Pharmacodynamicsby

Dr. Sherif Ahmed Shaltout

Types of pharmacodynamic effects:: 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.

Mechanisms of drug actions: 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.

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 Coupled2- G-Protein CoupledComprised of single peptide that has seven Comprised of single peptide that has seven membrane-spanning regions, linked to a G-membrane-spanning regions, linked to a G-protein with 3 subunits – alpha (binds GTP) and protein with 3 subunits – alpha (binds GTP) and beta gamma subunits. beta gamma subunits. Binding of appropriate ligand to extracellular Binding of appropriate ligand to extracellular region → activates G-Protein → GTP replaces region → activates G-Protein → GTP replaces GDP on alpha subunit → dissociation of G-GDP on alpha subunit → dissociation of G-Protein → both alpha-GTP and beta gamma Protein → both alpha-GTP and beta gamma interact with second messengers .Response last interact with second messengers .Response last several seconds to minutes 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.

4. Receptors Regulating Transcription (very slow) 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. AgonistInteracts 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. AntagonistInteracts 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 Noncompetitive Antagonist

competes with the agonist for the same

recognition site of the receptor.

binds to the recognition site of the receptor

or to an allosteric site.

Duration depends on the relative plasma

concentrations of agonist and antagonist.

Duration depends on the rate of turnover

of the receptor molecules or metab. of

ant.

parallel shift to the right in the dose-

response curve & no change in Emax

Downward, non-parallel shift in the

dose-resp. curve & decrease in Emax

   

 

Examples:

Blockers, histamine antagonists.

Example:

Phenoxybenzamine ( blocker).

Non Competitive antagonistNon Competitive antagonist

Reversible:

1-bind 1-bind reversiblyreversibly with with receptorreceptor

2- Duration depends on 2- Duration depends on metabolismmetabolism of of antagonistantagonist

3- 3- shortshort duration duration

4- e.g. 4- e.g. succinylcholinesuccinylcholine

Irreversible:

1-bind 1-bind irreversiblyirreversibly with with receptorreceptor

2- Duration depends on 2- Duration depends on synthesis synthesis of new recepof new recep..

3- 3- longlong duration duration

4- e.g. 4- e.g. OPC.OPC.

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: 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 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 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 action1-Dose: It is the amount of the drug given to the patient at a time.

Therapeutic dose: the average dose given to adult patient to produce therapeutic effect.

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

therapeutic effect. Toxic or lethal dose: the dose that produce toxicity or

death.

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

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

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: SalicylatesPregnancy: TeratogenicLactation: Sedative, purgatives

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 : 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 Racial: ephedrine is not mydriatic in negros . Species: rabbits tolerate large amounts of atropin Individual tolerance.

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

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: Addition or summation: 1 + 1 = 2 e.g. histamine and ACH on B.P. Synergism: 1 + 1 = 3 e.g. sulphonamide and trimethoprim. Potentiation: 0 + 1 = 2 . e.g. barbiturates potentiate the analgesic effect of salicylates.

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

12-Emotional factors: 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

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.MechanismTypes of drug allergy

Type I:Ag + IgE on mast cellsanaphylactic shock.penicillin

Type IIAg + IgM & IgG on blood cells.blood dyscrasias e.g. quinine-hemolytic anemia,

α methyl dopa - thrombocytopenia.

Type IIIAg + IgM & IgG in plasma + Complement sys.Organ degenration e.g.hepatitis, nephritis with antithyroid, antiepileptics

Type IVAg + 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.

Adverse effectsAdverse effects

During After stopp.During After stopp.

Predictable Unpredict.Predictable Unpredict.SSide effects & ide effects & TToxicity oxicity HHypersensitivityypersensitivity

TToleranceolerance (addiction) & (addiction) & IIntolerance ntolerance IIdiocyncrasydiocyncrasy

TTeratogenicity & eratogenicity & CCarcinogenicityarcinogenicity

IIatrogenicatrogenic