1. Pharmacodynamics Pharmacodynamics includes the experimental study of :
Mechanism of drug action.
Pharmacological effects.

2. Receptor Mediated Action
Mechanism of Action
A drug may produce its effect through:
Receptor mediated action.
Non-receptor mediated action.
Receptor Mediated Action
Receptor: receptor is a special molecular component of the cell (protein macro-molecule or DNA) which is capable of selectively recognizing and binding a drug, hormone, mediator or neurotransmitter, thereby eliciting a cellular response.
Kd = dissociation constant = concentration of drug at 50% binding to the receptors.

3. DRUG RECEPTORS AND PHARMACODYNAMICS
Specific molecules in a biologic system with which drugs interact to produce changes in
the function of the system

4. DRUG RECEPTORS AND PHARMACODYNAMICS
Determine the quantitative relations between dose or concentration of drug and pharmacologic effects

5. DRUG RECEPTORS AND PHARMACODYNAMICS
Selective in choosing a drug molecule to bind to avoid constant activation by promiscuous binding of many different molecules

6. DRUG RECEPTORS AND PHARMACODYNAMICS
Changes its function upon binding in such a
way that the function of the biologic system
is altered in order to have pharmacologic
effect

7. DRUG RECEPTORS AND PHARMACODYNAMICS
Selective in ligand-binding characteristics (respond to proper chemical signals and not to meaningless ones)
Mediate the actions of both pharmacologic agonists and antagonists

8. DRUG RECEPTORS AND PHARMACODYNAMICS
Majority are proteins which provide the necessary diversity and specificity of shape and electrical charge

9. DRUG RECEPTORS AND PHARMACODYNAMICS
RECEPTOR SITE/RECOGNITION SITE
Specific binding region of the macromolecule
High and selective affinity to the drug molecule

10. DRUG RECEPTORS AND PHARMACODYNAMICS
Interaction between the drug and the receptor
is the fundamental event that initiates the action
of the drug

11. DRUG RECEPTORS AND PHARMACODYNAMICS
CLASSIFICATION OF RECEPTORS
REGULATORY PROTEIN
Best characterized drug receptors
Mediates the action of endogenous chemical
signals like neurotransmitters, autacoids and
hormones
Mediates the effects of the most useful
therapeutic agents

12. DRUG RECEPTORS AND PHARMACODYNAMICS
CLASSIFICATION OF RECEPTORS
ENZYMES
Inhibited (or less commonly, activated) by
binding a drug
Eg, dihydrofolate reductase, the receptor for
methotrexate

13. DRUG RECEPTORS AND PHARMACODYNAMICS
CLASSIFICATION OF RECEPTORS
TRANSPORT PROTEINS
Eg, Na+/K+ ATPase, the membrane receptor
for digitalis

14. DRUG RECEPTORS AND PHARMACODYNAMICS
CLASSIFICATION OF RECEPTORS
STRUCTURAL PROTEINS
Eg, tubulin, the receptor for colchicine, an anti-inflammatory drug

15. DRUG RECEPTORS AND PHARMACODYNAMICS
EFFECTORS
Molecules that translate the drug-receptor interaction into a change in cellular activity
Eg, adenyl cyclase

16. DRUG RECEPTORS AND PHARMACODYNAMICS
EFFECTORS
Some receptors are also effectors
A single molecule may incorporate both
the drug binding site and the effector mechanism

17. Affinity: it is the ability of a drug to bind a receptor
Affinity: it is the ability of a drug to bind a receptor. It is determined by the dissociation constant (Kd) (the lower the Kd the higher the affinity).
Efficacy: it is the ability of a drug receptor complex to produce an effect. Maximal effect produced if a maximal dose is given. It is determined by the graded dose- response curve.
Response
Dose
Graded dose-response curve

18. ِ
Potency: it refers to the concentration (EC50) or dose (ED50) of a drug producing 50% of the maximum effect. It depends on the Kd which determines the receptor affinity to bind that drug. The lower the ED50, the more potent drug. A B
Response
50%
Dose
ED50
ED50
Drug A > drug B

19. DRUG RECEPTORS AND PHARMACODYNAMICS
GRADED DOSE-RESPONSE CURVE
Response of a particular receptor-effector system is measured against increasing concentration of a drug
Graph of the response versus the drug
dose

20. DRUG RECEPTORS AND PHARMACODYNAMICS
GRADED DOSE-RESPONSE CURVE
Sigmoid curve
Efficacy (Emax) and potency (EC50) are
derived from this curve
The smaller the EC50, the greater the
potency of the drug

21. DRUG RECEPTORS AND PHARMACODYNAMICS
Emax
Maximal response that can be produced
by a drug
All receptors are occupied
No response even if the dose is increased

22. DRUG RECEPTORS AND PHARMACODYNAMICS
Concentration of drug that produces
50% of maximal effect
Smaller EC50–more potent

23. DRUG RECEPTORS and PHARMACODYNAMICS
Emax 10
Drug effect 5
EC50
Drug dose

24. DRUG RECEPTORS and PHARMACODYNAMICS
Bmax
Total number of receptor sites
All receptors have been occupied

25. DRUG RECEPTORS and PHARMACODYNAMICSKD
Equilibrium dissociation constant
Concentration of drug required to
bind 50% of the receptors

26. DRUG RECEPTORS and PHARMACODYNAMICSKD
Measure of the affinity of a drug
for its binding site on the receptor
Smaller KD–greater affinity of drug
to receptor

27. DRUG RECEPTORS and PHARMACODYNAMICS
Bmax 10
Receptor bound
drug 5 KD
Drug dose

28. Therapeutic Index (TI) = Margin of Safety:
LD50 = lethal dose to 50% of the population in animal experiments.
ED50 = the effective dose in 50% of animals.
The higher the TI, the safer the drug e.g. barbiturate (TI=10)
The lower the TI, the greater the possibility of toxicity e.g. digitalis (TI=3), so death may occur if only 3mg has been administered because the usual therapeutic dose of cardiac glycoside is one mg.

29. General classification of drugs
Agonist = stimulant.
Partial agonist.
Antagonist = blocker.
Agonist: a drug has affinity, high efficacy and rapid rate of association and dissociation with its receptor e.g. adrenaline, morphine and histamine.
Partial agonist: a drug has affinity, weak efficacy and moderate association and dissociation. It produces an effect < the full agonist when it has saturated the receptors. It acts as antagonist in the presence of full agonist e.g. nalorphine, ergotamine, succinylcholine and oxprenolol.
Antagonist: a ligand having affinity, but no efficacy and slowly associated and dissociated from the receptor.

30. Signal Transduction Mechanism
Signal transduction is the subcellular cascade of events that occurs after binding of a ligand with a receptor to produce a unique cellular function.
Types of Receptors & Their Signaling Mechanisms
Channels-linked receptors: e.g. nicotinic receptor & GABA receptors. When acetylcholine (on nicotinic receptor), or GABA (on GABAA receptor), bind their receptors, a conformational change occurs in the channel resulting in altering of ion distribution across the cell membrane and a unique cellular function produced.
Na+

31. G-protein coupled receptors:
The receptors for catecholamines, prostaglandines and many peptide hormones are linked to G-protein (Gs , Gi , Gq , …) evolving in stimulation or inhibition of a second messenger R G
Second messenger

32. Examples
Stimulation of β1 & β 2 adrenergic receptors stimulate Gs  increase cAMP.
Stimulation of α1 adrenergic receptors  Gq  increase DAG, IP3.
Stimulation α2 adrenergic receptors Gi decrease cAMP.

33. Kinase-linked receptors:
When insulin, EGF and PDGF)bind their surface receptors, a tyrosine-kinase (on the inner part of the receptor) is activated. This leads to phosphorylation of certain protein on its tyrosine residue producing the specific cellular function. R
T.K

34. Nuclear Receptors = Gene active receptors:
The steroid hormones.
Thyroid hormones.
vitamin D and vitamin A.
These hormones can easily pass the cell membrane and bind with cytoplasmic mobile receptors.
Drug-receptor complex enters the nucleus and bind to DNA response element, which in turn regulates RNA transcription with production of unique protein concerned with the cell response.

35. Non-Receptor Mediated Mechanisms
Drugs act on enzymes:
Nitric oxide (NO) penetrates the cell membrane stimulating cytoplasmic guanylyl cyclase enzyme leading to increase of intracellular cGMP.
Digitalis inhibits Na+/ K+ ATPase enzyme.
Drugs Act on Plasma Membrane:
Polymixins and amphotricin B increase the permeability of bacterial plasma membrane.
Drugs Act on Subcellular Structures:
Erythromycin and chloramphenicol inhibit protein synthesis in bacteria by binding to 50 S ribosomal subunit. Tetracyclines and aminoglycosides bind 30 S ribosomal subunit.

36. Drugs Act by Chemical Action:
Antacids neutralize gastric acid secretion.
Protamine (alkaline & +ve charge) antagonizes heparin (acid & -ve charge).
Drugs Act by Physical Means:
Osmosis e.g. mannitol.
Lubricant e.g. liquid paraffin.
Adsorbent e.g. kaolin and charcoal.

37. Chelation:
Chelation is mainly employed in the treatment of heavy metal poisoning. A chelating agent holds the toxic metal ion to form a drug-metal complex, which is non-toxic, water-soluble and easily excreted in urine e.g.:
EDTA chelates calcium, lead and digitalis.
Dimercaprol (BAL) chelates mercury and copper.
Penicillamine chelates copper & used in treatment of Wilson’s disease.
Desfferioxamine chelates iron in cases of iron toxicity.

38. Sex: males need higher doses than females owing to the higher bulky muscles and androgen which is an enzyme inducer. Drugs should be administered cautiously during pregnancy and lactation (see latter)
Route of administration:
MgSO4 orally on empty stomach
(4g.) cholagogue
(15g.) saline purgative.
i.v inhibits the CNS and used in eclampsia seizures.
retention enema dehydration and used in cerebral edema and eclampsia.

39. Disease states: long duration of action or toxic effect of a drug may be related to liver or kidney disease and long period of time for absorption and distribution related to heart disease. Immune factors: a drug may stimulate the immune system causing urticaria or shock. From now on this patient should not received this drug or its related preparations e.g. penicillin and cephalosporins. .

40. Psychological factors:
the hopes, fears and expectation of the individual often affect the drug action.
Patients may even improve with placebo (tablet or capsule containing sucrose or lactose).
This may be due to release of endogenous substances like endorphins and enkephalins in the brain and other body parts

41. Timing of dosage:
A single dose of antacid or ranitidine taken at bedtime is more effective than two or three doses taken during the day.
Absorption is better on empty stomach.
Irritant drugs should be given after meals.
CNS stimulants never be given at bed time.

42. Cumulation:.
A drug is designated as cumulative when its elimination and/or detoxification are slow
E.g. digitalis, diazepam, amiodarone and large doses of aspirin or phenytoin.
The toxicity could be avoided by decreasing the dose

43. Tolerance It is a decrease or failed response to the usual
therapeuticdose of a drug.
Types of Tolerance:
Congenital tolerance: existing from birth examples:
Negroes are tolerant to the mydriatic action of ephedrine.
Eskimos are highly tolerant to fat diet (not develop acidosis).
Biological variation i.e. individual tolerance within any population. This may be related to genetic factors.
Rabbits are tolerant to large doses of atropine , probably due to the presence of atropine esterase in the liver (species tolerance).

44. Acquired tolerance: an acquired resistance to the usual dose of a drug repeatedly administered and more drugs are needed to produce the same effect.
It is reversible when the drug is stopped for a period of time.
Causes:
It may be due to increased metabolism of the drug.
or decreased sensitivity and number of receptors (down regulation).
Addiction is a phenomenon which often, accompanies the development of tolerance.
Examples: cocaine, heroine, morphine, alcohol, nicotine, barbiturates, nitrates and xanthines.

45. Tachyphylaxis:
It is an acute form of acquired tolerance
Occurring within few minutes.
Usually occurs if a drug is given repeatedly, at short intervals & generally by i.v route.
Tachyphylaxis probably occurs due to a transient saturation of the cell receptors with the drug.
Increasing the dose cannot produce the same effect.
Examples:
Disappearance of the hypertensive effect of ephedrine repeatedly administered i.v in an anesthetized dog.
Disappearance of the hypertensive effect of tyramine which releases and displaces noradrenaline from the adrenergic neurons.

46. Cross-tolerance: tolerance to a drug may extend to the related drugs
Cross-tolerance: tolerance to a drug may extend to the related drugs. Example: nicotine/lobeline, morphine / pethidine, and between members of barbiturates