Drug Dosage…What controls the dose of a medication?
- Degree of Absorption
- Volume of Distribution
- Rate of Elimination
1. Degree of Absorption
It could be anywhere from 0 to 100% and believe it or not there are drugs out there that have 0% absorption. There’s an antibiotic commercially available that you could ingest and it doesn’t go into the blood stream because you want it to act only in the gut. The less drug you absorb into the blood stream, the less side effects.
There’s only one route of administration where you’re guaranteed 100% absorption and that’s IV. The dosage form is also important. Suppositories have the poorest amount of absorption. You can’t get past the blood levels with it. There are no drugs that people need to take chronically that are suppositories. These are known as PRN drugs (as needed drugs; PRN stands for Pro Re Nata, which is Latin literally meaning “For the thing born.”).
2. Volume of Absorption (Distribution)
Ability to cross tissues: The more tissues that the drug crosses, the higher the dose and the greater the potential for side effects. Many drugs cannot cross the blood brain barrier. This is especially important if we talk about an infection that affects the brain like meningitis.
Protein Binding: Another concept we have to think of is protein binding. The higher the protein binding, the greater the potential for drug/drug interactions.
Let’s talk about warfarin, a commonly used anticoagulant. This drug is 99% protein bound. What’s the predominant protein that coagulates blood? Albumin. If a drug like warfarin comes in, 99% of it is bound up by this albumin. Only 1% is available to act as coagulation. The biggest dilemma we have is a drug/drug interaction with this drug. If the patient goes to multiple doctors and doesn’t tell the doctor they’re on warfarin, the patient gets another drug, for instance an arthritic drug, and that may displace the warfarin. This causes the warfarin drug to act free and the patient starts to bleed because instead of 1% of the dose being free in the blood stream, it goes to 5%. This is one of the most common problems we are getting today.
3. Rate of Elimination
Renal: If it’s predominantly renal, the kidneys will get rid of it. If a person has kidney disease, the dosage has to be reduced because they can’t get rid of it as easily. Geriatric dosages are decreased for this reason. We look at something called the creatinine clearance to understand how well ones kidneys are working.
Hepatic: Another route of elimination is hepatic, through the liver. If a person has liver disease, they may get toxic on the drug, so the dosage will be lowered. The liver function decreases as people age, so again, the dosage is lowered in the geriatric dosages.
Hepatic Enzyme Induction: The increase in the rate of a specific enzyme synthesis from basal to maximum level caused by the presence of a substrate or substrate analog that acts as an inducer.
There are some drug interactions we have to keep in mind when working with the liver. The liver has enzymes that metabolize enzymes. If something induces the production of enzymes in the liver, it will then speed up and metabolize other medications. For example, phenobarbital is a sedative that slows the brain but speeds up enzyme production of the liver. It’s sometimes used for managing seizures. Other seizure drugs go through the liver as well. The blood levels of these other seizure drugs may go down because they are metabolized so quickly, causing seizures to recur. So these other seizure drugs have to have an increased dosage to keep it up.
Hepatic Enzyme Inhibition: Some drugs slow down the enzyme metabolism of the liver and cause the drug levels to go up in the blood and potentially become toxic. We have to decrease the dosage of these drugs.
Half Life: The half life of a drug is the time it takes for the medication blood level to drop in half. We want to know this to know how often to take the drug. If we graph this out it comes out to be logarithmic and not linear. We especially want to know this in case the patient is toxic, to know how long it will take for them to get back to normal.
Additive: Two medications given together produce an effect equal to the sum of the effects of each agent. (1+1=2)
Synergy: Two medications given together produce an effect much greater than the sum of the effects of each agent (1+1=11). We like to use synergistic combinations when somebody has a life threatening condition and we use multiple antibiotics.
Potentiation: Two medications given together, where only one of them has the required action, but that action is enhanced by the second agent.
For example: Demerol is a narcotic. Vistaril is an antihistamine/antinausea drug. When a patient is in pain, demerol would be useful and vistaril would not. So only one of these drugs work on pain. But for whatever reason we can’t explain, if you mix these two together in a syringe and inject it, it becomes a SUPER powerful narcotic. That’s potentiation.
Another example: Augmentin is a combination drug of amoxicillin (an antibiotic) and clavulanate. Bacteria are feisty and they could create an enzyme that could destroy antibiotics. So what does clavulanate do? It binds up this enzyme that would otherwise destroy the antibiotic. This allows the amoxicillin to destroy the organism. So clavulanate does nothing alone, but together with amoxicillin, it is very powerful.
Agonist: An agent that stimulates a receptor. Let’s say there’s a Beta-1 receptor on a heart. If we stimulate this, the heart speeds up. Epinephrine would stimulate this receptor and speed up the heart. This makes epinephrine an agonist.
Antagonist: The agent that goes in and blocks the receptor. If we take a beta blocker, it will attach to the Beta-1 receptor, not allowing the epinephrine to attach and the heart rate will slow down.
Factors that influence the drug effects
- Body weight
- Surface area
- Sex (renal function, different in men or women; men have faster function)
- Disease states
- Genetics (metabolism)
- Immunology (allergies)
Untoward Effects (Unfavored)
Side effect: Unavoidable effect at proper dose.
Toxic effect: Avoidable effect due to improper dose but more commonly because of a drug/drug interaction.
Poison: Harmful no matter what the dose is.
Adverse effect: Unexpected effect, but may happen, including allergies.
- Not dose related. If you’re allergic to penicillin, you’re not going to get any.
- Requires prior exposure: An allergy can’t happen on the first dose. It could happen on the second or millionth dose, but not on the first.
- Reactions can be immediate to delayed for days
- Reactions may be mild to life threatening