Pharmacodynamics

What is Pharmacodynamics?

Pharmacodynamics is the study of the effects of drugs on the body. Based on the drug response, it can cause a primary and/or secondary physiologic effect. A primary effect is the desired response and the secondary can be desired or undesired.

Drug-Dose Relationship

- When a drug's dose can no longer increase to reach the desired therapeutic response, it is known as maximal efficacy

- The therapeutic dose of a drug (ED50) is the dose that produces a therapeutic response in 50% of the population

- The toxic dose (TD50) is the dose that produces a toxic response in 50% of the population

- The therapeutic index is the difference between the ED 50 and TD 50

- Drugs with a narrow therapeutic index means that they only need a small increase in dosage for a therapeutic dose to be come toxic and the patient requires close monitoring if they are on these drugs

- E.g. Warfarin, Digoxin, Phenytoin

Onset, Peak, and Duration of Action

- Onset is the minimum time it takes for a drug to reach the minimum effective concentration (MEC)

- A peak occurs when the drug reaches its highest concentration in the blood

- Duration of action is the amount of time that a drug exhibits a therapeutic effect

Peak Times

- Oral: 2-3 hours

- IV: 15-60 minutes

- IM: 2-4

- SQ: 15 minutes- several hours

- Sublingual/Buccal: 10-15 minutes

Agonist, Partial Agonists, Antagonists

- Agonists are drugs that activate receptors and produce a desirable response

- Partial agonists produce moderate activity when bound to receptors

- Partial agonists also prevent other drugs from binding and activating responses

- Drugs that prevent receptor activation and block a response are called agonists

Nonspecific and Nonselective Effects

- Many agonistic and antagonistic drugs lack specific and selective effects so they can affect many systems (nonspecific) and receptors (nonselective)

- E.g. Cholinergic receptors are located in the bladder, heart, eyes, stomach, blood vessels, and bronchi

- A cholinergic agonist prescribed for a specific condition with the bladder will also effect the other organs with cholinergic receptors (nonspecific)

- E.g. Epinephrine used to treat anaphylaxis will target alpha1, beta1, and beta 2 receptors (blood vessels, heart, and bronchus) and cause increased blood pressure, increased HR, and dilation and relaxation of the bronchioles (nonselective)

Mechanisms of Action

There are 7 mechanisms of action: stimulation, depression, irritation, replacement, cytotoxic action, antimicrobial action, and modification of immune status

- Drugs that stimulate enhance natural activity

- E.g. Adrenergics

- Depressants decrease neural activity and bodily function

- E.g. Barbiturates and Opiates

- Irritators have a noxious or unpleasant effect

- E.g. Astringents

- Replacement drugs replace essential body compounds

- E.g. Insulin, thyroid drugs, hormones

- Cytotoxic drugs selectively kill parasites and cancers

- Antimicrobials prevent, inhibit, or kill infectious organisms

- Drugs that modify immune status enhance or depress the immune system

- E.g. Interferons and Methotrexate

Side Effects, Adverse Effects, and Toxicity

- Side effects are expected secondary effects of drug therapy

- Chronic illness, sex, weight, and ethnicity play a part in side effects

- The occurrence of side effects is one of the primary reasons patients stop taking prescribed medication

- Adverse drug reactions (ADRs) are unintentional, unexpected reactions to therapy that occur at normal drug dosages

- ADRs are always undesirable and must be reported and documented

- Drug toxicity occurs when drug levels exceed the therapeutic range

- Factors that influence drug toxicity include disease, genetics, and age

- Tachyphylaxis refers to an acute, rapid decrease in response to a drug

- It may occur after the first or several doses of a drug

Drug-Drug Interactions

A drug interaction is defined as an altered or modified action or effect of a drug as a result of interaction with one or multiple drugs. Interactions can be divided into 2 categories: pharmacokinetics and pharmacodynamic.

- Patient factors that increase risk for drug interactions:

- Chronic illnesses

- Use of multiple medications

- See more than one provider

- Use multiple pharmacies

- Older age

- 20% of older adults take 5 or more medications

- The most common symptoms of drug-drug interactions are nausea, vomiting, heartburn, and lightheadedness

- The most feared interactions would cause a dramatic drop in BP or cause a rapid or irregular heartbeat

- Interactions that produce toxins that may damage vital organs need to be closely monitored

Pharmacokinetic Interactions

Pharmacokinetic interactions are changes in absorption, distribution, metabolism, or excretion.

Absorption

- A drug can block, decrease, or increase the absorption of another drug

- This can be accomplished by altering gastric emptying time, changing gastric pH, or by forming drug complexes

- Most drugs are absorbed in the small intestine with exceptions being barbiturates, salicylates, and theophylline, which undergo gastric absorption

- Opioids and respiratory anticholinergics decrease gastric emptying time and GI motility, which increases absorption rate

- When gastric pH is lowered, weakly acidic drugs are less ionized and are absorbed

- Drugs that raise gastric pH decrease the absorption of weak acid drugs

- Alterations in gut bacterial fauna can affect pharmacokinetics

Metabolism

- Drugs that inhibit or stimulate hepatic metabolic enzymes can alter the metabolism of drugs

Drug Induction

- Drugs that promote the activity of liver enzymes are known as enzyme inducers

- The use of enzyme inducers promote drug elimination and decreased drug concentrations in the blood

- Onset and termination of inducers are slow (approximately 1 week)

- Dosages may need to be increased with the use of an inducer

- Monitor serum drug levels if the drug has a narrow therapeutic range

- Chronic cigarette smoking and alcohol consumption lead to an increase in hepatic enzyme activity

Drug Inhibition

- Drugs that inhibit liver metabolic enzymes are known as enzyme inhibitors

- Enzyme inhibitors decrease metabolism of the drug and increase its blood concentration

- To avoid toxicity due to decreased metabolism, the dosage used must be reduced

- Inhibitor drug onset is rapid increases the half-life of the target drug which can prolong drug effect

- Monitor serum drug levels if the drug has a narrow therapeutic range

- Acute alcoholism and flavonoids inhibit metabolism

- Flavonoids inhibit certain drugs

- Carbamazepine, Calcium Channel Blockers, and drugs for ED

- Flavonoids are found in the juice and pulp of citrus fruits

#### Excretion

- Drugs that affect renal function can increase or decrease renal excretion of drugs

- The use of diuretics cause an increase in urinary frequency, which can lead to increased excretion

- Some diuretics decrease the reabsorption of potassium and can cause [[Hypokalemia]]

- Hypokalemia can alter the action of some drugs

- E.g. Hypokalemia enhances the action of digoxin and lead to toxicity

- 2 or more drugs that undergo the same route of excretion may compete with one another for elimination from the body

- Alkaline urine promotes the excretion of weak-acid drugs and acidic urine promotes the excretion of weak-base drugs

- Ionized drugs have a lower rate of reabsorption by the kidneys

- With patients with decreased hepatic or renal function, there is usually an increased in free drug levels and need close monitoring when taking multiple drugs

- Therapeutic drug monitoring (TDM) is important for drugs that have narrow therapeutic ranges

- E.g. Digoxin and Phenytoin

Pharmacodynamic Interactions

Pharmacodynamic interactions are those that result in additive, synergistic, or antagonistic drug effects

Additive

- When 2 drugs are administered in combination, the response is increased beyond what either could produce alone

- An additive interaction is the sum of the effects of the 2 drugs

- Additive effects can be desirable or undesirable

Synergistic

- When 2 or more drugs are administered in combination, one drug can have a synergistic effect on another

- The response is substantially greater than either drug alone

- Different than an additive effect in that 1 drug would increase the abilities of the other rather than simply adding itself to the combination

Antagonistic

- When drugs with antagonistic effects are added together one drug reduces or blocks the effects of the other drug

- Opposite effect of a synergistic interaction