medication reconciliation. Medication reconciliation is done at transitions of care where nurse pharmacist or other provider compares list of medications that patient was taking prior to admission or discharge to list of current medications that they are taking while in hospital or when they leave.

Even when we know pharmacokinetics and pharmacodynamic properties of medications and how these drugs can interact with each other, medications can still have individual drug response that can vary from individual to individual.

Factors that can have an effect on drug response in individuals include weight, age, gender, race and genetics. Some medications need to be adjusted for body weight in order to have intended effect some medications are even dosed based on body surface area because body fat percentage can change way drugs are distributed in tissues.

One example of type of medication that’s commonly dosed based on body surface area is chemotherapy for cancer. Age affects way that drugs can respond in individuals. Patients who are very young and very old can have increased toxicity with certain medications. Those who are very young have immature organs and those who are very old their organs are starting to wear out and so they do not metabolize drugs as effectively as before.

An example of how drugs can affect gender differently is alcohol. Females metabolize alcohol slower than males and therefore get intoxicated facts faster. Race is another factor that can alter individual dose response."

"One example of how race can affect drug response is with ACE inhibitors like Lysinophil used to treat hypertension. Studies have found that ACE inhibitors are not as effective in African Americans. Also, people with Asian ancestry may have a gene for HLA BE 150. Individuals with this gene have been found to have a serious adverse skin reaction when they take Carbamazepine, a drug used for epilepsy.

We are learning through pharmacogenomics that genetics can play a big role in how individuals are affected by different medications. One example of this is with the drug Trastuzamab which is used for breast cancer. Trastuzamab is only effective in treating breast cancer that is positive for the HER2 gene, HER2.

This is only one example of how genetics can affect individual drug response. Comorbid conditions are another factor that can affect individual drug response. For example, patients with liver disease and kidney disease can have different effects on drug accumulation because of these organs roles in metabolism and excretion.

Therefore, patients with liver or kidney impairment will need doses of their medications reduced to avoid toxicity. In addition to liver and kidney disease, acid-base imbalance or your body’s pH and electrolyte imbalance are two other ways that patients can be affected by individual drugs.

Digoxin is an example of how electrolyte imbalance can affect drug response. You should monitor potassium levels in patients receiving Digoxin to reduce the risk of dysrhythmia.

Individuals can also develop tolerance to medications that is they have a decreased response or require increased doses to have the same response. There are different types of tolerance. Pharmacodynamic tolerance develops over long-term use higher doses of a medication are required to have the same desired response.

Metabolic tolerance on the other hand is due to rapid metabolism of medications meaning higher doses of a medication are required to maintain consistent plasma levels to keep the medication within the therapeutic range.

Tachyphylaxis is a phenomenon where your body’s defenses build up quickly and stop responding to a medication so when de repeated doses of a medication are given in a short time frame the body reduces its response.

Another term that isn’t exactly related to tolerance is the placebo effect. The placebo effect is a psychological response to a drug independent of the biochemical actions of the drug. The placebo effect is neither a good or a bad thing. It’s been found that nearly all drugs have at least some degree of a placebo effect.

What this means is that attitude is everything. Sometimes just because a patient thinks a medication is working, it actually is. On the other hand, if you take a medication and think it’s not going to work, it may not have its intended response.

Even if a patient is only taking a medication for a placebo effect, it shouldn’t necessarily be discontinued because if they think the medication is going to help, it can speed recovery.

I hope this review has given you a better understanding of the fundamental principles of pharmacology. Thank you for listening.

 

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