Lec3

Pharmacology introduction Lecture three

Dr. nahlah 9-10-2016
Pharmacodynamic Phase
Describes the biochemical and physiologic action and effects of drugs in the body.
This phase occurs when the medication reaches the target cell, tissue, organ and a therapeutic effect occurs.
It is the study of the biological and therapeutic effects of drugs and their mechanisms of action i.e. effect of drug on the body.
Mechanism of drug action:
Physical action, alter of the environment of the cell through physical e.g., mannitol induces osmotic diuretics and kaolin adsorbs toxins in diarrhea.
Chemical action, alter of the environment of the cell through chemical processes that usually do not affect cell function. e.g,. NaHCO3 in hyperacidity and dimercaprol (BAL) to chelate mercury.
Cytotoxic action (stop cell division), e.g., anticancer drugs.
Interfere with selective passage of ions as Ca+2 and Na+ entry e.g. local anaesthetics and antiarrhythmic drugs.
Interference with normal metabolic pathway, e.g., sulphonamides competes with PABA which is essential for bacterial growth.
Action on enzyme either stimulation or inhibition. Enzyme inhibition could be:
1. Reversible which is usually short lasting as allopurinol (xanthine oxidase inhibitor), neostigmine (cholinesterase inhibitor, ....)
2. Irreversible which is usually long-lasting for new enzyme synthesis, e.g., irreversible anticholinesterases.
Action on specific receptors (Drug Receptor Interactions): receptors are macromolecular protein structures present on cell membrane or within the cell (cytoplasmic or nuclear) that react specifically with a ligand (drug, hormone or neurotransmitter) to produce a biological response. Receptors transduce (translate) the signal from the ligand to several subcellular elements e.g. enzymes, second messengers or ion channels to produce intracellular biochemical response.
Drugs can be categorized into:
Agonists are drugs, which stimulate receptors, i.e., initiate changes in cell function producing effects of various types. They have affinity, efficacy and rapid dissociation rate. Agonist potency depends on affinity (i.e. tendency to bind receptors) and efficacy (i.e ability to initiate changes which lead to effect).
Antagonists are drugs which block receptors, i.e. they bind to receptors without initiating change in receptors. They have affinity, no efficacy and slow dissociation rate. They have no effect in absence of agonist, but prevent action of agonist. Antagonist may be competitive or non-competitive.
A. Reversible competitive antagonist where antagonist competes for the same receptor and can be displaced by an excess agonist. A reversible competitive antagonism causes a parallel shift of the log dose response curve to the right. So slope and maximum effect are not changed.
B. Irreversible non competitive antagonist where the antagonist cannot be overcome by excess agonist. A non-competitive antagonist decreases efficacy of the agonist, so it shifts the log dose response curve to the right and changes the slope of the curve e.g. phenoxybenzamine.




Competitive antagonismNon competitive antagonismMaximum response (Emax) is the sameEmax is decreasedED50 is shifted to rightED50 is constant
Partial agonists are drugs which stimulate and block receptors, so they have affinity, efficacy (less than full agonist) and moderate dissociation rate.
Inverse agonists: produce effects opposite to that of agonist e.g. benzodiazepines (Bz) are agonists of Bz receptors _ sedation, muscle relaxation and anxiolytic action, while carbolines are inverse agonists of the same receptors_convulsions and anxiety.
AffinityEfficacy Dissociation rate ExamplesAgonist + +++ Rapid DiazepamAntagonist +  -- Slow FlumazenilPartial agonist + + Moderate BuprenorphineInverse agonist+ +++Rapid Carbolines

Types of Antagonists
1- Pharmacological Antagonists
Competitive Antagonist
They compete for the binding site.
Reversible & Surmountable
The effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with a fraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect.
Non-competitive Antagonist
Bind elsewhere in the receptor (Channel Blockers).
Irreversible & Non-surmountable
The effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors.
2-Functional Antagonists
Physiologic Antagonist
A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest.
Its intrinsic activity is = 1, but on another receptor.
Glucocorticoid Hormones ( Blood Sugar
Insulin ( Blood Sugar
Chemical Antagonist
A chelator (sequester) of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor.
A chemical antagonist does not depend on interaction with the agonists receptor (although such interaction may occur).
Heparin, an anticoagulant, acidic
If there is too much ( bleeding and haemorrhaging
Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.
Receptors and signal transduction mechanism
Binding of agonist to receptors activates effectors or signaling mechanisms of different types:
(1) Ion-channel linked receptors (Ligand-gated ion channel) e.g. nicotinic andGABAA receptors. The response takes milliseconds.
Acetylcholine binds to nicotinic receptors Na+ influx depolarization
GABA binds to GABAA receptors Cl- influx hyperpolarization.


(2) G-protein Linked Receptors
Examples: glucagon, α and β adrenergic receptors and muscarinic receptors. The time elapsed between binding to receptor and cellular response is few seconds. These receptors comprise a seven transmembrane or serpentine receptors because receptor polypeptide chain snakes across cell membrane 7 times. When the agonist binds to the binding domain, G-protein will be activated to transduce the agonist-induced signal to a variety of effector elements (adenylcyclase, phospholipase or ion channel) located either intracellular or in the cell membrane. These effector elements then change the concentration of an intracellular second messenger. Second messengers: include cAMP, Ca++ ion and phosphoinositides and cGMP
Types of G protein



(3) Membrane tyrosine kinase linked receptors : e.g. receptors for insulin whichact on membrane receptors which can phosp horylate signal transducers and activators of transcription (STAT) molecules, which dimerize and then dissociate from the receptor to cross the nuclear membrane and modulate gene transcription.
(4) DNA Linked receptors (intracellular receptor) e.g. corticosteroids, vitamin D and thyroxine. Agonist binds to its domain; the hsp 90 domain is released leaving DNA binding domain that regulates gene transcription, translation and consequently protein synthesis. The response has slow onset (hours) and has long duration.

Drug response curves

Graded dose response curves

Plot dose or log dose versus response

Efficacy is the maximal response produced by the drug.
Potency is a measure of how much drug is required to elicit a response. The lower the dose required for a given response, the more potent the drug.
Potency is expressed as the dose of drug that gives 50% of the maximal response (ED50). The affinity is an important factor in determining the potency.


-Drug A and B are two agonists with the same efficacy but drug A is more potent than drug B.
-Drug X and drug Y are two agonists. Drug X has higher efficacy than drug Y.
-Drug X is agonist and drug Y is partial agonist

Therapeutic index

Therapeutic Index = LD50
ED50
As long as the slopes of the curves are similar, however, if not similar, we use the Standard Margin of safety:


Standard Margin of safety = LD11 x 100
ED99

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Which determines the percent to which the dose effective in 99% of the population must be raised to cause toxicity in 1% of the population.

Variation in drug responsiveness

Individuals may vary considerably in their responsiveness to a drug
Idiosyncratic drug response unusual, one that is infrequently observed in most patients
Caused by:
Genetic differences in metabolism
Immunologic mechanism (allergy)
tolerance
Hyporeactive intensity of effect is decreased
Hyperreactive intensity of effect is increased
Hypersensitivity allergic or other immunologic response to drugs resulting from previous sensitizing exposure
Tolerance responsiveness usually decreases as a consequence of continued drug administration.
Need greater doses of a drug to produce original degree of effect as time progresses or need to substitute different drug
Tachyphylaxis responsiveness diminishes rapidly after administration of a drug (the first few doses), very rapid
Variation in drug responsivenessPatients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood which may alter the concentration of drug that reaches receptor
This can be due to age, weight, sex, disease state, liver and kidney function, and genetic differences
Variation in drug responsivenessFour general mechanisms:
1. Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood which may alter the conc of drug that reaches receptor.This can be due to age, weight, sex, disease state, liver and kidney function, and genetic differences.


2. Patients may vary in their concentrations of endogenous receptor ligand
Can vary in the response to pharmacologic antagonist
Ex: Propranolol (β blocker)
Pt with pheochromocytoma opposed to healthy runner

3. Patients may have differences in the number of receptor sites or differ in the function of their receptors due to the efficiency of coupling receptor to effector
Drug Induced down-regulation
The overshoot phenomena
Antagonists when discontinued, the elevated number of receptors can produce an exagerated response to physiologic conc of agonist
Agonist when discontinued, # of receptors that have been dec by down regulation is too low for endogenous agonist to produce effective stimulation
Ex: Clonidine (α agonist) decreases blood pressure. When withdrawn, can produce hypertensive crisis. Pt will have to be weaned slowly

4-Patients vary in functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems
Can be caused by age of pt or general health of pt. Most importantly, severity and pathophysiologic mechanism of the disease
Drug therapy will be most successful when there is correct diagnosis and if it is accurately directed at the pathophysiologic mechanism responsible for the disease

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