1. MBBS/BDS PHARMACODYNAMICS 2014/2015
DR. E.O. AGBAJE

2. DEFINITION WHAT IS PHARMACODYNAMICS? Derived from two Greek words:
Pharmakon =drug
Dynamikos =force or power
Thus pharmacodynamics is the study of the effects of drugs.
Sometimes described as what a drug does to the body.
It involves receptor binding (including receptor sensitivity), post- receptor effects and chemical interactions.

3. Pharmacodynamics cont’d
Most drugs are developed based on the theory that the drug interacts with a biological structure (receptor, enzyme, transporter etc).
The interaction leads to a specific effect on the body.
The strength and length of the interaction determines how quickly the drug initiates the effect and how long the effect lasts.

4. Cont’d
e.g. the penicillin molecule binds to a bacterial enzyme transpeptidase and prevents “cross links” in the bacterial cell wall.
Thus, inability of the bacteria to create strong cell walls kill bacteria.
The interaction between penicillin and the enzyme depends on the amounts of penicillin present.
Large amounts of penicillin completely blocks the enzyme and in the presence of small amounts, the enzyme resumes its normal function.

5. Cont’d
Thus, bacterial killing activity of bacteria changes with the levels in the body. This is the “pharmacodynamics” of penicillin.
This information helps the physician to prescribe the penicillin dosing frequency to ensure high drug levels over the course of treatment.

6. Cont’d
Therefore, a drug’s pharmacodynamics can be affected by physiologic changes due to disorders which can change receptor binding, alter the level of binding proteins or decrease receptor sensitivity. Among such are genetic mutations, malnutrition, thyrotoxicosis.
Other factors are aging as well as the effects of other drugs

7. Mechanism of Drug Action
Most drugs act by altering the various body control systems, which may be: receptors, enzymes, or ion channels.
The various mechanisms include:
Physical mechanisms i.e. when the drug does not produce any chemical reaction or change in the cells of the body and the effect is only physical.
Activated charcoal binds with poisons in the stomach
Mannitol as an osmotic diuretic, freely filtered but not reabsorbed.

8. Cont’d
2. Chemical mechanisms: drugs act by producing chemical reactions in the body:
NaHCO3 as an antacid.
Dimercaprol, penicillamine, desferrioxamine as chelating agents.
Pralidoxime as a choline esterase reactivator.

9. Cont’d
Most drugs produce their effects by binding to protein molecules such as:
Enzymes
Carrier molecules
Ion channels
Receptors

10. Cont’d
3. Drug enzyme interactions: this may take place as enzyme activation or enzyme inhibition.
Enzyme inhibition could either be competitive or non competitive.
Examples of competitive inhibition:
Angiotensin converting enzyme inhibitors e.g. captopril
Reversible anticholinesterases e.g. neostigmine, physostigmine
Allopurinol used in gout since it inhibits xanthine oxidase, the enzyme which converts xanthine and hypoxanthine to uric acid.

11. Cont’d Non-competitive inhibition (effects are prolonged):
Irreversible anticholinesterases e.g. organophosphorus compounds (insectisides and war gases).
Aspirin inhibits cyclooxygenase enzyme and therefore prostaglandin synthesis.
Monoamine oxidase inhibitors used to treat depression e.g. imipramine.
Proton pump inhibitors: e.g. omeprazole inhibit the hydrogen potassium ATPase in parietal cells of stomach.

12. Cont’d
4. Drug channel interactions: drugs interfere with the flow of ions through the channels specific for these ions. These are Na+, K+, Ca++ and Cl- channels. - Sodium channel drugs e.g. quinidine, procainamide, local anaesthetics block the channels, thus depolarization does not take place and there is no nerve conduction in that localized area. They are used respectively in cardiac arrhythmias and as local anaesthetic.

13. Cont’d
Calcium channels: e.g nifedipine, verapamil, diltiazem. Block the voltage gated calcium channels; useful in hypertension and arrhythmias.
Potassium channels: e.g. amiodarone, sulfonylureas. Amiodarone is used in arrhythmias, blockade of the channels leads to a prolonged refractory period.
Chloride channels: e.g. benzodiazepines.

14. Cont’d
5. Carrier molecule interactions: Transport of ions and some other molecules across cell membranes generally requires a carrier protein.
These carriers are inhibited by certain drugs, the mechanism which clearly describes their pharmacological activities.
Inhibition of choline carrier by hemicholinium.
Inhibition of noradrenaline vesicular uptake by reserpine.
Inhibition of weak acid (e.g. uric acid) carrier by drugs (e.g. probenecid, which prevents uric acid tubular reabsorption, thus enhancing its excretion).

15. Cont’d
6. Drug receptor interaction: receptors are macromolecular proteins. They are target sites for most drugs; located mostly on the cell membrane but some are located intracellularly as well. i.e the specific chemical constituent of the cell with which drug interacts to produce its pharmacological effects.1
There are three forms of ligands that can bind to receptors:
Agonists
Antagonists
Partial agonists

16. Cont’d
Ligands: are the endogenous substances, molecules or compounds e.g. Ach, adrenaline, noradrenaline, glutamate, aspartate and GABA.
They bind with receptors present in the body.
Agonists are drugs which bind to receptors to activate them; they have the capacity to produce chain reactions in the receptors, which ultimately bring about the effects.

17. Cont’d Agonists have two properties:
i. affinity (the “tenacity” by which a ligand binds to its receptor) for receptors
Capability to produce chain reactions in the body due to intrinsic activity (the property of how a ligand causes biological responses via a single receptor) or efficacy.

18. Cont’d
Coupling: this is the transduction process between occupancy of receptor by agonist and the ensuing response.
Most agonists bind to receptors to cause activation and thereafter act via the second messenger system to produce the chains of reactions.
There are three second messenger systems:
Cyclic AMP
Cyclic GMP
Calcium and phophoinositol

19. Cont’d
The levels of these second messenger may increase or decrease via these three steps:
Drug binds receptor
Stimulation of G-regulatory proteins. G-regulatory proteins exists in two forms; GS (stimulatory G-protein) and GI (inhibitory G-protein)
Change in the effector element, which may be enzyme or ion channel

20. Cont’d cAMP Second Messenger System:
Receptors associated with cAMP second messenger system are: beta 1, beta 2, alpha 2 and dopamine 1.
Ligands include: catecholamines, serotonin, histamine ACTH, FSH, LH etc.

21. Cont’d Calcium and phosphoinositol system:
Receptors are: muscarinic and alpha 1.
Ligands include: Ach, angiotensin, serotonin, vasopressin,

22. Cont’d Mechanism of action of Nitrates:
Nitrates generate NO radicals, which activate guanylate cyclase and accumulation of cGMP which provokes other cascades of reactions leading to vasodilatation, reduced workload and decrease oxygen consumption.

23. Cont’d There are four main types of receptors:
Type 1: ligand-gated ion channels
location: membrane
Effectors: ion channel
Coupling: direct
Examples: nicotinic Ach receptor, GABA type A
Structure: oligometric assembly of subunits surrounding central pore

24. Cont’d Type 2: G-protein coupled receptors location: membrane
Effectors: channel or enzyme
Coupling: G-protein
Examples: muscarinic Ach receptor, adrenoceptors
Structure: monomeric or dimeric structure comprising seven transmembrane helices.

25. Cont’d Type 3: Kinase-linked receptors: location: membrane
Effectors: enzyme
Coupling: Direct
Examples: insulin, growth factor, cytokine receptors
Structure: single transmembrane helix linking extracellular receptor domain to intracellular kinase domain.

26. Cont’d Type 4: Nuclear receptors: location: intracellular
Effector: Gene transcription
Coupling: via DNA
Examples: steroid, thyroid hormone receptors
Structure: monomeric structure with separate receptor and DNA binding domains.

27. Cont’d Binding of drug with receptor may be of two types:
Reversible binding
Irreversible binding
In reversible binding, the bond between the drug and receptor is very weak (ionic, hydrogen or van der wall. The effect so produced is short lived.

28. Cont’d
In irreversible binding, very strong covalent bonds are present, which prolongs the effects of drugs. The effect continues until the drug is excreted or new receptor is generated.

29. Cont’d Regulation of Receptors:
* Down-regulation (desensitization): here, number of receptors is decreased.
Prolonged contact of tissues with the agonists results in decreased number of receptors in the tissues (down regulation of receptors) e.g. in asthmatics on prolonged beta agonists.
* Up-regulation: here, number of receptors is increased.

30. Cont’d
Spare Receptors: in certain cases, only a small proportion of receptor is occupied by drugs to produce maximal effect. This is due to vast reserve or spare receptors.

31. Cont’d
Antagonists: also bind to the receptors, but cannot activate them; they also prevent agonist binding.
They have affinity but no efficacy. e.g.. Atropine, propranolol.
They could either bind reversibly or irreversibly’

32. Cont’d
Partial Antagonists: bind to receptor but have very small intrinsic activity. Even when the receptors are fully (100 %) occupied, the response is sub-maximal. E.g. pindolol, oxpranolol
Inverse agonists: bind receptors to activate them but produce effects that are opposite to the agonists. E.g benzodiazepines produce sedation, relieve anxiety and relaxation of muscles.
Beta carbolines bind to benzodiazepine receptors to activate it and produce stimulation, increase in tone, anxiety and convulsion.

33. Receptor Theory
A number of theories have been put forward to explain the relationship between drug binding and response.
1. Occupancy theory: response is proportional to the fraction of occupied receptors; maximal response occurs when all the receptors are occupied.

34. Cont’d
2. Rate theory: response is proportional to the rate of Drug-Receptor complex dissociation. Here, duration of receptor dissociation determines whether a molecule is agonist, partial agonist or antagonist.

35. Cont’d
3. Stephenson’s theory: response is proportional to the fraction of occupied receptor and the intrinsic activity.
4. Ariens’ theory: response is a function of affinity; maximum response can be produced without 100 % receptor occupation.

36. Cont’d
5. The induced-fit theory: binding site is not necessarily complementary with the ligand conformation. Rather binding produces a plastic molding of both the ligand and the receptor as a dynamic process (thus nullifying the obsolete “key and lock” concept)
Therefore, agonist induces a conformational change; antagonist, no conformational change and partial agonist induces partial conformational change.

37. Cont’d
6. Macromolecular Perturbation theory: when a drug-receptor interaction occurs, one of two general types of macromolecular pertubation is possible. Either a specific conformational pertubation (by agonist), which leads to a biological response.
Or a non-specific conformational pertubation (antagonist), leads to no biologic response.

38. Cont’d 6. Miscellaneous mechanisms: Vinca alkaloids Anthelmintics
colchicine

39. Cont’d