Pharmacology – Lecture 04 – Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion of Drugs

Make sure you know the learning objectives.
1. Describe 4 processes by which drugs penetrate biological barriers.

2. Explain how changes in pH can affect absorption and excretion of drugs.

3. Describe 4 common routes of drug administration, their advantages and disadvantages.

4. Explain how the route of administration affects bioavailability.

5. Explain 4 factors that influence drug metabolism.

What is absorption?
Absorption: The process by which the drug enters the blood (highly dependent upon the route of administration).

Note. No absorption in IV administration.

What is distribution?
Distribution: The distribution of the drug throughout the body.

What is elimination?
Elimination:
– Metabolism: Biotransformation of the drug.
– Excretion: Excretion of unchanged drug. Metabolites also undergo excretion.

Are these drugs acidic or basic?

aspirin, penicillins, barbiturates

Acidic

Are these drugs acidic or basic?

amphetamine, local anesthetics, morphine

Basic

For a weak acid, what form is non-ionized?
HA

A- and H+ are ionized.

For a weak base, what form is non-ionized?
B

BH+ and H+ are ionized.

What does it mean if pH-pKa is greater than 1?
More of a weak base solution.

When does pH = pKa?
When an acid or a base is 50% ionized.

How does the pH need to change for lipid solubility for an acidic drug to increase?
pH decreases.

This allows the drug to move more easily across the membrane.

How does the pH need to change for lipid solubility for a basic drug to increase?
pH increases.

This allows the drug to move more easily across the membrane.

What is the absorption pattern for IV drug administration?
Absorption circumvented.

Potentially immediate effects.

Suitable for large volume and for irritating substances or complex mixtures when diluted.

What is the absorption pattern for subcutaneous drug administration?
Prompt from aqueous solution.

Slow and sustained from repository preparation.

What is the absorption pattern for intramuscular drug administration?
Prompt from aqueous solution.

Slow and sustained from repository preparation.

What is the special utility for IV drug administration?
Valuable for emergency use.

Permits titration of dosage.

Usually required for high molecular-weight protein and peptide drugs.

What is the special utility for subcutaneous drug administration?
Suitable for some poorly soluble suspensions and for instillation of slow-relase implants.

What is the special utility for intramuscular drug administration?
Suitable for moderate volume, oily vehicles, and some irritating substances.

Appropriate for self-administration.

What is the special utility for PO drug administration?
Most convenient and economical; usually more safe.

What are the limitation and precautions for IV drug administration?
Increased risk of adverse effects.

Must inject solutions slowly as a rule.

Not suitable for oily solution or poorly soluble substances.

What are the limitation and precautions for subcutaneous drug administration?
Not suitable for large volumes.

Possible pain or necrosis from irritating substances.

What are the limitation and precautions for intramuscular drug administration?
Precluded during anticoagulant therapy.

May interfere with interpretation of certain diagnostic tests (ex. creatine kinase).

What are the limitation and precautions for PO drug administration?
Requires patient compliance.

Bioavailability potentially erratic and incomplete.

What are the advantages of PO?
– Convenient

– Relatively safe (compared to IV)

– Inexpensive

– Drug can be in any form: (e.g., liquid, solid or oil)

What are the disadvantages of PO?
– Incomplete absorption: Also, irregular absorption in the presence of food and other drugs.

– Destruction of the drug: Gastric acid (penicillin G) or digestive enzymes (insulin).

– Metabolism: Enzymes in the intestinal mucosa, intestinal flora or liver

Following oral ingestion, what do all drugs first pass through before entering the circulation? What is the significance of this?
The liver.

Drugs undergo metabolism by the liver following oral ingestion before reaching the systemic circulation.

What is the first pass effect?
First pass effect

– If a drug undergoes extensive
hepatic metabolism

– Little drug absorption

Drugs undergo metabolism by the liver following oral ingestion before reaching the systemic circulation.

This is why have to usually administer a higher dose PO.

What is bioavailability?
Bioavailability: fraction of administered dose absorbed into systemic circulation.

By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient.

What is the equation for bioavailability?
Area under plasma drug concentration vs. time plot (A.U.C.) is proportional to the amount of drug absorbed.

Bioavailability = AUC oral/ AUC IV

AUC = area under curve

What are the advantages of IV administration?
• Circumvents absorption step
• Rapid onset
• Valuable in emergency situations
• Accuracy

What is the therapeutic index?
Therapeutic Index = Toxic dose/Therapeutic dose

What does it means to have a higher therapeutic index?
High Therapeutic Index: Indicates that the drug can be tolerated over a wide range of doses.

What does it means to have a lower therapeutic index?
Low Therapeutic Index: Indicates that there is a narrow range of doses over which the drug is safe.

What are two special barriers to drug distribution?
• Blood-brain barrier
– Continuous endothelium with tight junctions between cells. Have capillaries with astrocyte foot processes.
– Lipid soluble molecules diffuse readily.
– Ionized or water soluble drugs cannot cross.

• Placenta
– Most small molecular weight drugs cross.
– Not much of a barrier.

What is penetration of drugs into the brain proportional to?
Penetration of drugs into brain is proportional to lipid solubility with some notable exceptions.

Lipid soluble: Heroin, codeine, caffeine, ethanol, nicotine, chloramphenicol, diazepam.

Water soluble: Dopamine, glycine, L-glucose, penicillin, potassium, epi.

Exceptions:
1. Phe: Amino acid; substrate for transport protein (facilitated diffusion).

2. D-Glucose; substrate for transport protein (facilitated diffusion).

3. L-DOPA: Amino acid derivative; substrate for transport protein (facilitated diffusion)
explained by transport.

What pharmacokinetic parameter most reliably indicates how much of the administered dose of drug is absorbed into the systemic circulation?
Area under the blood concentration-time curve.

In the kidney what types of drugs are excreted?
– Filtration, only free drug filtered

– Active tubular secretion, both free and protein-bound

In the kidney what types of drugs are absorbed?
– Passive absorption of lipid soluble, unionized drug. Proportional to how lipid soluble the drug is.

– Active tubular transport

How does an increase in urine pH affect excretion of drugs?
An increase in pH of the urine (bicarbonate infusion), reduces the excretion of basic drugs and increases the excretion of acidic drugs.

How does an decrease in urine pH affect excretion of drugs?
A decrease in pH of the urine (ammonium chloride infusion), increases the excretion of basic drugs and reduces the excretion of acidic drugs.

What is the role of drug biotransformation?
• Protection against undesirable ingested compounds (xenobiotics).

• Drug metabolites are usually more polar and thus more readily excreted by the kidney.

• Drug metabolites are usually less active but can have enhanced activity or toxicity.

What are the constitutes of phase I and phase II biotransformation reactions?
• Phase I Reactions
– Oxidation
– Reduction
– Hydrolysis

• Phase II Reactions
– Conjugation: This is coupling of drug to endogenous substrate.

What are six sites of drug metabolism?
• Liver: Quantitatively the most important
• Gastrointestinal tract
• Lungs
• Skin
• Kidney
• Blood

What are the cytochrome P450 enzymes? Describe them.
Microsomal mixed function oxidase.

• Oxidations carried out by a group of related cytochrome P450 enzymes (about 50 different types present in human).

• Located on the smooth endoplasmic reticulum of the liver and other cells.

• Oxidizes xenobiotics and some endogenous compounds (steroid hormones, bilirubin, fatty acids and thyroxin).

• Requires atmospheric oxygen (O2) and NADPH. This makes sense since doing oxidation.

What is the associated flavoprotein required for cytochrome P450 enzymes?
NADP cytochrome P450-reductase.

What does conjugation usually do to a drug?
Almost always makes it inactive.

What type of conjugation do you see with Acetaminophen and Benzoic Acid?
Glucuronidation.

What are four factors influencing drug metabolism?
• Age
• Enzyme Induction
• Inhibition of drug metabolism
• Genetic differences (polymorphisms) in drug metabolizing enzymes

How does age effect drug metabolism?
• Drug metabolizing enzymes are not fully developed in the neonate.
– Microsomal mixed function oxidase (P450)
– UDP-glucuronyl transferase
— Bilirubin: kernicterus (degeneration of neurons, particularly in the basal ganglia).
— Chloramphenicol: “gray baby” syndrome

• Decrease in phase I reactions in elderly patients.

What is the most common genetic polymorphism in phase I drug metabolism?
CYP2D6.

Can have over or under expression.

What happens if you have defect in expression of CYP2D6?
CYP2D6: defect in expression (3-10% of Caucasians); autosomal recessive trait.

– Reduces the metabolism of numerous drugs:
— Clomipramine, clozapine, thioridazine, tricyclic antidepressants.
—- increase in adverse side effects.
— Codeine (analgesic), tamoxifen (anticancer).
—- decreases in metabolic activation of these prodrugs. Less sensitive to drug.

What happens if you have over expression of CYP2D6?
CYP2D6: over expression (several gene copies in tandem).

– Most common in Ethiopians and Saudi Arabians (up to 30%).

– Require two- to three-fold higher doses of nortriptyline, a substrate for CYP2D6.

– Experience excessive side effects from codeine, a prodrug metabolized to the active agent, morphine. Make sensitive to them.

Give two examples of drug interactions based on inhibition of drug metabolism.
• Cimetidine
– Chlordiazapoxide, diazepam, warfarin.

• Grapefruit juice (CYP 3A4)
– Alprazolam, atorvastatin, cisapride,
cyclosporine, midazolam, triazolam.
– Increases bioavailability.
– Inhibits many drugs.

Give four inducers of drug metabolism?
• Phenobarbital
• Steroid hormones
• Rifampin
• Cigarette smoke

How is metabolism of Acetaminophen to hepatotoxic
metabolites clinically signifiant?
• Overdose to acetaminophen accounts for more call to poison control centers in the US as compared to any other substance.

• 35% of severe liver failure are caused by acetaminophen overdose, which may require organ transplantation.

• N-acetyl cysteine is an effective antidote, especially if administered within 10 h of ingestion.

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