Pharmacology - Drug Metabolism and Excretion

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The pharmacological activity of many drugs is reduced or abolished by

enzymic processes

What is the main mechanisms by which drugs are inactivated

drug metabolism

What drugs increase in activity by metabolism?

metabolism activates prodrugs, e.g. decarboxylation of levodopa to dopamine in neurons.

What hinders elimination of drugs from the body?

The lipophilic characteristics of drugs that promote their passage through biological membranes & subsequent access to their site of action

Why is renal excretion of an UNCHANGED DRUG not a major elimination route?

because lipophilic compounds filtered through the glomerulus are largely reabsorbed through the tubular membrane.

What must happen to terminate the biological activity of a drug and to eliminate it?

Biotransformation must occur to convert the drug from being lipophilic into being hydrophilic so that it can be more easily excreted

What is the major site for drug metabolism?

The liver - but drugs may also be metabolized in other tissues

IMPORTANT - First-order kinetics - two factors

1. Rate of drug metabolism is directly proportional to the concentration of free drug
2. Constant fraction of drug is metabolized per unit of time

Zero-order kinetics - two factors

1. Rate of metabolism remains constant over time
2. Constant amount of drug is metabolized per unit of time

Explain Phase 1 reactions of metabolism

Convert lipophilic molecules into more hydrophilic by introducing or unmasking a polar functional group, such as -OH, or -NH2.
Phase I metabolism may increase, decrease, or leave unaltered the drug´s pharmacological activity.

The Phase I reactions most frequently involved are catalyzed by

the cytochrome P-450 system

Explain Phase II reactions of metabolism

Many metabolites are highly lipophilic and reabsorbed. They are conjugated with an endogenous substrate which is more water soluble, allowing for excretion from kidney

What is the most common & most important conjugation?

Glucuronidation

Do all drugs undergo Phase I and Phase II?

Certain drugs enter Phase II directly and become conjugated without prior Phase I.
Certain drugs undergo Phase II reaction then Phase I reaction.

What sub cellular organelles are most important in metabolism?

the endoplasmic reticulum & the cytosol.

Where are the oxidative enzymes located?

Phase I enzymes are in the ER
Phase II enzymes are in the cytosol

What is enzyme induction?

exposure to certain drugs or enviro pollutants (ethanol, phenobarbitol) enhances enzyme activity due to increased enzyme synthesis.

What enzyme is increased in content and activity?

cytochrome P450

What are the consequences of enzyme induction?

Increased rate of metabolism
Decrease in drug plasma concentration
Enhanced oral first pass metabolism
Reduced bioavailability
If metabolite is active or reactive, increased drug effects or toxicity

Enzyme inhibition

Inhibition of drug metabolism by a concurrently administered drug can lead to drug accumulation & toxicity and also potentiate the action of unrelated drugs.

Consequences of enzyme inhibition (4)

1. Increased plasma concentration of parent drug
2. Reduction in metabolite concentration
3. Exaggerated & prolonged pharmacological effects
4. Increased likelihood of drug-induced toxicity

Effects of grapefruit juice

elevates peak concentration
causes reduction in small bowel protein
effects last ~4hrs and require new enzyme synthesis

Excretion of drug is defined as:

the process whereby drugs or metabolites are irreversibly transferred from internal to external environment through renal or non renal route.

What is required for the termination of a drug's pharmacological action?

Excretion of drug is required

The principal organ of excretion is

kidney

Are drugs required to be metabolized to be excreted by the kidney?

no.
gentamicin

What type of drugs are efficiently reabsorbed?

Non-polar lipid-soluble drugs

How are non-polar lipid-soluble drugs eliminated?

metabolic conversion in liver or intestine to more polar metabolites, and then excreted in the urine.

IMPORTANT- Factors that affect renal excretion (6)

1. Physicochemical properties of drug
2. Urinary pH
3. Blood flow to the kidney
4. Biological factors
5. Drug interaction
6. Disease state (renal dysfunction)

Phisiochemical properties of drugs include: (2)

Molecular size - macromolecules do not filter through glomerulus
Binding characteristics - must be free or unbound

Does a protein bound drug have a long or short half life?

long

Biological factors for excretion include:

sex - renal excretion 10% lower in F
age - infant 30-40% less
old age - GFR reduced, tubular function slower = prolonged halflife

What alters renal clearance of a drug?

drug interaction that alters binding, renal blood flow, secretion, urine pH, forced diuresis

What occurs when a drug highly bound to plasma proteins is displaced with another drug?

renal clearance is increased

What can cause reabsorption of a parent drug when it is conjugated?

drug conjugates may be hydrolysed by gut bacteria, releasing the parent drug which may be reabsorbed (enterohepatic circulation). E.g. oral contraceptives.

Minor routes of excretion:

saliva
sweat
expired air
breast milk

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