2. PHARMACODYNAMICS
• Studies show mechanism of drug action on
living tissues.
• Concerned with response of tissues to
specific chemical agents at various sites in
the body.
• Drugs modify physiological activity but do
not confer any new function on a tissue or
organ in the body.
3. • Means by which drugs produce alterations in
function at their sites of action is known as
mechanism of action.
• Utility of a drug pharmacologically is
determined by its ability to act on specific
tissues/ cells i.e. show binding site
specificity.
• Specificity is reciprocal i.e. individual classes
of drugs bind to only certain targets and
individual targets recognize only certain
classes of drugs.
4. • The common protein molecules on which
drugs bind to include
– Enzymes
– Carrier molecules
– Ion channels
– Receptors
5. 1. Enzymes
• These are biological catalysts that control all
biochemical reactions of the cell.
• Drugs may alter enzyme activity because they
resemble the natural substrate and hence compete
with it for the enzyme.
• Drugs resembling enzyme substrate (natural) are
called antimetabolites.
• These can either block normal enzyme function or
result in production of other substances with unique
biochemical properties.
• E.G. Angiotensin converting enzyme is inhibited by
enalapril (an antihypertensive).This leads to less
formation of angiotensin II, causing vasodilatation
and less sodium and water retention.
6. 2. Ion channels
• Protein molecules designed to form water-
filled pores that span the membrane and
can switch between open and closed states.
• Ligand-gated ion channels/ ionotropic
receptors incorporate a receptor and open
only when an the receptor is occupied by an
agonist.
• Others are voltage – gated ion channels
e.g. Na+, K+ and Ca++ channels – open
when there is polarization of the cell.
7. Effect on ion channels
• Drugs affect ion channels function by interacting
either with the receptor site of ligand – gated
channels or with other parts of the channel molecule.
• Interaction can be: Direct – Drug binds to the channel
& alters its function or indirect which involves G-
protein and other intermediaries like allosteric sites.
Examples of drug that bind to accessory sites on the
channel protein and thereby affect channel gating
include benzodiazepines which bind to allosteric site
of GABA receptor/ chloride channel complex (ligand-
gated channel) that is different from the GABA
binding site.
• Most benzodiazepines facilitate the opening of the
channel by the inhibitory neurotransmitter GABA.
8. 3. Carrier molecules
• Carrier proteins are for transport of ions and
small organic molecules across cell
membranes – since the permeating
molecules are often too polar (insufficiently
lipid soluble) to penetrate the lipid membrane
on their own.
• Carrier proteins have sites that are
recognized by certain molecules
9. Examples of carrier molecule mediated
processes:-
• Glucose and amino acid transport into cell
• Renal tubule transport of ions and many
organic molecules.
• Transport of Na+ and Ca+
• Uptake of transmitter precursors e.g.
choline or neurotransmitter e.g.
noradrenalin, 5 hydroxytryptamine
(serotonin (5HT), glutamate and peptides by
nerve terminals.
10. This transport system can be inhibited by
some drugs e.g.
• Weak acid carrier – probenecid
• Noradrenalin uptake by reserpine
• Proton pump – omeprazole (gastric mucosa)
• Na+/ K+ pump – cardiac glycosides
• Na+/ K+/ Cl- co-transporter – loop diuretics
(loop of henle)
11. 4. Receptors
• Drugs bind to receptors which may/ may not
result in activation (elicit tissue response).
• Binding and activation are distinct processes.
• Receptors don’t remain constant in number:
continuous exposure to agonist causes
decrease (down-regulation) while prolonged
contact with antagonist causes increase (up-
regulation).
• Receptor binding can be as a result of weak
bonds e.g. hydrogen, Van der Waals,
electrostatic – reversible or the strong covalent
bonds – irreversible.
• Agonist and antagonist compete to occupy the
receptor according to the law of mass action.
12. 5. Others
Pharmacodynamics of Antimicrobials
• Selective toxicity is the principle behind the action of
antimicrobials.
• The drugs have to cause alteration of metabolic
process of micro-organisms without affecting the
human body.
• This is possible because there are exploitable
differences between the micro-organism cell and
the human cell.
Such mechanisms of action include:
• Inhibition of peptidoglycan cell wall by beta-lactam
antibiotics
• Inhibition of bacterial ribosome by some antibiotics
• Inhibition of ergosterol formation by antifungal
agents
13. DRUG INTERACTIONS
• Patients or clients usually use more than
one drug at a time (polypharmacy)
• This is especially so in:
– Elderly, who tend to have multiple problems,
e.g. heart disease, increased blood pressure,
rheumatism etc.
– Acute events/ situations e.g. myocardial
infarction, trauma injuries etc.
14. Drug interaction…..
• Interaction may be between drugs, food
substances and other chemical like alcohol
and nicotine.
• Drug interactions is said to have occurred
when two or more drugs are given together
and alter each other’s pharmacological
action in terms of:-
– Duration of action
– Magnitude of action
15. • Beneficial interactions
• Aminoglycoside plus penicillin synergic
antimicrobial effect.
• Probenecid plus penicillin – action of penicillin
prolonged.
• Morphine poisoning -Naloxone used as antidote
• NB: Therapeutically useful interactions are the
basis of rational polypharmacy.
• Harmful interactions
• Oral contraceptives pills and antiTB- contraception
failure
• Tetracycline and antacids – ineffectiveness of
tetracycline
• Anticoagulant warfarin and Aspirin- Bleeding
• NB: - Most drug interactions are clinically trivial.
16. Clinically important drug interactions may
occur under the following circumstances:
• With drugs that have steep dose- response
curves and small therapeutic index i.e. small
quantitative changes at target site lead to
substantial changes in effect e.g. Digoxin,
theophylline and Lithium.
• Enzyme inducers/ inhibitors
• Drugs that exhibit saturable metabolism
(zero-order kinetics) e.g. Phenytoin,
theophylline.
• In polypharmacy
• In extremes of age
• Patients with kidney or liver dysfunctions.
18. Synergism
• Synergism is of two types
1. Summation/ Addition
• Occurs when the effect of two drugs having the same action is additive
i.e. 2 + 2 = 4.
• E.g. B-adrenoceptor blockers plus thiazide diuretic have an additive
antihypertensive effect.
2. Potentiation
• Means to make mere powerful.
• Occurs when the action of one drug increases the action of another i.e.
2 + 2 = 5 or 0 + 2 = 3
• Sometimes both drugs have the action concerned e.g. trimethoprim
plus sulfamethoxazole 2 + 2 = 5 or one drug lacks the action concerned
i.e. 0 + 2 = 3
• Carbidopa + levodopa – co- careldopa.
• When the above levodopa combinations are used only 25% of
levodopa is required to achieve same concentration as when used
alone. This reduces the rate of adverse reactions from about 80% to
<15%. Another example is clavulanic acid + amoxicillin – co-amoxiclav
(augmentin®). NB: Clavulanic acid has no pharmacological action.
19. 2. Antagonism
• Occurs when two or more drugs oppose the
action of one another.
Types
• Chemical antagonism
• Pharmacokinetic antagonism
• Antagonism by receptor block
• Non-competitive antagonism i.e. block
receptor – effector- linkage
• Physiological antagonism
20. A. Chemical antagonism
• Where two or more substances combine in
solution, hence the effects of either or of the
drugs is lost e.g. use of chelating agents e.g.
dimercaprol that bind to heavy metals and
reduce their toxicity. Other example is where
antacids + tetracycline form a complex which is
excreted in feces.
B. Pharmacokinetic antagonism
• Situation where the concentration of the active
drug at the site of action is reduced.
• This occurs remotely from the site of action.
This can happen at any of the pharmacokinetic
21. C. Antagonism by receptor block
• Receptor – block antagonism involves two
mechanisms:-
– Reversible competitive antagonism
– Irreversible, non-equilibrium competitive
antagonism.
22. • NB:-Competitive antagonism
• Situation whereby a drug binds selectively to a
certain type of receptor without activating it but
in such a way that it prevents the binding of the
agonist.
• The chemical structure of the agonist and
antagonist is similar.
• Competitive antagonism is the most direct
mechanism by which one drug can reduce the
effect of another or that of endogenous
23. i. Reversible competitive antagonism:
• This is surmountable antagonism where increase in agonist
concentration increases antagonist dissociation from the
receptor.
• Agonist occupies a proportion of the vacant receptors; hence the
rate of antagonist association is reduced as dissociation
increases.
• Weak bonds are usually involved e.g. hydrogen and electrostatic
bonds.
ii. Irreversible/ Non equilibrium competitive antagonism
• Occur when antagonist dissociate very slowly or not at all from
the receptors.
• The result is that no change in antagonist occupancy takes place
when agonist is applied.
• This usually occurs with drugs that possess reactive groups
which form covalent bonds with the receptor.
24. iii. Non-competitive antagonism
• Situation where the agonist blocks at some point the chain of
events that lead to the production of a response by the agonist
e.g. verapamil & nifedipine prevent influx of Ca++ ions through
the cell membrane and thus block the contraction of muscle
produced by some drugs e.g. cholinesterase inhibitors like
neostigmine
iv. Physiological antagonism/ functional
• Interaction of two drugs whose opposing actions in the body
tend to cancel each other. Also called functional antagonism
• e.g. B-adrenoceptor blocker overdose causes bradycardia. This
is relieved by atropine which increases heart rate by blocking
parasympathetic nervous system.
• Bronchoconstriction by histamine during anaphylactic shock can
be counteracted by adrenaline which relaxes bronchial smooth
muscles (B2 adrenoceptor effect).
• Histamine acts on parietal cells to increase Hcl production while
omeprazole blocks this effect by inhibiting proton pump.
• In all these cases the pharmacological effect (or effect of
endogenous substance) is overcome by another drug (a drug)
which acts in a different physiological mechanism.
25. Types of drug interactions
• Pharmacokinetic interactions
• Drugs interact remotely from the target site
to alter plasma and site of action
concentrations. For pharmacokinetic
interaction to be clinically important it’s also
necessary that the concentration – response
curve of a drug is steep – so that a small
change in plasma concentration leads to a
substantial change in effect.
Pharmacokinetic interactions can occur at
any of the pharmacokinetic stages.
26. Absorption
• Usually affects those drugs that are administered orally.
• E.g Antacids (Fe, Al++ Mg+) form insoluble complexes with tetracycline.
Milk rich in calcium combines with tetracycline.
• Colestyramine (bile acid-binding resin used treat
hypercholesterolemia) binds several drugs e.g. warfarin, digoxin,
thyroxin and prevents their absorption.
• GIT absorption also affected by drugs that inhibit gastric emptying e.g.
atropine or opiates or accelerated by drugs that hasten gastric
emptying e.g. metoclopramide, purgatives – hence poorly soluble
drugs e.g. digoxin, adrenal steroids not well absorbed.
• Drugs may also alter gut-flora i.e. usually the antibiotics. This may alter
the action of anticoagulants since they reduce bacterial synthesis of
vitamin K in the colon.
• Enterohepatic recycling also affected since bacteria may not release
active drug from conjugate.
• An example of interaction outside the gut during absorption is where
adrenaline (epinephrine) is added to local anesthetic injections. The
resulting vasoconstriction slows the absorption of the anesthetic thus
prolonging the local effect.
• NB: Since interaction occurs because both drugs are in stomach at the
same time, avoid by separately giving the two drugs or food by 2 hrs
27. Distribution interactions
• Drugs may alter each other’s distribution though this is rarely clinically
important.
• Displacement of a drug from binding sites in plasma proteins or tissue
transiently increases the concentration of free (unbound drug). This is followed
by increased elimination so a new steady state results in which total drug
concentration in plasma is reduced but the free drug concentration is similar to
that before introduction of the second “displacing drug”.
• Clinically important interaction may occur when:
• Toxicity results from transient increase in concentration of free drug before the
new state is reached. Chloral hydrate, sulfonamides may displace bilirubin in
jaundiced premature neonates could be clinically disastrous. Bilirubin
metabolism is undeveloped in premature liver & unbound bilirubin can cross
immature BBB and cause kernicterrus (staining of the basal ganglia by
bilirubin).
• This causes distressing and permanent disturbance in movement known as
choreathetosis. This is characterized by involuntary writhing and twisting
movements in the child
• When the displacing drug or additionally reduces elimination /metabolism of
the first, so that the free concentration is increased not only acutely but also
chronically at new state, severe toxicity may ensue. For example,
Phenybutazone displaces warfarin from plasma binding sites and selectively
inhibits its metabolism resulting to prolonged prothrombin time and resulting to
increased bleeding. Salicylates displace methotrexate from binding sites &
reduce its secretion by competition with the anion secretory carrier. Guanidine,
verapamil, amiodarone displace digoxin from tissue-binding sites while
29. Enzyme induction
• Enzyme induction decreases the
pharmacological activity of drugs.
• The inducing agent is itself a substrate of the
induced enzyme, hence tolerance may develop.
• Enzyme induction can increase toxicity of a
second drug if its toxic effects are mediated by a
metabolite e.g. paracetamol toxicity. Its
metabolite N-acetyl-p-benzoquinone imine
which is formed by cytochrome P-450 may lead
to hepatotoxicity in patients with induced
cytochome P-450 e.g. alcoholics.
• NB: Individual variability in drug metabolism
may be due to varying exposure to
environmental contaminants which are strong
enzyme inducers e.g. nicotine, industrial
30. Examples of enzyme inducers
Inducer Drug affected
- Phenobarbital - Warfarin
- Rifampicin - Oral contraceptives
- Griseofulvin - Corticosteroids
- Phenytoin - Cyclosporin
NB: Enzyme induction is exploited
therapeutically by administering
Phenobarbital to premature babies to induce
glucuronyltransferase, thereby increasing
bilirubin conjugation and reducing the risk of
kernicterus.
31. Enzyme inhibition
• Especially of the P-450 system slows
metabolism and increases the action of other
drugs metabolized by the enzyme.
• Examples:
Inhibiting Drug Drug affected
- Chloramphenical- Phenytoin
- Ciprofloxacin - Theophylline
- Disulfuram - Warfarin
- Corticosteroids - TCAs
- MAOI - Pethidine
- Cimetidine - Amiodarone, Phenytoin,
pethidine
32. • NB: Therapeutic effect of some drugs is due
to their enzyme inhibition effect e.g.
Xanthine oxidase inhibitors e.g. allopurinol
(used to prevent gout)
• NB: Hemodynamic effects -Variation in
hepatic blood flow influences the rate of
inactivation of drugs that are subject to
extensive pre-systemic hepatic metabolism
e.g. lidocaine & propranolol.
33. Excretion interactions
• Drug interactions at the excretion phase
take different forms.
– By altering protein binding, hence filtration.
– By inhibiting tubular secretion
– By altering urine flow and/or urine pH.
34. A. Inhibition of tubular secretion
• Probenecid was developed expressly to inhibit penicillin
secretion and hence prolong its action.
• Also inhibits excretion of other drugs e.g. zidovudine.
• Other substances have probenecid –like effect on other drugs
e.g.
Drug inhibiting secretion Drug affected
i. Aspirin - Indomethacin
ii. Quinidine , - Digoxin
Amiodarone,
Verapamil
iii. Indomethacin - Furosemide
iv. ASA, - Methotrexate
NSAIDS
v. Phenylbutazone - Penicillin
35. B. Urine pH or flow
• Loop diuretics and thiazide diuretics
increase proximal tubular re-absorption of
lithium – toxicity is possible.
• Diuretics generally increase excretion of
other drugs though this is clinically not
important. The pH relates to ionization and
subsequent change of lipid solubility.
37. 2. Pharmacodynamic interactions
• These occur when there is alteration of
pharmacological effect without altering
concentration in the tissue fluid
• e.g. MAOI – Interact adversely with tyramine
containing foods, ephedrine leading to
hypertensive crisis.
• E.g. sulphonamide inhibits folic acid synthesis
and trimethoprim inhibits tetrahydrofolate
synthesis – synergism.
• Interactions at the receptors through
antagonism and agonism has been covered
before.
38. Interactions outside the body
Drugs might be mixed before giving them
e.g. in iv fluids, injections.
These may form precipitates.
Follow manufacturer’s instructions to know
which drugs can be mixed or not.
39. UNWANTED EFFECT OF DRUGS
• Despite all the care taken to use drugs
rationally there is always negative aspects
of using drugs.
• These undesired effects should be
minimized or avoided by skilled choice.
• A critical knowledge of drugs, Patient/client,
disease process can really reduce the rate
of occurrence of these effects.
40. Types of unwanted effects
1. Side effects
• Response other than expected that occurs at
normal, therapeutic doses.
• Usually occurs to everyone e.g.
hypokalemia, headache etc.
• These could be beneficial such that drugs
are administered to exploit their side effects
as therapeutic effects e.g. Valium is an
anxiolytic but can used as sedative.
• Chlorpheniramine (antihistamine) can be
given to promote sleep.
41. 2. Adverse effects
• Confined to harmful, serious unpleasant
effects occurring at dosage intended for
therapeutic effects.
• Usually call for reduction, or withdrawal of
the drugs e.g. hypersensivity
42. 3. Toxicity reactions
• Type of adverse reaction referring to direct
damaging action of a drug usually at high
doses. E.g. paracetamol metabolite, N –
acetyl--p-benzoquinine imine may cause
hepatoxicity.
• Gentamicin may damage 8th cranial nerve.
• All drugs are practically toxic at high doses.
• Overdose can be: - Absolute due to high
dose or relative - due to altered
physiological state e.g. Liver and kidney
disease.
43. 4. Secondary effects
• Indirect consequence of primary drug
action e.g. Broad spectrum antibiotic may
disturb normal flora and cause
pseudomembranous colitis e.g.
tetracycline.
• Diuretics – hypokalaemia which causes
digoxin toxicity.
44. Classification of adverse effects
1. Type A (Augmented)
• Occur to everyone.
• Due to excess of normal, predictable, dose related, pharmacodynamic effects.
• Common & treatment reduces incidence e.g. postural hypotension, CNS
depression.
2. Type B (Bizarre)
• Occur to some people .Not part of normal pharmacology of the drug. Not dose
-related.
• Due to unusual attributes of the patient interacting with the drug e.g. Drug
allergy, idiosyncratic reactions.
3. Type C (Continuous)
• Due to long term e.g. analgesic neuropathy, tardive dyskinesias,
carcinogenesis.
4. Type D ( Delayed)
• These include reactions like teratogenesis and carcinogenesis. Teratogen is a
substance, agent, process that interfere with normal prenatal development –
i.e. cause developmental abnormalities in fetus. Teratogenic agents may
include tetracycline (bone and teeth problems); Thalidomide which cause
Phocomelia
5. Type E (Ending of use)
• Reactions like rebound adrenocortical insufficiency e.g. in steroid use that is
prolonged. Rebound insomnia – withdrawal of benzodiazepines
46. 1. Non-drug factors
A. Intrinsic to the patient
– Age, sex, extremes of age – metabolism and
excretion decrease
– Genetics – pharmacogenetics
– Tendency to allergy
– Disease – especially liver and renal diseases
– Personality – compliance determined
– Habits – alcohol, smoking
B. Extrinsic to the patient
e.g. the prescriber and environment
47. 2. Drug factors
• Intrinsic to the drug e.g. interactions
between drugs and high doses
48. Hypersensitivity
• Due to interaction of drug or its metabolite
with patient and disease and subsequent
re-exposure. Exposure is not necessary
medical e.g. penicillins occur in dairy
products following treatment of cattle.
• Chief target organs/ systems of drug allergy
include the skin, respiratory tract, GIT,
Blood and blood vessels.
49. Types of allergic Reactions
1. Type one reactions (Immediate type)
2. Type II reactions (Auto allergy)
3. Type III reactions
4. Type IV (delayed – cell mediated allergy)
50. 1. Type one reactions (Immediate type)
• Also called anaphylactic reaction.
• There is formation tissue – sensitizing 1gE
which are attached to mast cells and/or
leucocytes.
• In subsequent exposure – allergen reacts with
these 1gE which leads to degranulation of cells
to produce pharmacologically active
substances e.g. histamine, leukotrines,
prostaglandins, platelet activating factor, these
cause such symptoms like urticaria, asthma
and anaphylactic shock.
• Allergy develops within minutes and lasts 1-
51. 2. Type II reactions (Auto allergy)
• Drug or drug metabolite combine with
proteins and the complex recognized as
foreign.
• Drug metabolite + protein = “hapten”.
52. 3. Type III reactions
• Antigen and antibody form large complexes
which damage or block small blood vessels.
• Leucocytes engulf these immune complexes
releasing active substances e.g. lysosomal
enzymes.
• Such reactions include serum sickness,
glomerulonephritis, vasculitis and pulmonary
disease.
53. 4. Type IV (delayed – cell mediated allergy)
• Antigen – specific receptors develop on T-
lymphocytes.
• Subsequent administration leads to a local
or tissue allergic reaction e.g. contact
dermatitis.
• First exposure leads to immunological
change in certain lymphocytes.
• Second exposure lymphocytes release
pharmacologically active chemicals – lead to
edema, inflammation and vesiculation
54. Cross – allergy
• Cross-allergy within a group of drugs is
usual e.g. penicillin vs. cephalosporin
(10%)
• Patients with allergic diseases e.g.
eczema are more likely to develop allergy
to drugs.
55. Factors affecting individual response to
drugs
1. Pathophysiologic factors
2. Psychosocial factors
3. Pregnancy
4. Age
5. Genetic factors
6. Ethnic differences
7. Idiosyncratic factors
8. Body mass/weight
9. Gender
10.Environmental factors:
11.Route and time of administration
12.Nutrition
56. Drug therapy and developmental stage
• Drug therapy in child bearing clients
• Pediatric/breastfeeding clients
• Drug therapy for the elderly
