Subject: Pharmacology Topic: Pharmacodynamics 2 Lecturer: Dr.

Delacruz Date of Lecture: Ages ago Transcriptionist: JC Luna Pages: 7

Dose response curves

concentration there is no increase in response. This then is the drug s maximal efficacy.
Fig. 6-5: Model of Simple Occupancy Theory

dose response data are typically graphed with the dose or dose function on the x-axis and the measured effect (response) on the y-axis log[dose] are used; if the actual value of the dose is used the scale will be very wide

slope (change in response per unit dose) the more receptors are occupied, the higher the response o the amount of the drug that can occupy the receptors is, in turn, dependent on the drug s concentration; the higher the concentration the more drugs are available to interact with receptors

with increasing dose there is an increasing effect Threshold: area of the curve that corresponds to the concentration of the dose that doesn t produce an effect. The end of the threshold marks the onset of the drugs effects

Two types of Dose response curves 1. Graded dose response curve

Graded Dose-Effect Curve Dose100 1 00 Maximal effect

80 80

% of Maximal Effect

60 60

40 40

20 20

0 0 200 20 0 EC550 0 4 00 400 60 0 600 800 8 00

[Drug]

Potency: location of the curve along the xaxis. It is the function of the dose o A drug that produces the maximal effect at a lower dose compared to another drug is said to be more potent. maximal efficacy or ceiling effect (greatest attainable response) o there are some drugs that when there is an increase in

Log Dose-Effect Curve Dose100 100

80

% of Maximal Effect

60

40

20 EC550 0 0 1 10 10 100 1000 1 000

[Drug] [Drug]

Fig. 6-2: os -R spons C rv s & ot ncy S owing E i

EFFICACY

F ull A go nists Th at D if fer Fu ll go nist s Th at D iff er nists iffe r In Pot enc y: Po te nc ten cy:
iii. Drug classification
M ax R esp onse % M ax R esp on se

B B

100

80

40

1. ED50 the dose that will produce 50% of the maximal effect of the drug.

Agonists E
% M a x r e s p on s e po ns

r in

A B C

Lo g D ru g Co nc n tra ti on L og Dr ug C on c e ntr a tio n

  

- It can be seen from the diagram above that Drug A is the most potent drug while Drug C is the least potent drug. ii. Measures efficacy

20

0 1 10 100 [ r ] [ 1000 1000

1. Full Agonist 2. Partial Agonist even at maximal dose will only produce submaximal response 3. Competitive Antagonist function of numerical superiority; the agonist will still produce the response if its concentration is greater than that of the antagonist. Competitive Antagonists reduce the potency of a drug. 4. Non-competitive Antagonist these drugs are covalently bound to the receptor hence it cannot be easily

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Dr ug Con cen trati on (log scale ) D ru g C on ce ntr ation (l og sc ale)

% f im l Eff t

60

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For Drug lassification

i t i t+ m titiv t i t

a. Measures response in a single biological unit (e.g. a single person, a single animal) b. Continuous scale: dose effect c. Relates dose to intensity of effect d. ED50 / EC50 dose that will produce 50% of the maximal effect of the drug. e. ED100 / EC100 dose that will produce maximal effect of the drug. f. Determines efficacy g. Uses: i. Measures potency amount of drug that will produce the response; this is the function of the dose

- It can be seen
from the diagram above that Drug A is the most effective drug while Drug C is the least effective drug.

POTENCY

i t+

titiv

i t

removed; increase in concentration doesn t result in increased response (there is a reduction in drug efficacy) 2. Quantal dose response curve

a. Population studies studies groups of patients b. All or none pharmacologic effect the effect of a drug is either present or not. c. Relates dose to frequency of effect d. Y-axis represent the frequency of the response e. Graphically express the frequency with which a defined effect occurs in a population at a given dose f. Can also be represented in a sigmoid curve. However in a graph such as this the Cumulative Response is the one that is measured. This means that the percentage of the population that responds to a given dose of a drug is inclusive of the percentage that responded at a lower concentration of the drug. For example, if a drug elicits an effect in 3% of the population when it is given in a 5 mg dose and elicits an effect in 40% of the population when it is given at a 7 mg dose, the 40% is also inclusive of the 3% that responded at the 5 mg dose. g. Uses: i. Measures Efficacy ED50 / EC50 here this represents the dose of the drug in which 50% of the population exhibited an effect ii. Measures safety

1. margin of safety a. Difference between the DR curve for the therapeutic effect of the drug and the DR curve for its toxic effect. b. The greater the difference, the wider is the margin of safety of the drug; the smaller the difference, the narrower is the margin of safety of the drug. c. Therapeutic index is equal to LD50/ED50 (LD=Lethal dose, only for animals; for humans Toxic Dose is used) h. ED50 dose where 50% of patients in the population produces the response i. TD50 dose of the drug that produces the toxic effect in 50% of the patients Adverse Drug Experience - Adverse Drug Reaction - Adverse Drug Interaction Adverse Drug Reactions - noxious, unintended and undesired effects that occur at normal drug doses - serious ADRs occur in 6.7% of hospitalized patients - adverse drug reactions are known to be responsible for 3%-12% of hospital admissions - fatal drug reactions account for about 5% of deaths of patients in US hospitals - Adverse Drug Reaction Types: o Type A Augmented - Predictable, dose dependent. Sub types:  Extension effect

Type B     

60

 

40

20

0 3.5 4.5 6 7 9

Type D  

    

Type E 

   o Type F  

Pharmacodynamics o Age neonates, elderly  Sensitivity of target organs o Gender  More in females (60%) than males (40%)  Varying life cycle in females (menarch, lactation, pregnancy) o Concurrent diseases  Cardiac, hepatic, renal  Malnutrition likely to induce toxicity because of decrease in protein o Inherent toxicity of the drug  Low therapeutic index Pharmacokinetics o Route of administration  Intravenous, oral, intramuscular y Ex. Phenytoin produces hypotension and cardiac arrhythmias if administered as a bolus, Diazepam is not given by slow infusion o Absorption o Distribution o Metabolism o Excretion o Genetics

)( ( ( 2) 1)( (0 ( )(

Type C 

An exaggeration of the therapeutic effect Side effect y Effect different from desired therapeutic effect Bizarre Unpredictable Effect in not related to the usual pharmacologic effect Idiosyncrasy Possible immunologic mechanism Ex. Hypersensitivity or allergic reactions to Penicillins, Aplastic anemia with Chloramphenicol, Malignant hyperthermia with Succinylcholine Continuous Occurs on long term use of drug Related to dose and duration of treatment Ex. Osteoporosis with Heparin, NSAID-induced nephropathy, Gynecomastia with Cimetidine, Gingival enlargement induced by Phenytoin, Thioridazineinduced retinopathy Delayed Occurs after a longer time May affect offspring of mother who took the drug during pregnancy Carcinogenicity Teratogenicity Immunotoxicity Common in anti-cancer drugs Ex. Phocomelia with Thalidomide, Vaginal adenocarcinoma with Diethylstilbestrol (DES) Ending of Use Occurs when drug is suddenly stopped and withdrawal react ions set it E.g. acute adrenal insufficiency prednisone Rebound hypertension clonidine Rebound insomnia diazepam Failure of treatment Resistance or tolerance to drug effects Ex. Penicillin G Staphylococcal infection , y

Antibacterial drugs for viral infection Causes of Adverse drug Reactions - Pharmaceutical o Dose and Duration of Therapy o Sustained release preparation  Altering release rate will decrease local effect o Compliance with dosing regimen  Decreasing dose for fear of adverse effects  Increasing dose for better effects o Total number of medications  ADRs occur with increasing number of drugs
100

80
Pati ts x ri i v ts (%)

sid

G6PD deficiency DNA polymorphism y CYP polymorphism y isonizid acetylation rapid acetylators are likely to experience hepatotoxicity; Neurotoxicity is more frequent among slow acetylators miscellaneous factors  diet  smoking y stimulates activity of CYP 1A2  alcohol intake y Acute intake inhibits activity of DME (drug metabolizing enzymes, e.g. CYP) y Chronic intake stimulates activity of DME  

o o

Object Drug is a drug whose action is affected Interactant or Precipitant drug is a drug which initiates or precipitates the interaction

Drug interactions may be: - Beneficial enhancement of efficacy or reduction of toxicity - Adverse decrease or loss of efficacy or increased toxicity Types of Drug Interactions - Pharmaceutical o Physico-chemical interactions either of a drug with an intravenous solution or two drugs in the same solution o Addition of excipients or pharmaceutical adjuvant inert substances added to facilitate formulation that enhance dissolution, stability o Physicochemical incompatibility  Dopamine (acidic, pH 2.54.5) vs. Furosemide (basic, pH 8-9.3)  Calcium and NaHCO3  Gentamycin and Penicillin in the same IVF solution  IVF Incompatibility y Phenytoin is incompatible with 5% Dextrose containing IV solution because it precipitates causing microemboli y Drugs should not be added to total parenteral nutrition solution or to blood transfusions o Container incompatibility  Diazepam, Nitroglycerin, Lidocaine, Hydralazine in polyvinyl containers  KCl (electrolyte solution) in plastic containers  Paclitaxel (Anticancer) is incompatible with PVC bags or administration sets - Pharmacokinetic occur when the absorption, distribution, metabolism or excretion of the object drug is altered by the interactant drug o Absorption  Gastric motility y Increased gastric motility decrease absorption in the stomach; increase

Drug-Food Interaction - Food in the stomach o Delay drug absorption o Decrease gastric motility o Increase intragastric pH o Increase hepatic blood flow - High protein diet o Decrease absorption of Levodopa - Effect on CYP o Inhibits CYP 1A2 and CYP 3A4  Grapefruit juice o Induces activity of CYP 1A2  Cruciferous vegetables (broccoli, cabbage, brussel sprouts)  Charcoal-broiled beef - Tyramine-rich food o Toxicity with MAO inhibitors Adverse Drug Interactions - Drug combinations o Use of 2 or more drugs to attain a desired therapeutic objective such as  Improve therapeutic efficacy  Decrease adverse drug reaction  Delay emergence of resistance Potential Adverse Drug Interaction - Is the possibility that one drug (interactant drug) may alter the intensity of the pharmacologic effect of another drug (object drug) given concurrently

Acidic pH weak acid more unioinized more lipid soluble weak base less unionized less lipid soluble Alkaline pH weak acid less unionized less lipid solub le weak base more unionized more lipid soluble
Transport mechanism y Levodopa with high protein meal Distribution  Determined largely by blood flow to the site and the binding properties of the drug to plasma proteins  Ex. Quinidine displaces Digoxin from protein binding sites Metabolism  Activity of drug metabolizing enzymes (Cytochrome P450) y Enzyme inducer e.g., Phenobarbital y Enzyme inhibitor e.g. Cimetidine Excretion  Competition for active tubular secretion y E.g. Penicillin and Probenecid  pH dependent tubular transport y E.g. Phenobarbital and NaHCO3, Aspirin and Vitamin C 

Alkaline pH e weak acids p less unionized p not reabsorbed p gets excreted weak base p more unionized p reabsorbed p not excreted Ex. Barbiturate weak acid Barbiturate poisoning alkalinize the urine

Unionized drugs lipid soluble reabsorbed by simple diffusion in the renal tubules p excretion Acidic pH weak acids p more unionized p reabsorbed p not excreted weak base p less unionized p not reabsorbed p gets excreted e.g. Aspirin (weak acid) and Vitamin C
Pharmacodynamic o Occur when the interactant drug alters the effect of the object drug at its site of action o Interaction at same site or on two different sites with similar or opposite results  Synergism  Antagonism

Types of Drug Interaction: Resulting in Increase of Effect - Additive Effect ( 1+1=2) o The total effect of the 2 drugs is the sum of the individual effects o Ex. Gentamicin + Carbenicillin; Diazepam + Alcohol; Paracetamol + Ibuprofen - Synergism (1+1=3) o When the effect of two drugs is greater than the sum of their individual effects o Ex. Trimethoprim + Sulfamethoxazole (antibacterials) produce sequential blockade in the synthesis of bacterial folic acid; Leucovorin + 5-FU (anticancer drugs) in the treatment of colorectal cancer, Leucovorin stabilizes the complex of 5-FU and thymidylate synthase (TS)

5 4 33 54

5 3 79 8 7

absorption in the small intestines Gastric pH y Weakly basic drugs are not readily absorbed in the stomach

Unionized drugs lipid soluble reabsorbed by simple diffusion in the renal tubules p excret

Potentiation (1+0=3) o The activity of one drug is increased by another drug that does not posses the same activity o Ex. Lidocaine + Epinephrine; Penicillin + Probenicid

Types of Drug Interactions: Resulting in Decrease of Effect (Antagonism): - Pharmacologic same target site, same receptor o Noncompetitive o Competitive - Physiologic / Functional same target site, different receptor - Dispositional / Pharmacokinetic - Chemical Types of Antagonists: Pharmacologic - Competitive o Surmountable, reversible o Ex. Dipenhydramine (antihistamine) H1 Receptor Blocker; Atropine (Antimuscarinic) Muscarinic Receptor Blocker - Noncompetitive o Insurmountable, irreversible o Usually compound is bound covalently to the receptor o Ex. Phenoxybenzamine Alpha1 Receptor Blocker Types of Antagonists: Physiologic - Two substances acting on the same target cell but at different receptors - Ex. Treatment of anaphylactic shock Histamine acts on histaminergic receptors while Epinephrine acts of adrenergic receptors o Captopril + Indomethacin  Captopril ACE Inhibitor p prevents the generation of Angiotensin II p Vasodilation  Indomethacin Prostaglandin synthesis inhibitor pinhibits generation of PgI2 p Vasoconstriction Types of Antagonists: Dispositional - A substance can decrease the effect of another by affecting its fate in the body - Ex. Phenobarbital and Warfarin; Tetracycline and Antacids Types of Drug Interactions: Resulting in Decrease of Effect - Chemical o Heparin (acidic) + Protamine sulfate (basic) Drug Tolerance

Decreased responsiveness to a drug due to repeated drug administration Types: o Pharmacodynamic  Cellular Adaptation  Down Regulation o Pharmacokinetic  Enhanced clearance

Tachyphylaxis rapid development of tolerance

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