1

II. Pharmacodynamics
Dose response relationship ) ‫(كمان مهم في العملي الميكروالب‬
• Dose – response relationship of the drugs is presented graphically in DOSE _ RESPONSE CURVE
• Types of Dose response curves:
1. Graded (quantitative)
2. All/non (qualitative)
Differences between types of dose response curves
Graded (quantitative) All/non (qualitative)
Degree of response (variable) of the drug is % of patients who respond (responders) to specific effect
plotted against log doses of the drug is plotted against log doses
EC50 The dose that produces 50% of Emax The dose that cures 50% of cases
LD50 Can not be calculated The dose that kills 50 % of animals
Therapeutic
Can not be calculated = LD50 divided by ED50
index
Efficacy: ‫هي أألهم في العالج‬
Potency:
• Is the maximal effect (response) induced by the drug
• Is the smaller dose that produces a specific response
• Measured by Emax
• Measured by EC50 & Slope of dose response curve
• Higher Emax of a drug → more effective drug
• Lower EC50 or higher slope → more potent drug
2
 Emax
Graded dose response curve
% of responders
% of response

• A, B, C, D have the same efficacy

• D, is the least potent
• A, has the highest potency
Log dose
All/Non dose response curve
Therapeutic index (TI);

‫نسبه الي حصل عندهم التأثير المطلوب‬

Lethal
effect
• Therapeutic index is: LD50 divided by ED50
• Give an idea about range of safety of the drugs. Larger TI → safer drug
• Drugs with low TI → Have ilow safety margin (not safe)
• Examples of drug with low Therapeutic index LD50
➢ Theophylline (Bronchial asthma ‫)يستخدم في الربو الشعبي‬ Dose
ED50
➢ Lithium (antidepressant ‫)يستخدم في االكتئاب‬ LD50
➢ Digoxin ( ‫)يستخدم في هبوط القلب‬, Warfarin
Uses of calculation of LD50:
1. Give ideas about drug toxicity and safety margin (↓LD50 → ↑ toxicity).
2. Used to calculate human dose (< 10% of LD50) ‫يستخدم لتحديد الجرعه في التجارب االوليه علي الدواء‬
3
 Mechanism (mode) of actions of drugs
1. Receptor mediated 2. Non receptor mediated: e.g. enzyme, channels,…….
1- Receptor meditated mechanisms:
Ligand (drug) bind with the receptors → ❶❷❸❹
Type of ligand Affinity Efficacy Pharmacological action Examples
❶ Full agonist ✓ ✓ Has an action Ach on Nm receptors → muscle contraction
Agonist in absence & antagonist Buprenorphine on opioid receptors.
• Acts as analgesic ‫( مسكن لاللم‬agonist) in absence of
❷ Partial agonist in presence of full agonist
(agonist/antagonist)
✓ Less
‫من االخر عمله يعتمد علي وجود او عدم وجود‬
morphine ‫ذي المورفين مسكن في عدم وجود المورفين‬
Pure agonist • Antagonizes analgesic effect of morphine in its
presence ‫عكس تأثير المورفين في وجود المورفين‬
❸ Inverse agonist ✓ ✓ Opposite to full agonist Antihistamines ‫ادويه ضدد الحساسيه‬
Has an pharmacological action Curare prevent action of Ach on Nm receptors →
❹ Antagonist ✓ X (by preventing action of agonist) Muscle relaxation
Dose of the drug
4
 Types of antagonisms:
Type of antagonist Characteristics Examples
• Negative charge on heparin (Acidic) neutralized
non-receptor antagonism

Chemical Interact chemically away from the receptors by +ve charge of protamine (Basic)
• Protamine is (antidote) ‫ ترياق‬for heparin
• Epinephrine (EP) → (Bronchodilation &
Vasoconstriction) antagonizes Histamine effect
Physiological One drug antagonizes the effect of another by acting
(Bronchospasm & Vasodilation).
(functional) on a different receptor producing opposite effect.
• EP is life saving in treatment of anaphylactic
shock. WHY ? (Rapid onset) ‫مهم‬
Pharmacological: Act on the same receptor (affinity no efficacy)
• Competitive • On the same recognition site (reversible) • Curare & Ach on Nm receptor
• Non-competitive • Other site → Ө binding of agonist (Irreversible) • Phenoxybenzamine (α blocker) &
Norepinephrine (NE) on α receptors
Receptor recycling (Turnover):
• Receptors are protein formed intracellular → inserted to cell membrane (Externalization)
• Old receptors are taken inside and degraded (Internalization)
• Rate of externalization & internalization = Rate of turnover ‫معدل التكوين والتكسير‬ ‫الجسم ييغلس علي تاثير الدواء‬
• Up regulation: ↑ number of receptors (due to continuous use of antagonist) ‫وممكن يضعف تأثيره‬
• Down regulation: ↓number of receptors ( due to continuous use of agonist)
5
 • Comparison between competitive and non- competitive antagonists ‫مهم‬
Difference Competitive antagonist Non competitive antagonist
competes (reversible) with the agonist for the binds (Irreversible) to the recognition or
Binding of antagonist same recognition site of the receptor to an allosteric site of the receptor
Duration of antagonism Relative plasma concentration (CP) of
agonist/antagonist ‫االكتر يكسب‬ Rate of receptor turnover
depend on
Shift of Dose response
Parallel shift to right Non parallel (Down) shift
curve
Emax No change → no change in efficacy Decreased → ↓efficacy
EC50 Increased → ↓ potency No change
Curare & Ach on Nm receptors
Examples Isoprenaline & propranolol on β receptors
Phenoxybenzamine & NE on α receptor
Emax
•
‫التتغير‬ Agonist
Agonist
Dose response curve Agonist + antagonist
↓ Emax
Agonist + larger dose

Response
of antagonist Agonist + antagonist

Response
Agonist + larger dose
of antagonist
Dose
Dose
Dawn shift
Parallel shift EC50 No change in EC50
No change in Emax ‫التتغير‬
Competitive antagonist Non competitive antagonist
6
 Signaling mechanisms’
The most important signal transduction includes:
Type of receptor Characteristics Examples
Receptors are ion selective channels in • N receptors (Na+/K+ channels)
plasma membrane • GABA receptors (CL- channels)
❶ Ion channels
(fast transmission) Nm GABA receptors
Na + or Cl -
❷ G protein linked receptors Ligand binds to G-protein → regulate the Gs: β receptors → ↑cAMP
activity of several effectors e.g. AC & PLC Gi: α2 & M2 → ↓ cAMP
(Slow transmission)
enzymes or channels → action Gq: α1 , M1 & M3 → DAG , IP3
8 ‫إنظر صفحه‬
• Extracellular part binds with drug
❸ Receptors linked to tyrosine kinase • Intracellular part (effector) is an enzyme Insulin receptors
TK → autophosphorylation → action TK
Enter target cells & bind with intracellular • Steroid hormones (cortisone, Androgen..),
❹ Receptors regulating transcription
nuclear receptor → affect transcription and • Estrogen, Progesterone, Thyroid hormone,
(very slow transmission) change protein production → action • Vitamin D (SEPT -D)
• Nitro vasodilators (Nitrates ‫الدوا الي بيتاخد‬
‫( تحت السان في الذبحه‬
Intracellular receptors bind with GC (guanyl
❺ Nitric oxide (NO) receptors • M3 vascular receptors agonist →
cyclase) → ↑ cGMP → action
Vasodilation (VD)
‫إختصارات‬
AC = Adenyl cyclase IP3 = Inositol Triphosphate DAG = diethyl glycerol VC = Vasoconstriction VD = vasodilation BS= Bronchospasm
BD = Bronchodilation cGMP = cyclic guanyl monophosphate PDE= phosphodiesterase enzyme PLC= Phospholipase C BV = Blood vessels
7
❷ G protein linked receptors (SLOW transmission) ‫ هايفهمك حاجات كتير وهايتشرح بالتفصيل الحقا‬....‫ده أشهر نوع موجود في الجسم‬
• Ligand binds with the receptor → activation of G-protein →Stimulation (Gs) OR inhibition (Gi) of the effector (A.C. or PLC) →
Intracellular changes → pharmacological action
• G protein is trimer used as an AMPLIFICATION of signals
• Receptors ‫مين هو‬
K+
β1 α2 α1
MCLK
• G-protein β2 M2 ⊕ M1
D1 D2 Gq M3
Gs Gi
⊕ ⊖
• Effector A.C.
PLC
• 2nd Messenger cAMP ATP PIP2 In endothelium of BV →
↓ Release NO → ↑ cGMP → ↓Ca ++
PK-A IP3 DAG →Vasodilation ( VD)
↓ ↓ ↓
Phosphorylation PK-C
Release of Ca++
↓ ↓
ACTION
From SR. Phosphorylation
↓ K+
↓ Hyper.
ACTION ACTION ⊖
‫تجميعه‬
EXAMPLES: ..‫حاول تفهم‬
• β1 in the heart → ↑ cAMP → phosphorylation of Ca++ channels → ↑
intracellular Ca++ → myocardial contraction. X
• α1 in smooth muscles including Blood vessels → release of Ca++ from
sarcoplasmic reticulum (SR) → contraction including vasoconstriction → ↑ BP. CL- ⊕ Na+
• β2 in the smooth muscles of bronchi → ↑ cAMP → phosphorylation of MLCK Hyper. Dep.
→ relaxation -→ bronchodilation Dep.
8
 2-Non- receptor mediated mechanisms:
1 Drugs acting on enzymes
• Aspirin • Ө COX enzyme → ↓Pgs • As Analgesic, Antipyretic & anti-inflam.
• Neostigmine • Ө CHE → ↑Ach • Myasthenia gravis ‫مرض وهن العضالت‬
• Captopril • Ө ACE → ↓Ang II • Hypertension, …
2 Plasmatic membrane
• Ө Na/K ATPase pump. • Heart failure
• Digoxin
• Ө Na+ Channels → ↓propagation of impulse. • Local anesthesia ( --- caine)
• Local anesthetics
3 Subcellular structures
• Colchicine • Ө microtubules → Ө mitosis • Gout
4 Genetic apparatus
• Antibiotics • 30S: e.g. tetracycline, 50 S: chloramphenicol
• Anticancer • Affect DNA synthesis or function
5 Physical reaction
• Paraffin oil • Lubricant • Constipation
• Charcoal • Adsorbent to gases in the intestine • Anti-flatulent ‫عالج غازات البطن‬
• Bismuth salts • Demulcent (soothing) effect on the intestine • Peptic ulcer
• Mannitol • Osmosis • Diuretic
6 Chemical reaction
• Antacids • Neutralize HCL • Hyperacidity
• Protamine • Neutralizes heparin by +ve charge • Heparin toxicity
Chelation
• Organic drugs Chelate Heavy metals → non-absorbable easily excreted chelates (H2O Soluble)
• Used in treatment of heavy metals toxicity.
• Examples
1. Desferrioxamine: Iron Toxicity 2. EDTA: Lead & calcium toxicity
3. Penicillamine: Copper in Wilson disease 4. Dimercaprol: Arsenic & gold toxicity
9
1. The following may be used to asses drug efficacy in graded dose- 5. Regarding the receptors, the incorrect
response curve: statement is ..
a. Slope of the curve b. ED50 c. Emax d. a &d a. β receptors are receptors for slow
2. Which of the following is/are correctly matched to signaling mechanism? transmission
a. Receptor linked to tyrosine Kinase/ corticosteroids b. Corticosteroids act via intracellular receptor
b. Increased cAMP / β2 agonists in bronchial asthma
for rapid transmission
c. Decreased cGMP / nitrates in angina pectoris.
c. M3 receptors in non - vascular smooth
d. a and b
muscles act by increase calcium release
3.The fastest neurotransmitters activate the following type of receptors:
a. Receptors linked to tyrosine kinase d. β receptors increase cAMP.
b. G protein linked receptors 6. Regarding competitive antagonist, which
c. Ion channels statement is correct?
d. Receptor regulating transcription a. Causes non parallel shift in dose response
4. Drug X & Y are oral hypoglycemic drugs. Drug X at a dose of curve
50 mg reduces blood glucose level by 50 mg/dl. Drug Y at a b. It ↓ maximum effect induced by agonist.
dose of 5 mg reduces the blood glucose level by 50 mg/dl. c. t ↓ affinity of the agonist to the receptor
Therefore: d. High dose of the agonist cannot overcome it
a. Drug x is less efficacious than drug Y effect
b. Drug X is less potent than drug Y e. It does not cause changes in ED50
c. Toxicity of drug Y is less than that of drug X
d. Drug Y will have shorter duration of action than drug X
1= 2= 3= 4= 5= 6=
10
 Factors affecting dose response relationship:
1. Age: Q. How to calculate pediatric dose ‫جرعه االطفال‬
Child dose (Cd) =
Surface area Cd = Adult dose X surface area of child/Surface area of adult (1.73)
weight Cd= Adult dose X Weight of child in Kg/weight of adult (70 Kg)
2. Pathological conditions: certain diseases → ↑ sensitivity of patients to certain drugs:
• Bronchial asthma: Beta blockers → acute attack of asthma ‫بيتلكك‬
3. Psychological factors: some patients respond easily to Placebo ‫الدواء الوهمى‬
• Uses of placebo: Psychotherapy and drug evaluation
4. Sex:
• Teratogenic drugs affect pregnant female. E.g. Phenytoin ‫دواء لعالج الصرع‬
• Drugs secreted in milk → affect neonates after labor. E.g. tetracycline ‫مضاد حيوي‬
5. Drug interactions: SEE drug interactions
11
6. Tolerance ‫مهم جدا‬
Definition: decrease the effect of the drug due to its Chronic use. ↑ doses are needed to produce the same effect.
Mechanisms of tolerance:
I. Pharmacokinetics Tolerance: Change drug level (↑ plasma concentration)g at the site of action
Enzyme inducers: Phenobarbitone ↑ its own metabolism →↓ its effect. Enzyme inducer
‫غب بعيد عنك‬
‫دواء ي‬
‫تكسي نفسه‬
‫ر‬ ‫رز‬
‫بيود‬ Metabolized
by
II. Pharmacodynamic tolerance: dNo change in drug level (plasma concentration) at site of action
Mechanism Example
↓ sensitivity of the receptors ▪ Opiates ( morphine)
↓ Number of receptors = down regulation ▪ Β2 agonists
↑ Number of receptors = Upregulation ▪ H2 antagonists
↑ release of neurotransmitter (e.g. Ach) ‫الرسمة‬ ▪ Ipratropium: M antagonist ‫دواء غب‬
↓ release of neurotransmitter e.g. Dopamine ▪ Amantadine (Parkinsonism)
Counter regulatory mechanisms (↓ BP by VD → ↑ volume of blood) ▪ Salt & H2O retention with vasodilators
Tachyphylaxis: CROSS Tolerance
• Acute tolerance Adverse drug reactions: Tolerance to drugs related
• Rapid ↓ in drug response. ↑ dose do not induce the same effect pharmacologically but not chemically:
e.g. Depletion of NE stores from few doses of ephedrine ‫التعود علي االدويه الي شبه بعض‬
(sympathomimetic: act by ↑ release of stored NE) e.g. - Cross tolerance between
‫ الجرعه الثانيه ال تؤثر خالص‬,‫نتيجه نفاذ المخزن من اول جرعه‬ members of opioids.
12
 Adverse drug reactions
• Is the harmful (unwanted) effect of the drug.
• May be predictable (dose dependent) or unpredictable (dose independent)
Type A: Augmented (dose dependent & predictable)
Intolerance At dose < therapeutic Tinnitus ‫ طنين‬/Aspirin
Side effect At dose = therapeutic 1ry pharmacological action: dry mouth & sedation with antihistamines
2ry pharmacological action: Oral thrush with antibacterial drugs
Over dose At dose > therapeutic Seizures ‫ تشنجات‬/ lidocaine
Toxicity At dose >>> therapeutic Hepatic toxicity/ acetaminophen (paracetamol)
Type B: Bizarre (dose independent & unpredictable)
Immune based (acquired). Due to prior Penicillin/ Anaphylactic shock.
Hypersensitivity (allergy)
contact with antigenic drug ‫من تاني مره‬ see later
Idiosyncrasy (Pharmacogenetic) Genetic based ‫من أول مره‬ Favism,…… see later
Type C: Continuous: After chronic use of the drug
Corticosteroids Hypertension, DM,…
NSAIDs ‫المسكنات‬ Analgesic nephropathy
13
Type D: Delayed
• Mutagenic: Metronidazole
• Carcinogenic: Radioactive isotopes
• Teratogenic: → congenital abnormalities due to taking drugs during pregnancy
①Thalidomide Phocomelia
② Phenytoin Cleft palate
③Tetracyclines Teeth coloration & dental hypoplasia
Type E: Ending of use: Due to sudden withdrawal of the drug ① ② ③
Drug Effect Cause
Beta blockers ➔ Precipitate Angina or infarction Upregulation of β receptors → sudden ↑in O2 Demands
Corticosteroids ➔ Addison crisis ↑ -ve feed back → ↓ACTH
Morphine ➔ Withdrawal (abstinence) syndrome
Clonidine ➔ Clonidine rebound Sudden release of stored NE ‫الرسمه‬
Other adverse effects:
• Drug abuse: Non-therapeutic uses of the drugs
• Iatrogenic DISAESE: Drug or doctor induced disease ‫تعرف مثال مشهور‬
Beta blockers → block β2 of bronchioles → Bronchial asthma.
NSAIDs → decrease Prostaglandins → Peptic ulcer
14
 Pharmacogenetic Disorders:
Definition: Abnormal response of the drug due to an abnormal gene ‫طلع العفريت من الؤمؤم‬
Defect in gene → Abnormal response Drug responsible
Favism G6PD deficiency Hemolytic anemia oxidant drugs (Aspirin, Sulfa, antimalarial)
Succinyl choline Apnea (paralysis of
Pseudo ChE. enzyme deficiency Succinyle choline
apnea respiratory muscle)
Malignant Failure of Ca++ sequestration in
Fever with muscle rigidity Succinyle choline
hyperthermia skeletal muscles
Acetylation Neuropathy Isoniazid (in T.B)
Slow acetylators
polymorphism Systemic lupus Procainamide
Porphyria Disorders in porphyrin metabolism Attack of porphyria ↑ ALA synthetase e.g. Barbiturates
Drug Allergy:
Drugs act as antigen→ stimulates immune response. (during 2nd exposure).
Dose independent (Unpredictable)
Occurs after second exposure (Prior exposure to antigen) ‫الزم تكون اتعرض قبل كده لالنتجن‬
Diagnosis:
o History & type of reaction
o Intradermal & conjunctival tests.
Type I: Immediate anaphylaxis.
Examples: Anaphylactic shock with Penicillin
Treatment: Epinephrine (life saving ‫)ينقذ حياه المريض علشان سريع‬, Cortisone & Antihistamines.
Cross allergy: Allergy occurs within a group of chemically related drugs
15