UG Graphs-1

Dept of Pharmacology , KIMS 1
• Bioavailability (BA)
• Is the rate and extent to which the drug appears into
blood stream; from the site of drug administration;
in biologically active form.
• Usually expressed as a fraction or percentage of
the given dose which appears in the blood stream at
the given interval.
1. What does this graph indicate
• It indicates the bioavailability of three different
formulations (tab/cap/coated…)
2
2. Which formulation is least bioavailable of the
three- A, B, or C.
• formulation C is least bioavailable
3. What is the difference b/w drug A & B. What is
its therapeutic value.
• Drug A reaches above therapeutic conc & may
cause drug toxicity & is shorter acting
• Drug B is slow & sustained but not reaches the
therapeutic conc, so cause therapeutic failure.
4. On what factors does bioavailability depend on
• Drug factors, Biological factors, Food factors,
Pharmacological factors 3
a. Drug factors :
• Dose, physical consistency, pharmaceutical
factors (Particle size, coating materials, rate of
disintegration & dissolution.), stability, lipid
solubility, molecular weight/ size.
b. Biological factors
• Absorptive surface, pH, GI blood flow, motility,
Functional integrity of GIT.
c. Food factors
• Presence/ absence of food & Type/ content of
food
4
d. Pharmacological factors
• One drug may alter the absorption of another
drug by several mechanisms:
1. Altering gastric emptying (accelerating/
slowing)
2. ↓ acidity
3. Binding the drug firmly
4. Modifying the absorptive surface
5. Competing at the absorptive surface
5
4. What is the clinical importance of assessing
bioavailability.
a)Can find out peak plasma conc.
b)Time to reach peak plasma conc.
c)Maximum amount of drug absorbed (area under
curve).
d)For dosing schedules & frequency of admn.
6
• 1. Comment on the graph. What does the
term therapeutic range means.
• Graph depicts a effect of different doses of
phenytoin on its plasma conc.
• Range is a optimum plasma conc. of a drug to
produce optimum pharmacological response.
• It lies b/w maximum tolerated dose (Above
which produces toxicity ) & minimum effective
dose (below is therapeutic failure).
8
2. What are the reasons for such a phenomenon
• Initially gradual ↑se in dose of phenytoin there is
gradual ↑se in plasma conc. But on subsequent ↑se
in the dose there is sudden ↑se in plasma conc
• This phenomenon is due to phenytoin follows
saturation kinetics.
• I,e. initially phenytoin follows 1st order kinetics &
later due to saturation of enzymes it follows zero
order kinetics.
• Eg: Digoxin, Warfarin, aspirin…..
9
3. What is zero order kinetics & 1st order
kinetics. Explain with appropriate examples.
• Zero order- Irrespective of the total amount of
drug +nt in the body a constant amount is
disposed off in unit time E.g.: 10mg/hr
(in100/200/500mg) . Eg: Alcohol
• Plasma Half life is variable and dose dependent
• First order: A constant fraction of the drug is
eliminated at a constant interval of time. Rate of
elimination directly proportional to plasma conc.
• Majority of the drugs.
10
11
• 1. Write briefly on the source of digoxin
• Digitalis lanata, D purpurea, Strophanthus kombe,
S Gratus, Urginea maritima, Thevetia Nerifollia.
• 2. What is the effect of Digoxin on the ECG.
• Prolongs PR interval - slowing of AV conduction
(AV block at toxic doses).
• Shortens QT interval- (short systole).
• Depression ST segment with T wave inversion (at
high doses interfere with repolarization)
• 3. What is the effect on the CVS.
• + ve inotropic & -ve chronotropic action.
13
• 1.What phenomenon is observed in the above
graph. Explain the underlying mechanism.
• Tachyphylaxis acute tolerance) may occur
following repeated & too frequent admn of certain
drugs within a short interval.
1. Depletion of endogenous substance- NA store by
tyramine, ephedrine
2. Firm binding & slow dissociation from receptors
3. Denaturing the receptor or acute down regulation
or desensitization
4. Post receptor changes
15
• 3. Mention the other drugs which may show this
phenomenon.
• Tyramine, amphetamine, ephedrine, xylometazoline,
Salbutamol, oxytocin, ADH, pituitary hormones,
nitroglycerine.
• 4. What is the clinical significance of the
phenomenon.
• Some drugs should not be admn too frequently ,
repeatedly & in short interval.
• Tachyphylaxis – is rapidly reversible & disappears
shortly with discontinuation.
• It is best avoided by maintaining adequate dosing
16
intervals.
• This graph depicts the effect of drugs on
anaesthetized dog BP
• 1. Explain the effects of A, B, C, D & TD on the
BP of the dog
• Drug A (Adrenaline) - Has produced biphasic
response - initial pressor response is due to α1 & β1
stimulation , foll by depressor response is due to β2
mediated vasodilation of Sk. muscle bl vessels.
• Biphasic response with Adr was 1ST noted by
Dale’s. Hence called Dale’s vasomotor reversal, in
which prior admn of ergot shows only depressor
response, becoz ergot is a α blocker 18
• Drug –B (Nor adr)- Only pressor response is
due to α1 & β1 stimulation & no depressor
response becoz no β2 action.
• Drug C (Isoprenaline)- Has depressor response
due to predominant β2 action, initial pressor in
some graphs is due to mild β1 action
• Drug D (ACh)- Has produced depressor response
due to M3 mediated EDRF release induced
vasodilation.
• TD – Also produced same effect that of Ach
• TD+D (Test drug +Ach) –In the +ce of Ach, TD
has produced more fall in BP. 19
• 2. What is the possible nature of the test drug.
• So test drug could be anticholinesterase
compound, like physo/neostigmine.
• Anticholinesterase compounds acts by inhibiting
cholinesterases enzymes and thus intensify the
actions of Ach.
20
• 1. Explain the effects of A, B, C & TD on the BP
of the dog
• Drug B (Nor adr)- Only pressor response is due
to α1 & β1 stimulation & no depressor response
becoz no β2 action.
• TD- Has produced depressor response like that of
Isoprenaline.
• Drug P (β blocker) & Isoprenaline – Drug-P
alone has not produced any response
• But in the +ce of Drug- P the response to
Isoprenaline has reduced. 23
• 2. What is the possible nature of the test drug.
• Even, in the + ce of β - blocker the response to test
drug also reduced.
• So test drug could be β2 stimulants like salbutamol,
or isoprenaline itself.
24
25
• 1. Explain the effects of A, B, C & TD on the BP
of the dog
• Drug B (Nor adr)- Only pressor response is due
to α1 & β1 stimulation & no depressor response
becoz no β2 action.
• TD- Has produced pressor response like that of
NA.
27
• Explain the effects of A, B, C, & TD after the
admn of Tolazoline
• Drug-P (Tolazoline) alone has not produced
any action
• In the +ce of Tolazoline
• The pressor response of Drug-A (Adr) has
abolished.
• The pressor response of Drug –B is reduced
• The depressor response of isoprenaline is
unaltered
• The pressor response of TD has reduced
28
• 3. What is the effect of Tolazoline
• Tolazoline is a α- blocker and has blocked the α
mediated responses of ADR, NA.
• The test drug could be α1 agonist like phenyl ephrine
29
• The graph depicts effect of drugs on
• 1. Explain the effects of A, H, & TD
• Drug A (Ach), Drug B (histamine) & TD have
produced depressor response on dog BP
• Drug –P (β-blocker) , Drug Q (antihistaminic) &
Drug- R (muscarinic blocker) have not produced
any responses on their own.
• Also in the +ce β-blocker, antihistaminic &
muscarinic blocker the response to the TD is
unchanged.
31
• 2. What is the possible nature of TD.
• It could be directly acting vasodilators like
Diazoxide, papaverine, hydralazine, sod
nitroprusside.

• The graph depicts effect of drugs on
• 1. Explain the effects of A, H, & TD
• Drug A (Ach), Drug B (histamine) & TD have
produced depressor response on dog BP
• Drug –P (β-blocker) , Drug Q (antihistaminic) &
Drug- R (muscarinic blocker) have not produced
any responses on their own.
• In the +ce β-blocker & antihistaminic & the
responses to the TD is unchanged.
• But in the + ce of muscarinic blocker the
response of the TD is abolished 34
• 2. What is the possible nature of TD.
• It could be Ach like muscarinic agonist like
Bethenachol.

• 1. Comment on the graph
• Effect of drugs on anesthetized dog BP
• This phenomenon is called as Tachyphylaxis (acute
tolerance) may occur following repeated & too
frequent admn of certain drugs within a short
interval.
1. Depletion of endogenous substance- NA store by
tyramine, ephedrine
2. Firm binding & slow dissociation from receptors
3. Denaturing the receptor or acute down regulation
or desensitization
4. Post receptor changes
37
• Other drugs which may show this phenomenon.
• Tyramine, amphetamine, ephedrine, xylometazoline,
Salbutamol, oxytocin, ADH, pituitary hormones,
nitroglycerine.
• 2. What is the clinical significance of the
phenomenon.
• Some drugs should not be admn too frequently ,
repeatedly & in short interval.
• Tachyphylaxis – is rapidly reversible & disappears
shortly with discontinuation.
• It is best avoided by maintaining adequate dosing
intervals.
38
• 1. Explain the effects of Acetylcholine
• Ach has produced depressor response/fall in BP due
to vasodilation mediated through the release of
EDRF
• What phenomenon is observed when the dose is
increased after atropine.
• Administration of atropine alone has not produced
any response.
• In the + ce of atropine there is no response to 4 μg of
Ach due to blockade of muscarinic receptors.
40
• 2. What phenomenon is observed when the
dose is increased after atropine
• But in the +ce of atropine when large dose of
Ach (3mg) is admn there is a sudden rise of BP
(pressor response)
• It is due to stimulation of both sympathetic &
parasympathetic ganglia through Nn receptors.
So that there is a release of catecholamines (NA)
from the adrenal medulla & ganglia, which
causes peripheral vasoconstriction & rise in BP.
41
• 1. What does this graph indicate
• It is the effect of Ach & d-Tc on isolated frog
rectus muscle
• First they have taken 3 consecutive contractile
response to Ach to show the consistency of the
prepn.
• Then they have recorded the response of Ach in
the +ce of d-Tc. The response of Ach is reduced
in the + ce of d-Tc, subsequent response to Ach
is increased in amplitude.
• This graph indicates the competitive antagonism
b/w Ach & d-Tc 43
• 2. What experiment has been done on this
rabbit. What does it demonstrated.
• Head drop method is done on rabbit, it
demonstrates the flaccid paralysis due to skeletal
muscle relaxant action of d-Tc
• D-Tc acts on Nm receptors by blocking Na+
channels.
• 3. What is the difference b/w the mechanism of
action of D-tc & Succinylcholine
• D-Tc is competitive blocker & SCh is
depolarizing/ non competitive blocker
44
• Explain the graph
• The 1st three contractile response to Ach are similar
showing consistency of the preparation.
• 4th response is due to addition of 0.5 ml of serum (which
contain pseudo cholinesterase (PC)) added with same dose
of Ach immediately, there is no change in response (action
of PC is slow).
• 5th response is recorded 10 mins after the admn of serum,
which shows a decrease in the response to Ach (due to
hydrolysis of Ach by PC)
• Other responses are recorded after addition of
physostigmine +Ach + serum, which shows increase in the
initial response foll by regaining of original response.
46
• Explain the effect of physostigmine on the frog
rectus abdominus muscle preparation.
• It is reversible anticholinesterase, which by
inhibiting the hydrolysis of Ach by inhibiting
cholinesterase enzymes, increase the conc of Ach,
thus increases the contractile response of Ach on
rectus abdominus muscle.
• Subsequent contractile response to Ach starts
reducing in amplitude indicating the actions of
physostigmine is reversible.
47
• Ach is a substrate for both true & pseudo
cholinesterase, but with pseudo cholinesterase the
hydrolysis of Ach is slow.
• True cholinesterase is +nt in synapse, RBC & Grey
matter.
• Pseudo cholinesterase is + nt in the plasma, liver,
intestine & white matter.
48
• Explain the graph. What is the nature of test
drug
• There is a similar contractile response to Ach (acts
through Nm receptors on rectus muscle(skeletal))
& 0.5ml of test drug
• There is ↑ se in the response after addition of 1 ml
of TD (↑ se in the dose there is corresponding ↑ se
in the response)
• In the + ce of D-Tc the response of both Ach & Td
are reduced.
50
• Explain how d-Tc acts.
• It is peripherally acting non depolarizing
neuromuscular blocker, acts by blocking Na+
channels. Thus competes for Ach at Nm
receptors.
51
• 1. What is meant by graded dose response curve
• When the dose a drug is increased, the magnitude
of the response also increase.
• 2.What is meant by supra-maximal dose
• The dose which produce a maximum response is
called as maximal dose/celing dose, the dose which
is above the maximal dose is supra-maximal dose
53
• 3. What do the two curves in the graph
represent. Why are they different. Which
method of plotting is preferred & why.
• The hyperbolic/curvilinear line represents a
simple graded dose response curve (arithmetic
curve) & straight line represents log dose response
curve
• When the doses are plotted against the response on
an arithmetic scale, it is impossible to measure the
magnitude of ↑se in response corresponding to the
small ↑se in the doses. On this scale it is difficult
to display a dose range. I,e smallest to largest dose
54
• To accommodate this, a wider gauge paper is
required, in which the responses are compressed to
a straight line & this can be recorded on log dose
papers called log dose response curve.
• 4.What are the three basic attributes of dose
response curve
• Potency, efficacy, ED50 (effective dose which
produces 50% of max response)
• 5.What is EC50
• Is effective conc which can provide 50% of the
maximal response.
• Smaller the EC50 more potent is the drug. 55
• 1. Comment on the effects of carbachol &
Epinephrine
• The 1st three consecutive contractile responses on
rat colon shows consistency of the prepn
• Carbachol is a Cholinomimetic agent acts through
muscarinic receptors to produce the contractile
response.
• Unlike Ach, Carbachol has a relatively selective
muscarinic effect on smooth muscle of GIT, urinary
bladder & also stimulates autonomic ganglia & sk
muscle.
• Muscarinic actions of carbachol are not adequately
58
antagonized by atropine.
• Epinephrine is sympathomimetic agent, which acts
through α receptors to produce relaxant on smooth
muscle of the GIT.
• 2. What is the nature of antagonism exhibited in
this experiment
• Here it has antagonized the action of carbachol by
acting at different receptors (differing mech). This
type of antagonism called as physiological
/functional antagonism.
• Other examples are
• Adr & histamine, Ach & Adr, carbachol &
papaverine
59
• 1. Comment on the responses.
• The 1st three consecutive contractile responses on
rat colon shows consistency of the prepn
• Carbachol is a Cholinomimetic agent acts through
muscarinic receptors to produce the contractile
response.
• Unlike Ach, Carbachol has a relatively selective
muscarinic effect on smooth muscle of GIT, urinary
bladder & also stimulates autonomic ganglia & sk
muscle.
• Muscarinic actions of carbachol are not adequately
antagonized by atropine.
61
• Papaverine is a Benzoisoquinoline opioid having no
analgesic activity. It is a smooth muscle relaxant. In
the +ce of papaverine response to Carbachol is
reduced.
• 2. What is the nature of antagonism exhibited in
this experiment
• Here papaverine has antagonized the action of
carbachol by acting at different receptors (differing
mech). This type of antagonism called as
physiological /functional antagonism.
• Other examples are
• Adr & histamine, Ach & Adr, Carbachol &
62
papaverine
• Effect of drugs on isolated guinea pig ileum
• First response was recorded with Adr, it has
produced smooth muscle relaxation, through α
receptors.
• 2nd response with Ach shown contractile response,
which is due to stimulation of M3 receptors.
• Next contractile response was recorded with
histamine, which acts through H1 receptors.
• Then TD also has produced contractile response
64
• Then in the +ce of atropine the response Ach is
abolished, but response to TD has remained
same
• But in the +ce of antihistaminic the response to
histamine & TD both have reduced.
• Becoz in the +ce of antihistaminic the response
to TD has reduced, TD could be histamine like,
Betahistine- which is a H1 selective analogue.
65
• The 1st two responses are recorded with Ach &
histamine, both have shown contractile
responses.
• But in the +ce TD the response to Ach has
remained the same, but response to histamine has
reduced
• 2. What is the possible nature of the test drug
So the possible nature of the TD drug could be an
antihistaminic.
67
• The 1st three responses were recorded with Ach,
histamine & TD.
• All of them have shown contractile responses.
• In the +ce antihistaminic the response to TD has
remained the same, but in the + ce of atropine the
response to Ach & TD both have reduced.
• 2. What is the possible nature of the test drug
• So the possible nature of the TD drug could be an
Ach like.
69
DOSE RESPONSE CURVE OF AN AGONIST
100-
Response (% of maximum) A B
-
50-
C
-
0-
LOG DOSE
A: Agonist alone; B: In the presence of antagonist B; C: In the presence of antagonist C
QUESTIONS
1. Comment on the graph.
2. Explain the clinical significance 70
1. Comment on the graph.
• Dose response curve of an agonist alone & in the +ce
of antagonist.
• Here in the ‘X’ axis the log doses are recorded & in the
‘Y’ axis responses are recorded.
• Curve A is - agonist alone
• Curve B – agonist response in the presence of
competitive antagonist
• Curve C – agonist response in the presence of non
competitive antagonist.
2. Explain the clinical significance
72
• Clinical implication of antagonism
1. To choose the most suitable antidote in the treatment of
drug poisoning/ serious drug reaction.
• E.g.:Naloxone in opioid poisoning
• Atropine in OP poisoning
• Adrenalin in anaphylactic shock
• flumazenil to benzodiazepines
2. To counter or nullify the adverse effect of one drug with

another drug.
• E.g.: Haloperidol (antipsychotic may cause extra
pyramidal toxicity) and benzhexol
73
• Ether anesthesia causes ↑airway secretions, which
are countered by atropine as pre anesthetic
medication
• Antacid combination- Aluminium salt & Mg salt (Al

alone = constipation & Mg alone = diarrhea)

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Dept of Pharmacology , KIMS 1

Dept of Pharmacology , KIMS 32

Dept of Pharmacology , KIMS 35

2. To counter or nullify the adverse effect of one drug with

• Antacid combination- Aluminium salt & Mg salt (Al

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