Transcript ph.dynamics

Pharmacodynamics
by
Dr. Sherif Ahmed Shaltout
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Types of pharmacodynamic effects:
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Local or topical action, where drugs act on site of
application e.g. ointment or eye drops.
Systemic or general action, where the drug acts after
administration and distribution by circulation to
various tissues.
Reflex or remote action, where the drug acts locally
at one site to produce reflex action elsewhere.
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Mechanisms of drug actions:
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Physical action: As adsorption e.g. kaolin and pectin in cases
of diarrhea.
Chemical action: As neutralization of hyperacidity by antacids.
Interference with cell division as cytotoxic drugs.
Inhibition of enzymes e.g. choline esterase inhibitor drugs.
Interference with normal metabolic pathwayse.g. sulfonamide
interfere with para-aminobenzoic acid which is essential
metabolite for bacteria.
Action on cell membrane: e.g. local anesthetics.
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action on cell receptors:
The most common method by which most drugs generally act
e.g. acetyl choline on cholinergic receptors, adrenaline on
adrenergic receptors.
Receptor: a chemically reactive (chemosensitive)
macromolecule, protein in nature, present inside or on the
surface of the cell .it is the site of drug attachment and action,
can be stimulated by agonist drugs and blocked by antagonist
drugs.
Classification of receptors:
1-Ligand gated ion channels:
-Nicotinic Receptors : Stimulated by acetylcholine and
results in sodium influx.
-GABA-receptor : Stimulated by benzodiazepines and
GABA and results in increased chloride influx
2- G-Protein Coupled
 Comprised of single peptide that has seven
membrane-spanning regions, linked to a Gprotein with 3 subunits – alpha (binds GTP)
and beta gamma subunits.
 Binding of appropriate ligand to extracellular
region → activates G-Protein → GTP replaces
GDP on alpha subunit → dissociation of GProtein → both alpha-GTP and beta gamma
interact with second messengers .Response last
several seconds to minutes
3. Receptors linked to Tyrosine Kinase (RTKs)
 The receptor is formed of two domains:
a. An extracellular domain, to which the agonist (e.g. insulin)
binds.
b. An intracellular domain, which is a tyrosine kinase enzyme
(effector).
 Binding of insulin causes 2 single tyrosine-kinases receptors
to aggregate into a dimmer with subsequent
autophosphorylation. Then, the activated-phosphorylated
dimmer binds to relay proteins, activating them. These relay
proteins trigger the cellular response through either
production of a second messenger or turning on gene
expression.
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4. Receptors Regulating Transcription (very slow)
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Steroid hormones, estrogen, progesterone, enter the target cell and combine
with intracellular receptor proteins associated with nuclear chromatin (DNA) to
activate or inhibit transcription of the nearby gene. This will modify protein
production and cause changes in the structure or function of the target tissue.
Types of ligands
1. Agonist
 Interacts with the receptor (affinity) activating it (efficacy) →
pharmacologic effect, i.e. it has affinity and efficacy, e.g.
acetylcholine (Ach) activates nicotinic receptors → depolarization
→ skeletal muscle contraction.
2. Antagonist
 Interacts with the receptor without activation (affinity without
efficacy), e.g. curare blocks nicotinic receptors → prevents
depolarization by Ach → relaxation. 2 types of antagonists:
 Competitive antagonists: compete with agonists for the same
recognition site of the receptors → the agonist behaves as if it
were less potent.
 Noncompetitive antagonists: prevent binding of the agonist or
prevent activation of the receptor by the agonist.
Competitive Antagonist
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Noncompetitive Antagonist
competes with the agonist for the same 
binds to the recognition site of the receptor
recognition site of the receptor.
or to an allosteric site.
Duration depends on the relative plasma 
Duration depends on the rate of turnover
concentrations of agonist and antagonist.
of the receptor molecules or metab. of
ant.
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parallel shift to the right in the dose-
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response curve & no change in Emax
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Examples:
 Blockers, histamine antagonists.
Downward, non-parallel shift in the
dose-resp. curve & decrease in Emax
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Example:
Phenoxybenzamine ( blocker).
Non Competitive antagonist
Reversible:
1-bind reversibly with
receptor
2- Duration depends on
metabolism of antagonist
3- short duration
4- e.g. succinylcholine
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Irreversible:
1-bind irreversibly with
receptor
2- Duration depends on
synthesis of new recep.
3- long duration
4- e.g. OPC.
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3. Partial Agonist (Agonist-Antagonist)
 it activates the empty receptor, but with lower efficacy than
that of a full agonist
 Agonist present: block the receptor, if abscent: as weak agonist
 Example: succinylcholine → initially activates nicotinic
receptors → fasciculations (agonistic effect) →followed by
relaxation (antagonist effect).
4.Inverse agonist:
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Affinity for specific receptor.
 Efficacy is opposite to that of endogenous agonists
 Examples:
B-carbonlin binds to GABA receptors and produces CNS
stimulation which is opposite to the effect of endogenous agonist
GABA which binds to GABA and produces CNS depression.
Dose-response Relationship
I. Graded (quantitative) dose-response curve is
obtained if the degree of response is depicted against log
the dose e.g. decreases of blood glucose against the dose.
Parameters that can be obtained from the graded
dose-response curve:
1. Efficacy (Emax):is the maximal effect produced by the drug (=
the maximum value of the dose-response curve)
2. Potency
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ED50 it is dose that produces 50% of the maximal response and is
estimated similar to the “All or none curve”. The lower the ED50 the more
potent the drug is
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Slope of the middle portion of the curve (it reflects the effect of the drug
produced by one unit of the dose. The steeper the curve (i.e. the higher the
slope) the more potent the drug is.
II. All/None(quantal) dose-response
curve is obtained if the percentage of patients who respond to
the drug is depicted against log the dose e.g. the % of
patients in whom the arrhythmia is terminated by different
doses of an antiarrhythmic drug
Parameters that can be obtained from the
All/None curve:
1. ED50: It is the dose that cures 50% of cases. It is used for
comparison between drugs e.g. drug with a lower ED50 is >
potent than that with a higher ED50.
2. LD50: relation between the % mortality in animals treated by
the drug and the log of the dose, we will obtain the LD50 (the
dose that kills 50% of animals). the drug with lower LD50 is
considered more toxic than the drug with higher LD50
3. Therapeutic index (TI):
It is the ratio between ED50 & LD50 → TI = LD50/ED50.
It gives an idea about the safety of the drug: if the TI is large, i.e.
the LD50 is much higher than the ED50  the drug is safer.
Factors affecting drug action
1-Dose: It is the amount of the drug given to the
patient at a time.
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Therapeutic dose: the average dose given to adult
patient to produce therapeutic effect.
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Maximal tolerated dose: the largest dose of drug that
can be taken safely.
Initial dose: the dose used at start of treatment.
 Maintenance dose: the dose required to maintain the
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therapeutic effect.
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Toxic or lethal dose: the dose that produce toxicity or
death.
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Dose -response relationship
2-Age, weight and surface area:
Adult dose is calculated depending on age from 20 to 60 years
old, and weight about 70 kg.
 Children dose:
According to age:
Young formula:
 Child dose = adult dose x age in years / age in years + 12
Diling formula:
 Child dose = adult dose x age in years / 20
According to weight (for infant less than 1 year):
Infant dose = adult dosed in pounds / 150
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Newborn infant especially premature infants are more
susceptible to the effect of the drugs because:
1-Underdevelopment of many hepatic microsomal
enzymes that detoxify drugs.
2-Reduced renal excretion of drugs due to low
glomerular filtration and renal blood flow
3-Lower total plasma protein levels.
4-Immaturity of blood brain barriers (B.B.B).
e.g. Infants are more sensitive to morphine and
chlormphenicoal
 The elderly dose:
From 60 - 80 years old =3/4 adult dose.
Above 80 years old =1/2 adult dose
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3-Sex:
Female patients need less dose than male patients
because:
1-Female contain more fatty tissues (which have low
oxidation rate and are inert tissues).
2-Estrogens inhibit hepatic microsomal enzymes, while
androgens stimulate these enzymes.
 Menstrual period: Salicylates
 Pregnancy: Teratogenic
 Lactation: Sedative, purgatives
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4-Route of administration
 Magnesium sulfate: orally act as a purgative, while
IV it cause depression to cardiac, skeletal, smooth
muscles and C.N.S.
5-Time of administration :
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Non irritant drugs: before meals
Irritant drugs: after meals .
C.N.S stimulant: not be given at night
Drugs producing drowsiness as antihistamine drugs
not be given at day time.
6-Tolerance: Failure of responsiveness to the usual
dose of a drug.
Types:
1-Acquired tolerance:
 It occurs on repeated administration of the drug.
 More drugs is needed to obtain the original effect.
 It is reversible i.e. it disappears when the drug is
stopped for some time.
 Examples: morphine, nitrates, xanthines and
barbiturates.
Mechanism of acquired tolerance
1- PK.:
1- Decreased intestinal absorption of drugs.
2-Increased renal excretion of drugs.
3-Increased metabolism of drugs due to enzyme induction.
2- PD.:
1- Decreased Sensitivity of receptors.
2- Down regulation: Decreased number of receptors
3- Development of antihormone against insulin & parathormone.
Special types of acquired tolerance:
1-Tachyphylaxis:-acute rapid -not obtained by increasing dose.
Example: ephedrine on blood pressure. (3D: dissociation,
downregulation, depletion)
2-Cross-tolerance: e.g. morphine and pethidine.
3-Tissue tolerance: to some actions of the drug. e.g.
morphine tolerance not to its miotic and constipating
actions .
4-Bacterial resistance to antibiotics.
2-Congential tolerance
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Racial: ephedrine is not mydriatic in negros .
Species: rabbits tolerate large amounts of atropin
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Individual tolerance.
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7-Drug intolerance (hypersusceptibility):
 It is exaggerated pharmacological response to the
usual dose of the drug e.g. adrenaline in
thyrotoxicosis.
8- Genetic a bnormalties(idiosyncrasy):
 It is congenital abnormal reactions to drugs due to
genetic abnormality.
 antimalarials (primaquien) , sulpha, salicylates may
induce hemolytic anemia in patients with congenital
G-6-PD deficiency
 Isoniazid induces peripheral neuritis in patients with
congenital slow acetylator
Malignant hyperthermia: may occur in some patients
following halothane anaethesia or succinylcholine
administration
 Succinyl choline apnea: occur in patients with
congenital deficiency of plasma pseudo-choline
esterase enzyme.
9-Pathological state:
 Aspirin lower body temperature in case of fever
 The dose reduced in patients with renal impairment
and hepatic impairment
 The effect of subcutaneous drugs is delayed in
patients with shock or heart failure
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10-Cumulation:
when the rate of administration of the drug
exceeds the rate of its metabolism or excretion
which leads to toxic effect e.g. digitalis.
11- Drug interactions:
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Addition or summation: 1 + 1 = 2 e.g. histamine
and ACH on B.P.
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Synergism: 1 + 1 = 3 e.g. sulphonamide and
trimethoprim.
Potentiation: 0 + 1 = 2 . e.g. barbiturates potentiate
the analgesic effect of salicylates.
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Antagonism:
 Physiological: 2 drugs with opposing actions on 2
receptors e.g. histamine and adrenaline.
 Chemical: one drug reacts chemically with an active
drug e.g. heparin and protamine sulphate.
 Pharmacological:
Competitive antagonism:
Non-Competitive antagonism
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12-Emotional factors:
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Administration of placebo (inert medication formed
of sucrose or lactose) may give therapeutic effect in
psychic patient just to please him).
13-Drug dependence:
Habitation:
psychological or emotional dependence .
No physical disturbance
If sudden stoppage….> emotional distress.
e.g. coffee and tea habits.
Addiction:
psychological + physical dependence .
If sudden stoppage….> withdrawal symptoms
e.g. morphine, barbiturates
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14-Drug allergy (hypersensitivity):
It is acquired abnormal reactions to drugs due to
antigen - antibody reaction.
 It is unrelated to the dose.
 It occurs when the drug is given repeatedly.
 as penicillin, aspirin, sulpha.
 Mechanism
 Types of drug allergy
Type I:
 Ag + IgE on mast cells
 anaphylactic shock.
 penicillin
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Type II
 Ag + IgM & IgG on blood cells.
 blood dyscrasias e.g. quinine-hemolytic anemia,
α methyl dopa - thrombocytopenia.
Type III
 Ag + IgM & IgG in plasma + Complement sys.
 Organ degenration e.g.hepatitis, nephritis with
antithyroid, antiepileptics
Type IV
 Ag + lymphocytes (delayed cell mediated type).
 Inflammatory mass e,g. BCG
Manifestations of drug allergy:
 Acute allergy (anaphylactic reactions):
-within one hour
-shock, acute bronchial asthma, laryngeal oedema,
generalized urticaria and conjunctivitis
 Subacute allergy:
-1 - 24 hours
- skin rash, bronchial asthma, rhinitis, fever.
 Delayed allergy:
- e.g. thrombocytopenic purpura, agranulocytosis and
heamolytic reactions.
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Adverse effects
During
Predictable
After stopp.
Unpredict.
Side effects & Toxicity
Hypersensitivity
Tolerance (addiction) & Intolerance
Idiocyncrasy
Teratogenicity & Carcinogenicity
Iatrogenic