Introduction to Pharmacology

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1. Define pharmacology.
Definition-the study of the interaction of chemicals, other than food, with living systems. It is a science based on the understanding of organic chemistry, biochemistry, pathology and microbiology.
2. Identify the purpose of drug-receptor interactions.

The drugs interact at receptors by bonding at specific binding sites. Most receptors are made up of proteins, the drugs can therefore interact with the amino acids to change the conformation of the receptor proteins.

These interactions are very basic, just like that of other chemical bondings:

Types of agonist
Chemical Antagonists
One drug may antagonize the action of another by binding to and inactivating the second drug
Example: Protamine binds to heparin causing heparin to be ineffective
Physiological Antagonist
Glucocorticoids cause increase in blood sugar
Give insulin to oppose the effect of glucocorticoids, full, partial, inverse (causes opposite affect)
Drug receptors
are natural body components intended to respond to a chemical that is normally present in blood/tissue. Most drugs act through receptors
Drugs have different affinities for different receptors
Histamine receptors
Beta receptors in heart
Response of drug related to number of receptor-drug complexes
3. Explain the role and function of drug receptors.
Specialized target macromolecules on the cell surface or intracellular
Proteins on the cell surface or intracellular that mediate the effects of chemical signals
Like neurotransmitters or hormones
Drugs bind to receptors
Simple model is the lock and key-binding of drug to receptor-selectivity
Initiate events
Alters biochemistry or biophysical properties of the cell
Changes the function of an organ
Formation of drug-receptor-complex leads to drug effect
4. Differentiate between the roles and functions of agonists,antagonists, and partial agonist antagonists
antagonists, and partial agonist antagonists
Agonist-
Chemical fits receptor site well-response to the chemical is usually good
Agonist is a drug that has affinity for and stimulates physiologic activity at cell receptors normally activated by naturally occurring substances
Strong affinity and good efficacyPrevents binding of the agonist-blocks its effect
partial
Stimulates receptor poorly-
prevents binding of full agonist-total response is lower than with full agonist alone.
Slight chemical action produced
5. Differentiate between quantal dose response and graded dose response.
Quantal Dose Response or all or nothing response
The dose that a population will respond to
Plot on a curve to determine the dose that will help the most peopleGraded Dose Response – response to a drug dose is continual and gradual
As the drug concentration increases – the drug effect increases

6. Differentiate between the following types of noncovalent bonds:
ionic
hydrogen
VanderWaals
hydrophobic
Electrostatic
Most common
Reversible chemical bond between drug and receptor due to electrostatic relationship
Ionic bond the strongest type
Hydrogen
Van der Waals forces – weak
Covalent
Uncommon in pharm
Irreversible bond
Share a pair of electrons
Example: Acetylcholinesterase inhibitors (organophosphate
7. Compare covalent and noncovalent bonds.
Ionic bond the strongest type
Hydrogen
Van der Waals forces – weak
Covalent
Uncommon in pharm
Irreversible bond
Share a pair of electrons
Example: Acetylcholinesterase inhibitors (organophosphate
8. State the importance of dose-effect relationships interactions, and therapeutic indexes interactions, and therapeutic indexes
.Side Effect
Undesirable effect of the drug
Often confused with allergy
Example: Erythromycin – GI upset
Hypersensitivity
Allergic reaction or immune response to medication
May be life threatening
Example: Penicillin – swelling and difficulty breathing
Toxic Effect
Undesirable effect that may permanently affect patient
Example: NSAID – renal impairment
Idiosyncratic
may involve a genetic predisposition – Rare
therapeutic indexes interactions
Therapeutic Index= TI=
LD50/ED50-it is a measure of the drugs safety
Effect of drug results from receptor drug complex
Causes both therapeutic response and toxic response
No drug causes only a single effect
An effect may be therapeutic in some tissues and toxic in other
Different receptors may produce therapeutic response while other may produce toxic response
therapeutic indexes interactions
Therapeutic Index= TI=
LD50/ED50-it is a measure of the drugs safety
TI= Ratio of LD50 to ED50
Range between when a drug dose is effective and when the dose is toxic.
Therapeutic Index between 7-10 is acceptable
Clinically must determine what is acceptableNarrow Therapeutic Index
Small range of dosages in which a drug is therapeutic
Example: Coumadin
At higher doses – toxic effects
Large Therapeutic Index
Wide range of dosages that a drug may be administered without adverse effects
Example: Penicillin
May give 10x amount without consequencesSafety

dose-effect relationships interactions
Increased dose results in a disproportionate increase in serum concentration
Non linearity may be the result of
saturation of binding sites
saturation of clearance mechanisms or
active transport or other absorption mechanism
Clearance and T1/2 may vary with the change in drug concentration
clearance may decrease as concentration increases
Drugs with large first pass effect are extensively metabolized and larger doses are given orally to account for extensive metabolism
Prodrug- I
Is a drug that is pharmacologically inactive
The drug is biotransformed to an active compound in the body
These compounds can avoid first pass effect If a drug has First Order Kinetics
Serum concentration achieved is only 50% of desired drug level
If double the dose – will get the desired drug level
Renal function must be normal
Should have already achieved a steady state
Example: Gentamicin
dose effect Amount of drug in body / concentration in blood
Vd = Amount of drug in body / concentration in blood
Relationships exist between blood level and amount in tissues
Once know the relationship
Can estimate tissue levels based on measurable blood levels
Large Vd – lots in tissue
Small Vd – lots in blood
9. Explain the concept of potency and efficacy and differentiate between the two.
The amount of drug needed to produce a certain effect
ED50 – the concentration of the drug to produce 50% of the effect
A drug with a lower mg dose is more potent than a drug with a high mg dose
Example: Candesartan 4-32 mg vs. Irbesartan 75 -300 mg for same effect
Factors contributing to ED50
Affinity of drug to receptor
Can determine ED50 by looking at curve
Usually more drug leads to more effect
Initially, magnitude of the response increases with increasing drug concentration.
Max effect is eventually reached (=Emax)
EMAX = maximal efficacy
Concentrations higher than EMAX produce no further desired effect (waste and toxicity)
Dose-effect relationship
Relationship between dose of a drug that produces harmful effects and severity of effects on client. Body’s response to a drug or toxic agent increases as overall exposure to substance increases
drug potency
Dose-effect relationship; drugs with lower EC50 are more potent
Describe ED50 LD50, Emax, and Therapeutic index – T!.LD50, Emax, and
Ability of the drug to illicit a physiologic response when it interacts with a receptor
Depends on
Number of drug receptor complexes
Coupling of the drug and receptor
Emax – maximum response or efficacy
Drug with greater efficacy is more therapeutic than a more potent drug
EC50
the concentration of the drug when it has achieved 50% of the maximum effect of the drug; the potency of the drug
10.. Define antagonism potentiation, and
.
11. Explain a dose-response relationship for a full agonist and a mixed agonist-antagonist.
summation potentiation
When two drugs are given together and their effects are additive this is called summation. However, if the effect of the two drugs exceeds the sum of their individual effects, this is referred to as potentiation or synergism.
ED50
the point at which 50 percent of the test organisms show a negative effect from a toxin.
15. Define and explain the Henderson-Hasselbach equation.
Effect of pH
Stomach pH 1.0-1.5
Blood pH 7.4
Certain drugs are absorbed better based on pH
Changes in urinary pH will effect drug excretion
17. List the variables that determine a dose regimen.
18. Explain the two phases of distribution.
19. Explain the principles that affect drug dosing in various populations – elderly and pediatrics. pregnant, and pediatrics
.
Explain the principles that affect drug dosing in various populations pregnant,
21. Define drug nomenclature:
Chemical name Generic name Official name
Trade name
22. Identify the means in which drugs are distributed throughout the body.
23. State the order of permeability of the various body tissues.
24. Indicate the ways in which the body excretes and stores drugs.
25. State the benefits and possible side effects that occur with administration of drugs by the
following routes:
GI tract subcutaneous inhalation
oral route injection transdermal
sublingual intravenous epidural
rectal intramuscular ophthalmic
aural vaginal intrathecal
26. Define the first-pass effect.
27. List the risks of IV administration.
28. Explain how the following drug characteristics affect dosing:
Formulation Concentration Lipophilic
Basic Acidic
29. List the patient characteristics that affect a drug’s response.
30. Compare first and zero order kinetics.

31. Outline the factors that produce variation in drug responsiveness.

Clinical Pharmacology I – PHA 322 Fifth Semester

LEARNING OBJECTIVES FOR GENERAL PRINCIPLES OF PHARMACOLOGY
32. Outline the FDA Pregnancy Categories for medications.
33. List drugs that affect fetal growth and retardation.
34. List drugs with good safety records.
35. Explain the duration of drug action.
36. State how drug-drug interactions occurs and the possible effects on metabolism.
37. Describe how the Michaelis constant (Km) is utilized.
38. State the reasons why drug toxicity and side affects occur.
39. Identify the major pathways and reactions involved in drug metabolism.
40. Describe the enzyme that catalyzes drug reactions.
41. Outline the cytochrome P450 cycle in drug oxidations.
42. Discuss the significance of the Cytochrome P450 system
43. Compare and contrast Inhibitors and Inducers.
44. List examples of Inhibitors and Inducers.
45. Review the substrates isoenzymes, inhibitors, and inducers of the cytochrome systems:
Example: CYP2D6, CYP2C, CYA3A, CYP1A2, and CYP1A2
.
46. State how biological half-time affects drug elimination.
47. Define and describe how to calculate drug clearance.
48. List the major mechanisms by which drugs interact.
49. Review hepatic and renal drug metabolism
50. Outline the phase of drug development
51. Differentiate between side effect idiosyncratic reactions, and toxic effect.
idiosyncratic reactions
reactions unique to the individual
drug recepter interaction
Most drugs create effects in body by attaching to receptors At receptor site, drug is able to stimulate the cell to act in a way that cell is designed to act
Example of Receptor Partial Agonist
Aripiprazole (atypical neuroleptic agent) is partial agonist at selected dopamine receptors
Dopamine receptors that were overactive would be inhibited by the partial agonist binding
Dopamine receptors that were underactive would be stimulated
Aripiprazole helps with schizophrenia but causes few of the side effects of antipsychotics
efficacy DRUG
Can determine from dose response curve
Ability of the drug to illicit a physiologic response when it interacts with a receptor
Depends on
Number of drug receptor complexes
Coupling of the drug and receptor
Emax – maximum response or efficacy
Drug with greater efficacy is more therapeutic than a more potent drug
, Refers to the effectiveness of a drug to produce a response (ABSOLUTE)
LD50
the point at which 50 percent of the test organisms die from a toxin.
summation potentiation
When two drugs are given together and their effects are additive this is called summation. However, if the effect of the two drugs exceeds the sum of their individual effects, this is referred to as potentiation or synergism.
Emax
the maximal effect of a drug
Henderson-Hasselbach
pH=pKa+log[conjugate base / weak acid] pH=pKb+log[conjugate acid / weak base]when the concentrations are equal, aka halfway to equivalence point, log[1]=0 and pH=pKa or pH=pKb

therapeutic index
The ratio between the toxic and therapeutic concentrations of a drug. If the index is low, the difference between the therapeutic and toxic drug concentrations is small, and use of the drug is more hazardous.
goal of parmacokinetics
To optimize drug therapy for individual patients
Increases probability of desired effect
Reduces toxicity without compromising efficacy
Increases efficacy without unacceptable toxicity
Applied Pharmacokinetics
the process of using drug concentrations, pharmacokinetic principles and pharmacodynamic criteria to optimize drug therapy in individual patients
This helps reduce medical costs
Renal dosing of meds
substrate
Substrates of the CYP3A
Examples:
Cyclosporine-Tacrolimus(narrow TI)
CCB’s Verapamil/Diltiazem/Nicardipine/Nifedipine
Lovastatin
Theophylline
Protease inhibitors
Ethinyl estradiol
Cisapride and Seldane (drugs have been removed from the market), the reactant an enzyme acts on

Inhibitor examples
Inducers
Phenobarbital
Dilantin
Rifampin
Inhibitors
Nefazodone
Fluoxetine
Paroxetine
Azole antifungal
Cimetidine
Erythromycin
Protease inhibitors
Grapefruit juice
Example of CYP1A2 Inducer / Inhibitor
Patient takes Theophylline for COPD
He starts to smoke
Smoking is an inducer
This metabolizes the Theophylline faster than it would be in the absence of smoking
Level decreases
Patient gets SOB
Inducers and Inhibitors of CYP1A2
Inducers
Omeprazole
Phenobarbital
Dilantin
Rifampin
Smoking
Char-Broiled meatsInhibitors
Quinolone antibiotics
Cipro
Grapefruit juice

Inducer
Enzyme Induction
Drugs that induce these enzymes and increase the rate of drug metabolismCo administration of drugs that are inducers may require increased drug dosage to achieve same plasma level

Examples of Inducers:
Anticonvulsants-phenytoin, Phenobarbital, Tegretal (carbamazepine)
Antituberculous agents- Rifampin

drug inducer
speeds up metabolism, effects of drug DECREASE
Toxicity
harmful effects of a drug Toxicity is a problem
Example: Coumadin
At higher doses – toxic effects
Absorption
Lifestyle, co morbidity and the use of other meds affect drug adsorption more than potentially age alone. (Antacid use)
Drug absorption is complete in the elderly but usually proceeds slower resulting in lower peak conc, and increased time to onset of action.
This becomes clinically significant mainly for symptom relieving drugs. (anxiolytics)
absorption
uptake of meds for distribution in the body through or across tissues
Bioavailability
Measure of amount of drug that is actually absorbed from a given dose.
Bioavailability
Bioavailability
Affected by metabolism, first pass effect, and protein binding
May have decreased bioavailability due to co-existing conditions
Example – CHF
Drugs with high bioavailability should be started at low dose
acteristics of Drugs – Bioavailability
Formulation of Drug
How the drug comes – liquid, solid, etc.
Example: salt, size of molecules, enteric coatings
Concentration
Higher concentrations for drugs are absorbed faster
Lipophilic
More easily absorbed, but not soluble in plasma
If very lipophilic may need to bind with carrier protein like albumin
Hydrophilic
Soluble in plasma, but can’t cross membrane
Acidic
Absorbed in stomach
Acid in stomach may degrade drub
Basic
Better absorbed in intestine (large absorptive area)
Distribution drug
Blood takes drug to entire body.
Local blood flow determines amount of drug taken to certain organ.
Plasma Binding Protein: only drug molecules not bound to PBP take an effect on body.

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