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2.pptxNursing 2343: PathoPharmacology I Lecture 2 Chapters 4 to 8
Mark L. Winter, Ph.D., DABAT, FAACT
Texas Poison Center Network – Galveston
University of St. Thomas
| One sometimes finds what one is not looking for. |
| Sir Alexander Fleming, physician, scientist who discovered penicillin |
Pharmacokinetics
Application of pharmacokinetics in therapeutics
Passage of drugs across membranes:
Absorption
Distribution
Metabolism
Excretion
Time course of drug responses
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Fig. 4-1. The four basic pharmacokinetic processes.
Dotted lines represent membranes that must be crossed as drugs move throughout the body.
A Note to Chemophobes
Chemophobes: those who fear chemistry.
Chapter 4 contains some of the most difficult material in the pharmacology book.
Chapter 4 lays an important foundation for the rest of the chapters.
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Passage of Drugs Across Membranes
A general rule in chemistry states that “like dissolves like”
Cell membranes are composed primarily of lipids; therefore, to directly penetrate membranes, a drug must be lipid soluble (lipophilic)
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Passage of Non-Lipophilic Drugs Across Membranes
Polar molecules:
Uneven distribution of a charge
Water
No net charge
Ions:
Molecules that have a net electrical charge
Sodium (Na+)
Potassium (K+)
Chlorine (Cl-)
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Absorption
The movement of a drug from its site of administration into the blood:
Rate of absorption determines how soon effects might begin.
Amount of absorption helps determine how intense the effects will be.
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Characteristics of Commonly Used Routes of Administration
Intravenous (IV)
Irreversible, expensive, inconvenient, difficult, water soluble
Intramuscular (IM)
Depot preparations, poorly soluble
Subcutaneous (SubQ)
No significant barriers to absorption
Oral (p.o.)
Variable absorption, inactivation of some drugs, GI effects, awake, & cooperative
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Pharmaceutical Preparations for Oral Administration
Tablets
Enteric-coated preparations
Sustained-release preparations
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Additional Routes of Administration
Topical
Transdermal
Inhaled
Rectal
Vaginal
Direct injection to a specific site:
for example: heart, joints, nerves, central nervous system
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Variability in Absorption
Bioavailability:
Ability of the drug to reach the systemic circulation from its site of administration
Occurs primarily with oral preparations, not with parenteral administration
Tablet disintegration time, enteric coatings, sustained-release formulations
Other causes of variable absorption:
Changes in gastric pH, diarrhea, constipation, food in the stomach
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Distribution
The movement of drugs throughout the body
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Blood Flow to Tissues
Drugs are carried by the blood to tissues and organs of the body
Abscesses and tumors:
Low regional blood flow impacts therapy
Pus-filled pockets, no internal blood vessels
Solid tumors have limited blood supply
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Exiting the Vascular System
Typical capillary beds
Drugs pass between capillary cells rather than through them
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Blood-Brain Barrier (BBB)
Tight junctions between the cells that compose the walls of most capillaries in the CNS
Drugs must be able to pass through cells of the capillary wall
Only drugs that are lipid soluble or have a transport system can cross the BBB to a significant degree
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Placental Drug Transfer
Membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs
Movement determined in the same way as other membranes
Risks with drug transfer:
Birth defects:
mental retardation, gross malformations, low birth weight
Mother’s use of habitual opioids:
birth of drug-dependent baby
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Protein Binding
Drugs can form reversible bonds with various proteins.
Plasma albumin is the most abundant and important.
Large molecule that always remains in the bloodstream
Impacts drug distribution
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Entering Cells
Some drugs must enter cells to reach site of action.
Most drugs must enter cells to undergo metabolism and excretion.
Many drugs produce their effects by binding with receptors on external surface of the cell membrane:
Do not need to cross the cell membrane to act
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Drug Metabolism
Also known as biotransformation
Defined as the enzymatic alteration of drug structure
Most often takes place in the liver
Hepatic drug-metabolizing enzymes
Therapeutic consequences of drug metabolism
Special considerations in drug metabolism
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Hepatic Drug-Metabolizing Enzymes
Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system:
also known as the P450 system, cytochrome P-450.
Metabolism doesn’t always result in a smaller molecule.
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Therapeutic Consequences of Drug Metabolism
Accelerated renal drug excretion
Drug inactivation
Increased therapeutic action
Activation of pro-drugs
Increased or decreased toxicity
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Excretion
Defined as the removal of drugs from the body
Drugs and their metabolites can exit the body through:
Urine
Sweat
Saliva
Breast milk
Expired air
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Renal Routes of Drug Excretion
Steps in renal drug excretion
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Factors that modify renal drug excretion
pH-dependent ionization
Competition for active tubular transport
Age
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Non-renal Routes of Drug Excretion
Breast milk
Other non-renal routes of excretion
Bile
Enterohepatic recirculation
Lungs (especially anesthesia)
Sweat/saliva (small amounts)
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Time Course of Drug Responses
Plasma drug levels
Single-dose time course
Drug half-life
Drug levels produced with repeated doses
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Fig. 4-14. Single-dose time course.
Plasma Drug Levels
Clinical significance of plasma drug levels
Two plasma drug levels defined
Minimum effective concentration
Toxic concentration
Therapeutic range
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Therapeutic Range
The objective of drug dosing is to maintain plasma drug levels within the therapeutic range.
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Single-Dose Time Course
The duration of effects is determined largely by the combination of metabolism and excretion.
Drug levels above MEC – therapeutic response will be maintained.
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Half-Life
Defined as the time required for the amount of drug in the body to decrease by 50%
Determines the dosing interval
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Drug Levels Produced with Repeated Doses
The process by which plateau drug levels are achieved
Time to plateau
Techniques for reducing fluctuations in drug levels
Loading doses vs. maintenance doses
Decline from plateau
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Fig. 4-15. Drug accumulation with repeated administration.
This figure illustrates the accumulation of a hypothetical drug during repeated administration. The drug has a half-life of 1 day. The dosing schedule is 2 gm given once a day on days 1 through 9. Note that plateau is reached at about the beginning of day 5 (ie, after four half-lives). Note also that, when administration is discontinued, it takes about 4 days (four half-lives) for most (94%) of the drug to leave the body.
Pharmacodynamics
The study of the biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced
The study of what drugs do to the body and how they do it
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Dose-Response Relationships
Relationship between the size of an administered dose and the intensity of the response produced
Determines:
The minimum amount of drug we can use
The maximum response a drug can elicit
How much we need to increase the dosage to produce the desired increase in response
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Dose-Response Relationships
As the dosage increases, the response becomes progressively larger.
Tailor treatment by increased/decreased dosage until desired intensity of response achieved.
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Maximal Efficacy and Relative Potency
Maximal efficacy:
The largest effect that a drug can produce (height of the curve).
Match the intensity of the response with the patient’s need.
Very high maximal efficacy is not always more desirable.
Don’t hunt squirrels with a cannon.
Potency
The amount of drug we must give to elicit an effect
Rarely an important characteristic of the drug
Can be important if:
lack of potency forces inconveniently large doses
Implies nothing about maximal efficacy – refers to dosage needed to produce effects
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Drug-Receptor Interactions
Drugs
Chemicals that produce effects by interacting with other chemicals
Receptors
Special chemicals in the body that most drugs interact with to produce effects
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Receptor
A receptor is any functional macromolecule in a cell to which a drug binds to produce its effects
Technically, receptors can include:
Enzymes
Ribosomes
Tubulin
The term receptor is generally reserved for the body’s own receptors for:
Hormones
Neurotransmitters
Other regulatory molecules
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Receptor Binding
Binding of a drug to its receptor is usually reversible.
Receptor activity is regulated by endogenous compounds.
When a drug binds to a receptor, it will either mimic or block the action of the endogenous regulatory molecules and increase or decrease the rate of physiologic activity normally controlled by that receptor.
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Important Properties of Receptors
Receptors are normal points of control of physiologic processes.
Under physiologic conditions, receptor function is regulated by molecules supplied by the body.
Drugs can only mimic or block the body’s own regulatory molecules.
Drugs cannot give cells new functions.
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Important Properties of Receptors
Drugs produce their therapeutic effects by helping the body use its preexisting capabilities
In theory, it should be possible to synthesize drugs that can alter the rate of any biologic process for which receptors exist.
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Receptors and Selectivity of Drug Action
The more selective a drug is, the fewer side effects it will produce.
Receptors make selectivity possible.
Each type of receptor participates in the regulation of just a few processes.
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Receptors and Selectivity of Drug Action
Lock and key mechanism
Does not guarantee safety
Body has receptors for each:
Neurotransmitter
Hormone
All other molecules in the body used to regulate physiologic processes
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Drug-Receptor Interactions
Agonists
Antagonists
Non-competitive versus competitive antagonists
Partial agonists
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Agonists
Agonists are molecules that activate receptors.
Endogenous regulators are considered agonists.
Agonists have both affinity and high intrinsic activity.
Agonists can make processes go “faster” or “slower.”
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Antagonists
Produce their effects by preventing receptor activation by endogenous regulatory molecules and drugs
Affinity but no intrinsic activity
No effects of their own on receptor function
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Antagonists
Do not cause receptor activation but cause pharmacologic effects by preventing the activation of receptors by agonists.
If there is no agonist present, an antagonist will have no observable effect.
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Non-competitive Antagonists
Non-competitive antagonists:
Bind irreversibly to receptors
Reduce the maximal response that an agonist can elicit (fewer available receptors)
Impact not permanent:
cells are constantly:
breaking down “old” receptors
synthesizing new ones
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Versus Competitive Antagonists
Competitive antagonists:
Compete with agonists for receptor binding
Bind reversibly to receptors
Equal affinity – receptor occupied by whichever agent is present in the highest concentration
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Partial Agonists
These are agonists that have only moderate intrinsic activity.
The maximal effect that a partial agonist can produce is less than that of a full agonist.
Can act as antagonists as well as agonists.
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Regulation of Receptor Sensitivity
Receptors are dynamic cell components
Number of receptors on cell surface and sensitivity to agonists can change in response to:
Continuous activation:
Desensitized or refractory
Down-regulation
Continuous inhibition:
Hypersensitive
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Inter-patient Variability in Drug Responses
The dose required to produce a therapeutic response can vary substantially among patients
Measurement of inter-patient variability
The ED50
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Inter-patient Variability in Drug Responses
Clinical implications of inter-patient variability:
The initial dose of a drug is necessarily an approximation.
Subsequent doses must be “fine tuned” based on patient’s response.
ED50 in a patient may need to be increased or decreased after evaluating the patient response.
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Therapeutic Index
Measure of a drug’s safety
The ratio of the drug’s LD50 (average lethal dose to 50% of the animals treated) to its ED50
The larger/higher the therapeutic index, the safer the drug
The smaller/lower the therapeutic index, the less safe the drug
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Three Types of Drug Tolerance
Pharmacodynamic tolerance:
Associated with long-term administration of drugs such as morphine or heroin
Metabolic tolerance:
Resulting from accelerated drug metabolism
Tachyphylaxis:
Reduction in drug responsiveness brought on by repeated dosing over a short time
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Any response that a patient has to a placebo is based solely on his or her psychologic reaction to the idea of taking a medication and not to any direct physiologic or biochemical action of the placebo itself
Nurses need to present a positive but realistic assessment of the effects of therapy
Placebos are primarily used for the control groups in clinical trials
Placebo Effect
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Altered drug targets
Genetics can influence drug responses
Gender
Race
Comorbidities
Diet
Genetic variations
Psychosocial factors
Failure to take medicine as prescribed
Drug interactions
Variations
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QUESTIONS?
