Dental oriented selected pharmacological topics

Aimun AE. Ahmed, B. Pharm., M. Pharm., Ph.D.

Pharmacology Dept., Pharmacy-OIU

E-mail: aimun725@hotmail.com

1
Introduction
 Course contents
 Drugs used in Hypertension (CVS)
 Drugs affecting haemostasis (Blood)
 Local and general anaesthetics (CNS)
 Analgesics (pain killers)
 Anti-diabetic drugs (Endocrine)
 Antibacterial and antifungal drugs (chemotherapy)
 Disinfectants and antiseptic agents.
 Antiasthmatic drugs (respiratory)
 References
 Basic & clinical pharmacology, Clinical Pharmacy& Therapeutics,
Rang & Dale, and Medical Pharmacology at a Glance.
 

2
1-Drugs used in Hypertension
 Hypertension (HBP)
 Is a condition in which a consistent elevation of
arterial blood pressure above normal value.
 AHA: Is arterial blood pressure higher than 140/90
mm Hg (WHO: value 160/95)
 The normal values vary depending on gender, age
and race.
 HT is not a disease, but risk factor for CV
complications.
 Why we treat HT? …………..

3
•MI, Stroke, malignant HT, peripheral vascular diseases, RF.

4
Epidemiology
 Hypertension is the most common cardiovascular
disease.
 CVS disorders are categorized as 1st cause of death in
the world.
 Silent killer (serious complications without symptoms)
(Headache)…. Periodical check is required.
 HT has serious social impact on Life Expectancy and
Quality of Life.
 HT is continuously distributed in population.

5
 HT is continuously distributed in population.
 There is no clear cut-off point between hypertensive
and normotensive subjects.
 Nearly 25% of adults have hypertension.
 The prevalence of hypertension increases with
advancing age; about 50% of people between the
ages of 60 and 69 years old have hypertension, and
the prevalence is further increased beyond age 70.
 10-25% of population is of HT ttt Benefits.

6
Aetiology
 HT either 1o (essential or idiopathic) unknown or 2o
(5-10%) due to diseases or drugs.
 Malignant HT is uncommon condition and is medical
emergency, sudden increase in diastolic pressure
……… damage.
 HT risk factors include: life style, Cigarette smoking,
Hyperlipidemia, Diabetes, Obesity, Manifestations of
end organ damage at the time of diagnosis, Family
history of CV disease.

7
Pathophysiology
 Arterial blood pressure (BP) is directly
proportionate to the blood flow (cardiac
output) and the peripheral vascular
resistance:
 BP = CO x PVR

 Baroreflexes act in combination with humoral

mechanisms, including the RAAS to
coordinate function sites to maintain normal
blood pressure.
8
 Local vascular endothelium hormones also
involved in the regulation of vascular
resistance (NO + endothelin – 1)
 Carotid baroreceptors are stimulated by
internal pressure and inhibits central
sympathetic discharge.
 All antihypertensive drugs act by interfering
with these normal mechanisms.

9
10
11
12
Management of HBP
 1-Non-pharmacological approaches
 Very important measures, with disappointing effects.
 Includes: weight loss, salts intake reduction, calories
and saturated fat intake control, exercise (regular
3X/week), stop alcohol intake and cigarette smoking.
 It is important also to continue parallel with drugs.
 2-Pharmacologic aspects (Antihypertensive agents)
 Antihypertensive drugs can be classified according to
their sites or mechanisms of action.

13
•Identifying the genetic variation is important to improve
selection of antihypertensive drugs in individual patients
(polymorphism)
•Generally 4 drugs categories are implemented in HT
control
14
 Antihypertensive drugs

Diuretics Sympatholytics Vasodilators ACE inhibitors

CNS Ganglia Old Ca+2-blockers

Nerve terminals Receptors Parenteral

15
1.Diuretics
 Are renal system drugs, here is one of their
applications
 They lower BP by reducing the Blood volume and
direct unknown vascular effects.
 Act by altering Na/water balance.
 Thiazides (hydrochlorothiazide) are used alone for
moderate HT or in combination in severe HT.
 Loop diuretics (furosemide) have greater potency
and onset of action control Na level.

16
 K-sparing diuretics (spironolactone) cause
hyperkalemia.
 Are the major antihypertensive drugs for decays.
 diuretics alone often provide adequate treatment for
mild or moderate essential hypertension.
 Still best therapy choice for African-American and
elderly patients.
 Best agent for stroke prevention.
 They reduce clotting and osteoporosis in elderly.

17
2.Sympatholytics
 β and α1 blockers were used extensively rather
than others.
 They interfere with sympathetic functions in
several ways.
 1. Centrally acting: α2-selective agonist
(Clonidine and methyldopa)
 Act by unknown mechanism on medulla
oblongata at cardiac centre and decrease
sympathetic outflow.
18
19
 Methyldopa is pro-drug converted to α-methyl NE in
the brain.
 Methyldopa causes hematologic toxicity.
 MD reduces vascular resistance without causing
much change in cardiac output or heart rate.
 Sudden cessation of clonidine causes rebound HT.
 Both cause sedation
 2. Ganglionic blockers: Trimethophan,
Hexamethonium are nictonic antagonists.

20
 Due to its side effects it was restricted for emergencies only
 Cause orthostatic hypotension and PS blockade.
 Has short duration of action, given by continuous IV infusion.
 3. Nerve terminal blockers: reserpine, guanethidine, MAOIs
 They interfere with biochemical process of NE at synapse.
 4. Adrenoceptors blockers: prazosin (α1) and propranolol (β).
 Referring to ANS Pharmacology!!
 Only characteristics relevant to their use in hypertension are
described here.

21
 β-blockers regulate BP by different mechanisms:
 1-heart rate and contractility (CO),
 2- juxtaglomluar complex (RAAS),
 3- Alteration of the control of the sympathetic
nervous system at CNS level.
 4- Altered baroreceptor sensitivity.
 5- Altered peripheral adrenergic neuron function.
 6- Increased prostacyclin biosynthesis.

22
 They provide therapy for all grades of hypertension.
 Are highly preferred drugs for hypertensive patients
with other CVs
 Sudden cessation will produce withdrawal syndrome
due to receptor up-regulation.
 Enhanced tissue sensitivity to endogenous
catecholamines (rebound hypertension)

23
 α1-blockers reduce arteriolar resistance and
increase venous capacitance; this causes a
sympathetically mediated reflex increase in heart rate
and plasma renin activity.
 Suitable for hypertensive patients with benign
prostatic hyperplasia
 Used in combination and CI in Phenochromocytoma.
 Cause postural hypotension.
 Monotherapy increased the risk for developing CHF.

24
 A major precaution is the so-called first-dose
phenomenon.
 Combined α1 and β Adrenergic blockers
Pindolol, Carvedilol
 treatment of hypertensive emergencies (rapid
onset)
 Used for hypertension and symptomatic heart
failure.

25
3.Vasodilators
 Dilute vessels by direct action on smooth muscle
cells.
 Old: such as Hydralzine, is 1st orally active agent.
 Combined with sympatholytic agents and diuretics
with greater therapeutic success.
 Not used alone (Tachycardia & tachyphylaxis)
 Causes direct relaxation of arteriolar smooth muscle.
 Does not dilate epicardial coronary arteries or relax
venous smooth muscle.

26
 Stimulate baroreflex activity.
 Lowers blood pressure equally in the
supine and upright positions.
 Used for severe hypertension, evidence-
based therapy in patients with CHF, and
in the treatment of hypertensive
emergencies in pregnant women.

27
 KATP-channel opener: Minoxidil
 Proven as efficacious in patients with the most
severe and drug-resistant forms of hypertension.
 Not active in vitro (active metabolite)
 opening K+ channels in smooth muscle and thereby
permitting K+ efflux, it causes hyperpolarization and
relaxation of smooth muscle
 Increases blood flow to skin, skeletal muscle, the
GIT, and the heart more than to the CNS.

28
 Associated with a reflex increase in
myocardial contractility & CO.
 is a very potent stimulator of renin
secretion with complex renal effect.
 Have severe side effects: fluid and salt
retention, cardiovascular effects, and
hypertrichosis.

29
 Others: Na nitoprusside: is a
nitrovasodilator that acts by releasing
nitric oxide thus dilates both arterioles
and venules.
 Is a nonselective vasodilator.
 Used primarily to treat hypertensive
emergencies.

30
 Ca+2-channel blockers: verapamil, diltiazem, amlodipine,
felodipine, isradipine and nifedipine.
 Are an important group of drugs for the treatment of
hypertension.
 Intracellular calcium flux is a final common path for a spectrum
of cellular responses to a wide variety of stimuli.
 contraction of vascular smooth muscle is dependent on the free
intracellular concentration of Ca2+, inhibition of transmembrane
movement of Ca2+ through voltage-sensitive Ca2+ channels can
decrease the total amount of Ca2+ that reaches intracellular
sites.

31
 lower blood pressure by relaxing arteriolar
smooth muscle and decreasing PVR
 baroreflex stimulation.
 All Ca2+ channel blockers are effective when
used alone for the treatment of mild to
moderate hypertension.
 Develop headache, flushing, dizziness, and
peripheral edema.
 D-D: Digoxin and quinidine.

32
4.ACE inhibitors
 Represents an important advance in the
treatment of hypertension
 Captopril was the first such agent to be
developed for the treatment of
hypertension.
 Enalapril, lisinopril, quinapril, ramipril,
benazepril, moexipril, fosinopril,
trandolapril, and perindopril.
33
34
 Enhances patient adherence due to efficacy
and their very favorable profile of adverse
effects.
 Preferred as initial agent in diabetic
glomerulopathy patients and chronic renal
disease, such as glomerulosclerosis.
 Reduce morbidity and mortality of immediate
post-myocardial infarction period and patients
with hypertension and ischemic heart disease.
35
 ACE inhibitors tend to enhance the efficacy of
diuretic drugs.
 Hyperkalemia considered when ACE inhibitors
are used with other drugs that can cause K+
retention, including the K+-sparing diuretics,
NSAIDs, K+ supplements, and b receptor
blockers.
 Some patients with diabetic nephropathy may
be at greater risk of hyperkalemia.
36
 Angioedema is a rare but serious and potentially
fatal.
 Cough.
 Contraindicated during pregnancy.
 Response to the initial dose is a function of
plasma renin activity prior to treatment.
 Elderly African-American patients as a group are
more resistant to the hypotensive effect of
these drugs.

37
 AT1-angiotensin II receptor: Losartan,
candesartan, irbesartan, valsartan, telmisartan, and
eprosartan.
 nonpeptide antagonists of clinical use.
 The AT1 angiotensin II-receptor subtype is located
predominantly in vascular and myocardial tissue,
brain, kidney, and adrenal glomerulosa cells, which
secrete aldosterone.
 AT1 receptor mediates feedback inhibition of renin
release.

38
 Relax smooth muscle (vasodilation), increase
renal salt and water excretion, reduce plasma
volume, and decrease cellular hypertrophy.
 Prevent ACE-mediated degradation of
bradykinin and substance P.
 Needs 4 weeks after the initiation of therapy to
work.
 Less effective in African-American and low-
renin patients.
39
 cause hypotension, hyperkalemia, and
reduced renal function.
 Cough, an adverse effect of ACE
inhibitors, is less frequent and
Angioedema occurs very rarely.
 Should not be administered during
pregnancy.

40
 2- Drugs affecting haemostasis (The Blood)
(Drugs used to affect blood coagulation)

 Haemostsis and Thrombosis

 Epidemiology
 Thromboembolic diseases are common as well as
serious .
 It categorized with other CV diseases as the first
cause of death in the world.
 Etiology
 Thrombosis is a pathological condition resulting from
inappropriate activation of haemostatic mechanisms.

41
Pathophysiology
 Haemostasis: It is the arrest of blood loss
from damaged vessels.
 It is essential life process.
 It is activation results thrombus formation and
it is impairment lead to spontaneous bleeding.
 Thrombosis: Is pathological condition in
which the unwanted formation of haemostatic
blood took place.

42
 It occurs in three steps :
 A.Contraction of the vessels ↓Blood loss
 B.Adherence of platelets to vessel’s wall
 C.Formation of Fibrin (Coagulation process )
 Thrombosis takes place in vivo while blood clotting in
vitro.
 Blood clotting consist of Fibrin mesh, while
thrombosis composed of head (White Fibrin) and tail
(red-grey cellular elements + Rbcs).

43
 There are two types of Thrombosis :
 1- Arterial: In artery,↓blood flow (Ischemia or
infraction )
 2- Venous: In deep ones, Tail only…… DVT
 This deference in composition is essential in drug
selection (e.g. Veins …Fibrin….antifebrin drugs,
Artery….platelets ….Anti platelets)
 If it break away Embolism; Brain (Stroke),
Heart (infraction) and lung (Embolism).

44
 Drugs act by three mechanisms:
 1- Modify Fibrin formation Anti-Coagulants
 2- Modify platelets adhesion Anti-platelets
 3- Fibrinolysis or Fibrin removal.

45
Fibrin formation (coagulation process)
 It is conversion of the blood into a solid form.
 The main event is conversion of Fibrinogen Soluble
strands.
 It involves clotting factor Zymogens (inactive prolytic enzyme).
 There are two pathways for this process:
 1-Interintic: All components are found in the blood.
 Initiated by surface contact.
 Epithelia Collagen Kinin Activate F12
F12 F11 F9 F8 +Ca+2 F10 F2 F1
+Ca+2+13 Insoluble strands
 PF3

46
47
 2- Extrinsic: Some of the components comes from
out of the blood.
 Activated by tissue damage Tissue factor
 TF +Ca+2+PF F10 F2 F1 +Ca+2+13
Fibrin strands.
 Drugs used in two cases:
 1- Defect in coagulation
 2- Unwanted coagulation

48
 1-Coagulation defect
 May be genetically (Hemophilia ) due to deficiency in F12
(Hepatitis, AIDS)
 -In above case F8 manufactured by gene selection and cultured
in E.coli, where pure uncontaminated F8 was obtained by
nucleus damage.
 This defect is due to:
 1- Low Vit. K intake.
 2- Extensive use of Anticoagulants
 3- Liver diseases
 All three defects were treated by Vit.K1 (phytomendione) from
plants or Vit.K2 by normal flora.

49
Pharmacological Aspects
 1-Vitamin K1 & K2
 Are lipid soluble vitamins

50
 Mechanism of action
 Act as co-factor for carboxylase enzyme responsible for glutamic
acid of clotting residue, required O2 & CO2.
 Vit.K activate (1973) finished carboxylation Vit.K
epoxide Reductase Vit.K Reduction Vit.Khydroquinone
(Active form of co-factor ).
 Administration & Pharmacokinetic
 Lipid soluble vitamins requires bile salts.
 Administered I.V, I.M and orally.
 Not store in the body.

51
 Therapeutic Uses
 Treatment of haemorhage due to Anticoagulants
 Treatment of hypothrombineamia in born
 Mal absorption of Vit.K which due to steaorrhea
(Fatty diarrhea ) or sprue (chronic mal
absorption) that occur by:
 1. Lack of bile salts (Jaundice)
 2. Billary Fischula

52
2-Unwanted Coagulation
 In case of thrombembolic diseases
which associated with Atherosclerosis ,
two classes of anti-coagulants were
used:
 1. Oral: Warfarin
 2. Injectables: Heparin + Acord

53
 1-Warfarin
 Is the most important oral anti-coagulant
 Is natural plant product (Coumarin)
 Mechanism of action
 It acts by inhibition of reductase enzyme of
Vit.K ,so it block decarboxylation and
activation of blood factors (1973)
 It has slow onset of action that depend on
blood carboxylation factors.

54
Administration & Pharmacokinetic
 It absorbed rapidly from GIT.
 Highly bounded to plasma proteins 97%.
 Takes few minutes to reach PPC, with no relation
between Cp and response unlike Digoxin.
 It is effect was measured by Prothrombin time (time
required for oxalated blood to coagulate after addition
of thromboplastin and Ca+2).
 Metabolized by hydroxylation & conjugation.
 Basal metabolic rate was genetically determined.
 Excreted in bile and Hepatocytes.

55
Clinical uses
 Used for prolonged therapy.
 Used for prevention of:
 Deep vein thrombosis (DVT)

 Recurrence of pulmonary embolus.

 Thrombosis and embolism in patient with atrial

fibrillation.
 Thrombosis on prosthetic heart valve.

 Clotting in Extracorporeal circulation (heamodialysis

and bypass surgery).

 Cardiac events in patient with unstable coronary

syndrome (unstable angina).

56
 Unwanted effects
 Bowel hemorrhage treated by 1) dose cessation 2)
Vit.K
 Cause fetus hemorrhagic disorders when given to his mother.
 Interactions: (Drug and diseases interaction):
 There are two interactions; Pharmacokinetic and
Pharmacodynamic interaction.
 Pharmacokinetic inter action include ;enzyme inducers ,Enzyme
inhibition and decrease plasma proteins binding
 Pharmacodynamic inter action either synergistic or Antagonistic
effects.

57
1- Factors enhance warfarin effects includes:
 Certain pathological conditions such as (liver, thyrotoxicosis and
fever) enhanced clotting factors degradation, thus enhanced its
effect.
 Decrease Vit.K uptake & the used of broad spectrum antibiotic
 Certain drugs:
 1- Aspirin: decrease cycloxgenase enzyme ……. prevent clotting.
 - Decrease contribution of platelets in clotting process
 - Concomitant administration ….. severe bleeding.
 2- Phenylbutazone, Chloral hydrate and Ethacyric acid: displace it
from proteins binding sites.
 3-Enzymes inhibitors such as Cimitedine, Choloramphenicol,
Metronidazole, imipramine and Disulfuram …. ↓Met. Rate

58
2- Factors lessen warfarin effects includes
 Drugs that increase clotting factors during
pregnancy, Anemia and Nephritic disorders.
 Enzyme inducers such as Phenobarbitone.

 Oral contraceptives which cause:

 1- Increase clotting factors level.

 2- Decrease Level of Antithrombin III

 3- Lipoprotinkinase release.

59
Dosage
 Small initial dose of 5-10 mg should be used
daily for week
 Maintenance dose of 5-7mg was used after

one week and investigation of prothrombin

time.
 The term International normalized ratio (INR)

is used for therapeutic range (test/control).

60
 2-Heparin & LMWH
 It is injectable anti-coagulant drug.
 sulphate muco polysaccharide

 Contains two amino acids; Glycine and Serine.

 Found in the mast cell, plasma, Endothelial

blood vessels.
 Obtained from beef lung & intestinal mucosa

of dogs, so it need bio assay and

standardization.

61
 Mechanism of action
 Act as co-factor of anti thrombin III when bind to
thrombin and causing conformational change.
 This complex renders thrombin & other factors inactive.
 Prevent clotting & platelets aggregation & lipoprotinkinaes
release.
 Administration & Pharmacokinetic
 cannot given orally due to low molecular weight and low
absorption
 Is given I.M, I.V and S.C with onset of action of 40-90
minutes.
 Endothelium acts as a reservoir (slow heparine release).

62
 Unwanted effects:
 1- Hemorrhage (treated by cessation)
 2- Osteoprosis with bone fracture (prolonged use)
 3- Hyper sensitivity reactions (Antigenisity).
 4- Platelets reduction.
 Clinical uses
 Similar to Warfarin
 It defer from Warfarin in that it used for short – term action.

63
 2-Antipletelets Drugs
(Drugs used to inhibit Platelets aggregation)
 Platelets are v. important in Haemostsis, damage
tissue repair and inflammation process.
 It is deficiency lead to thrombocytopenic purpura
(bleeding under the skin), gut and brain.
 It implicated in thromboembolic diseases

64
 Normal endothelium produce some factors preventing
coagulation such as:
 1.Prostacycline (PC) that inhibit platelets aggregation .

 2. Heparin (co-factor of Antithrombin III)

 3. Plasmin or Fibrinolycine (digest fibrin)

 4. Thrombomedulin (Protein-C co-factor), remove Fibrin

 Antithrombin III react with thrombin to form inactive complex

with F 9, 10, 11 and 12.
 Protein C activated by Thrombin .. Tissue damage … Collagen
and finally Platelets adherence in presence of F8 and Von Wille
Brand disease or deficiency (inherited Haemolytic disorder)

65
 Platelets when adhere it:
 1- Change in shape from disc to sphere.
 2- Aggregate
 3-Release granules substances
 4- Release bioactive substances (5-HT, ADP, ATP, Fibrin, Heparin ..etc)
 It is aggregation involve thrompoxane A2 (TXA2), power ful aggregator
 Phospholipids PLA2 Arachidonic acid TXA2 / PC
 TXA2 released by Platelets ,aggregative compound ,vasoconstrictor
 PC released by Endothelium of blood vessels, Anti aggregative and
vasodilator.
 Formation of Atheromutus plague ….15 –hydroxyl peroxi Arachidonic acid
(fatty acid derivatives) ……. Inhibit PC synthesis ……. Platelets
aggregation.

66
 The balance between TXA2 and PC is v. essential in
thromboembolic diseases (ratio of TXA2/PC)
 Three categories of substances regulate the function of platelets.
 1- Agents generated outside and inter act with platelets
membrane receptors (Catecholamines, collagen, Thrombin and
PC)
 2- Agents generated within platelets and interact with platelets
membrane receptors (ADP, PGD2, PGE2 and serotonin).
 Agents generated within platelets and act within it (PG end
peroxides, TXA2, cAMP, cGMA and Ca+2).

67
1-Acetylsalicylic acid – ASA
(Aspirin)
 It is a chemical agent, salicylates.
 Mechanism of action:
 Inhibit Cyclooxgenase irreversibly by Acetylation reaction
 Inhibit synthesis of TXA2 and PC of both endothelium and platelets
 The main objective in treating thromboembolic diseases is to enhance
PC level and inhibit TXA2 Level.
 Aspirin in low dose (3.5 mg/kg/3day) inhibit COX of the platelets only.
 Endothelium cell can re-synthesize the enzyme, while platelets can’t
(absence of DNA and RNA) until new one is formed in 7-10 days.
 Higher doses inhibit COX in endothelium and not platelets.

68
 Administration & Pharmacokinetics
 Given orally
 Well absorbed from the stomach which may be affected by certain
diseases (Magrine).
 Aspirin metabolism pre systemically by esterase protect systemic
vasculature to Aspirin.
 Clinical uses:
 Indication:
 It has dose dependant effects.
 Unstable angina: to decrease risk of Myocardial infarction.
 Acute Myocardial infarction to decrease mortality rate.
 Transient Ischaemic attack to decrease stroke risk.
 Thromboembolic diseases to decrease platelets aggregation.

69
 contra-indications:
 Gastric and duodenal ulcer
 Hemorrhagic diathesis
 Hyper sensitivity to salicylates
 Asthma, G-6PD deficiency and pregnancy
 Inter action:
 Anti-coagulants: Effect potentiated
 Corticosteroids: Increase risk of GI hemorrhage.
 Frusemide, Spironolactone .. diminished.
 Unwanted effects:
 Over dose may cause Tinnitus, Dizziness.
 Hypersensitivity, Thrombenia.
 Dosage:
 Film coated: 100 mg , 300 mg
 Effervescent tabs: Aspirin C (400 mg + 240 Vit. C) for pain and colds

70
 2-Dipyridamole
 Is a phosphodiestrease inhibitor
 Posses additive effect with Aspirin
 Unlike Aspirin it caused no excess risk of bleeding
 Mechanism of action:
 It dilute the normal coronary artery (No anti anginal
effect)
 The actual mechanism is unknown with doubtful efficacy.
 Inhibit phosphodiestrease that catalyzed cAMP to cAMP,
thus potentiate Aspirin effect

71
 Administration & Pharmacokinetics:
 Clinical uses:
 Indication:
 decrease mortality rate in patient with transient cerebral Ischaemic
attack by decreasing stroke risk by about 15 % similar to Aspirin
 Used with Warfarin to prevent Thrombosis formation on Prosthetic heart
valves (Thromboprophylaxsis)
 Unwanted effects:
 Commonest one is headache
 Vomiting and nausea.
 Dosage:
 25 mg Twice daily.
 Others: Epoprostenol, Sulphinpyrazone.

72
 3- Process of Fibrin removal
(Thrombolysis)
 It initiated when blood clotting is turn on.
 It occurs by two pathways:
 1- F12 catalyzed production of plasminogen activator that
diffused to the surface of thrombus .. Plasmin (Fibrinolysis)
 2 - Activation of Protein C (anti coagulant & Fibrinolysis),
needs Thrombomedulin as co-factor.
 This process modify by:
 1- Increase Fibrinolysis ( Streptokinase & Urokinase)
 2- Decrease Fibrinolysis ( Tranexamic acid , E-
aminocaproic acid

73
 1- Streptokinase
 Protein obtained from β- Haemolytic strepto cocci
 Has enzymatic activity
 Mechanism of action:
 It bind to plasminogen causing conformational changes and
formation of complex (Active Plasmin)
 It has Antigenic effects (activate Antibodies) in previously
infected person
 It has some selectivity for clots because within thrombus the
conc. Of Plasmin inhibitors is low that neutralize circulating
Plasmin.
 Infused intravenously.

74
 Clinical uses:
 Indication:
 Myocardial infarction to lyse thrombi that block coronary
artery.
 Also it has additive effect with Aspirin in such case.
 Side effects:
 Nausea, vomiting, bleeding (restricted to the site of
injection)
 Allergic reaction
 Stroke may occasionally occur.

75
 2-Urokinase
 Obtained from culture of kidney fetus.
 It has enzymatic activity
 Mechanism of action:
 Act directly at plasminogen activator resulting Plasmin.
 Administration & Pharmacokinetic:
 Is given I.V for systemic effect and by catheter for local
effect
 Is given in loading dose (to overcome plasminogen
inhibitors that found in the plasma) followed by small
maintenance doses

76
 Clinical uses:
 Contra-indicated to internal bleeding, Surgery
Anticoagulants (Aspirin)
 Main side effect: bleeding treated by Epo. And
E-AcA

77
 3- Local and general anaesthetics (CNS)
A- General Anaesthetics

 Anaesthesia:
 (others: hypesthesia, hyperesthesia, paraesthesia or dysesthesia)
 Pain: unpleasant sensory due to tissue damage
associated with discomfort.
 It is a multifactorial process.
 All body tissues except the brain and liver contain
sensors for pain (nocisensors)
 Since nocisensors do not adapt, the pain can last for
days.
 Pain may be relief locally or generally.

78
79
80
81
 1- Stages of Anaesthesia:
 1. Analgesia: Pain less, with/without Amnesia.
 2. Excitement: Delirious, excited, but Amnesic,
irregular respiratory, vomiting, struggle and
finally, reestablishments of regular breathing.
 3. Surgical Anaesthesia: Suitable condition.
 4 planes for sign specification (Change in ocular
movement, eye reflex, Pupil size).

82
  - Plane 2 ……….. short operations.
 - plane 4 ……….. long Operations.

 4. Medullary depression: Sever

depression….. death
 Not always seen due to use of pre-
medication)
 Detected by EEG.

83
2- Aims of Anaesthesia:
 To depress CNS functions & to maintain other tissues
functions
 Maintain normal physiological stability with analgesia,
Amnesia, loss of consciousness, autonomic reflex
inhibition and muscle relaxant.
 GA: is a state of drug-induced reversible inhibition of
central nervous function, during which surgical
Procedures can be carried out in the absence of
consciousness, responsiveness to pain, defensive or
involuntary movements, and significant autonomic reflex
responses.

84
85
 Difficult to achieve by a single drug.
 Four steps process was used involves different drugs:
 1-Pre anaesthetic medications:
 Has two aims:
 To prevent vagal effects (secretion).
 Reduce Anxiety & relief Pain.
 BZDs, Muscarinic antagonists and Opioids were used.
 It may omit for minor operations.

86
 2- Induction of Anaesthesia:
 It most commonly achieved by I.V Anaesthetics ( Thio,
Methohextone)
 Short time 30 seconds only (V. rapid).
 3- Maintenance of Anaesthesia:
 Done by inhaled Anaesthetics
 Commonly combination is used ( NO2=more analgesic, while
Isoflurane is vice visa).
 4 - Post anaesthetic medications:
 Use of muscle relaxants.
 Also Anti-emetic I.V.
 Opioids during & after.

87
88
3-Pharmacological Aspects:
 GA: Relief pain with consciousness.
 Absence of sensation with reversible loss of
consciousness.
 Many drugs are used for animals, but only few can
be used for humans (Narrow therapeutic window).
 Historical GA: Ethanol, ether, chloroform, Nitrous
oxide, thiopentone and halothane ( STD).

89
 Ideal Anaesthetic Drug must possess:
 Induce it smoothly & rapidly.
 Permits rapid recovery.
 Posses wide margin of safety.
 Devoid of adverse effects.
 Question: Does a single drug capable to
be Ideal as above??

90
 There two types of G.A according to the route of
administration:
 Inhaled Anaesthetics.
 Intravenous Anaesthetics.
 Have rapid, smooth onset of action and clinically
desirable effect.

91
1-Inhaled Anaesthetics
 Their body conc. and Ph.Ks depend on their partial
pressure in lung & blood and brain tissue solubility.
 High PP … rapid induction.
 Site of action is the brain, exact mechanism unknown,
but related to lipid solubility and GABAa activation.
 Current evidence most intravenous GA act
predominantly through GABAa receptors and perhaps
through some interactions with other ligand-gated ion
channels.

92
A- Nitrous oxide (NO2)
 Simple chemical structure.
 Gas with distinguish odour.
 Neither flammable nor explosive.
 Rapid, strong ….. can be used alone.
 Rapid recovery & sooth (1 – 4 min).
 Widely used in conc. up to 70%/Oxygen as carrier
gas (Hypoxia prevention).
 Has no muscle relaxant activity.

93
 Mechanism of action:
 Depress spontaneous & evoked activity of
neurons in many regions of the brain.
 Non-specific interactions with lipid matrix of
nerve membrane … ( Meyer-Overton principle)(
close relationship of anaesthetic potency and
lipid solubility).
 N.T, GABA.

94
 Administration & Pharmacokinetic:
 Many factors influence GA transfer rate
from Lung to blood & CNS and recovery
rate.
 Solubility, conc. in the Inspired,

Pulmonary Ventilation & Pulmonary

blood flow.

95
 Organ systems effects:
 CVS: Decrease arterial pressure.
 Change HR directly or indirectly …… Bradycardia.
 Resp: No effect, but others decrease tidal volume.
 Brain: Decrease Brain metabolic rate.
 Increase cerebral blood flow, decrease resistance.
 Kidney: decrease GFR & blood flow, Increase
resistance.
 Liver: Decrease hepatic blood flow.
 Affect liver function.

96
 Unwanted effects:
 Nausea, Vomiting (repeated use)
 Bone marrow depression (Anaemia)
 Teratogenic (pregnant women)

97
 B- Halothane
 Chemically is halogenated hydrocarbon.
 Widely used volatile anaesthetic agent.
 Potent, non-irritating (cough + secretion) & non-flammable.
 Has smooth & pleasant induction.
 Less hepatotoxic, but when occurs is dangerous, usually
 happened after repeated exposure (should be avoid).
 3rd state is reached in 2 -5 min.
 Recovery is rapid & with less post-operative vomiting & nausea
incidence.

98
 Used in closed cycle.
 Can produce severe hepatitis…… fetal.
 Has narrow therapeutic window.
 Possess cardio toxic effects.
 Usually used in combination (Less conc.)
 Has no muscle relaxant activity.
 Increase cardiac muscle sensitivity to Catecholamines.

99
 Unwanted effects:
 Hepatic damage.
 Cardiac dysrhythmia.
 Delayed poisoning characterized by uncontrolled
vomiting (Not fetal).
 Contra-indicated:
 History of Jaundice.
 Hyperthermia (malignant).
 Arises cerebro-spinal pressure.

100
 Interactions:
 Potentiate antihypertensive effects.
 Pre anaesthetic medication (Atropine …….Bradycardia)
 Sever Catecholamine interactions.
 C.Others
 Enflurane, Isoflurane……..similar to halothane.
 Trichloroethelene.
 Cyclopropane.
 diethylether.

101
2- Intravenous Anaesthetics
 Used alone for short procedures.
 Used mainly for induction.
 Two classes, Barbiturates & Non-Barbiturates.

102
A- Barbiturates
 Thioparbital & Methohextone.
 Induction is achieved in less than 30 seconds.
 Recovery is determined by re-distribution process.
 Less accumulation risks.
 Adverse effects:
 Barbiturates effects.
 Laryngeal spasm.
 Respiratory depression.
 Hypotension & Myocardial depression.

103
 Precautions:
 Renal impairment.
 CHF.
 Contra-indications:
 History of sensitivity.
 Respiratory obstruction.
 Esophageal cavity inflammation.
 Oedema.
 Tetanus (Jaws muscle spasm).

104
B- Non-Barbiturates
 Ketamine & Propofol.
 Many agents with less cardiac depression & rapid elimination.
 Has rapid recovery without nausea & vomiting.
 Ketamine:
 Is true hypnotic agent with analgesic activity.
 Increase sympathetic activity (restricted use).
 Less potent & recovery is slow and complicated with hallucination
(used with BZDs).
 Used for diagnostic Operation.
 Metabolized in liver
 Used mainly in paediatric anaesthesia, shock & poor risk geriatric pnt.

105
 Mechanism of action:
 It may involve blockade of membrane effects of the
excitatory N.T glutamate at (NMDS) receptors sub type.
 Characterized by catatonia, Amnesia & analgesia
without loss of concisionsness.
 Cardio vascular stimulation (Sympathetic & decrease NE
re-uptake.
 Increase cerebro vascular blood flow, Oxygen
consumption & intra cranial pressure (like inhaled ones).

106
 Administration & Pharmacokinetic:
 Highly lipophilic drug.
 Rapidly distributed into vascular organs.
 Hepatic metabolism with only one active
metabolite.
 Has urinary & Biliary excretion.
 Side effects:
 Emergence phenomena (disorientation & vivid
dreams)… give I.V diazepam 5minutes before.

107
108
 B- Local Anaesthetics
 Drugs that used to prevent Pain by
reversible block of conduction along the
nerve fibers.
 used clinically to block pain sensation

from specific areas of the body.

 Lipophilic/Hydrophilic balance is

essential for optimal activity.

109
110
 They are weak bases and prepared in salts
forms.
 All end by the suffix caine (amide & ester).

 When absorbed …. Hyper sensitivity reactions.

 Cross mixing …… (fetal) .

111
 Desired properties for L.A:

Water solubility (Not to cross BBB).
 Capable to be sterilized by heat (stable).

 Rapid onset of action.

 Possess reasonable duration of action

(operation).
 Non-toxic.

 Complete recovery after use.

112
Mechanism of action:
 Two possible suggested mechanisms:
 1-Reversible block of impulses conduction along nerve
axons & excitable membranes by block voltage-gated
Na+-channels, inhibit action potential generation &
propagation.
 This effect is achieved by decrease Na+ ions &
increase threshold of excitability & paralysis the
effect of sensory nerve & motors.
 Their receptors are not accessible from out

membrane site.

113
 Uncharged from is important to cross the membrane.
 Has use-dependant Channel blocking feature (rate of
blocking α No of opened channels)
 Their rate of offset, central nervous system and
cardiac toxicity is determined by absorption and
distribution.
 2-Inhibits Substance P actions.

114
115
 Effects:
 Local: nerve blockade & direct vascular effects.
 Regional: Loss of sensation & vasomotor tone.
 Systemic: due to absorption or I.V administration
 Administration & Pharmacokinetics:
 Can be administered by one of the following methods:
 1.Surface Anaesthesia: topical or directly into mucous
surface

116
 2. Infiltration Anaesthesia: S.C + Vasoconstrictors.
 3. Nerve block: Infiltration around single nerve (Dental), epidural
(dura) & spinal (I.T).
 4. I.V regional Anaesthesia: into exangunated limb.
 Generally L.A has a high potency & long duration.
 Duration (1-1.5 hrs) increased by addition of
vasoconstrictors (doubled) .
 Although amide dealkylated in liver & esters hydrolyzed
by plasma pseudo cholinesterase, metabolism has little
effect on duration.
 Effective within 5 minutes.

117
 Used as HCl salts forms (week base).
 Inside the body either uncharged base or cations (pka = 8-9).
 The most active form is the cations (strongly bind to close
channels)
 L.A: exists as two chemical classes:
 1. Esters: cocaine, procaine, tetracaine and
Benzocaine.
 2. Amides: Lidocaine, Mepivacaine,

Bupivacaine….etc.
 esters has shorter duration (hydrolyzed rapidly)

118
 A-Lidocaine
 Longer duration, t1/2 = 1.5 hr.
 Drug of choice for surface anaesthesia.
 Relatively has low toxicity.
 If absorbed: psychological reactions, convulsion & cardiac
dysrhythmia.
 lidocine metabolised mainly in the liver.
 usually by N-dealkylation rather than cleavage of the amide
bond, with phatmacologically active metabolites.
 Useful as alternative in allergy cases.
 Cause malignant hyperpyrexia.
 Use IV as class I antiarrhythmic drug.

119
 B-Cocaine
 V. toxic (used in V. low conc.).
 Common & dangerous adverse effect.

 Can cause methaemoglobineamia.

 Inhipit NE re-uptake, cause euphoria.

 Veru useful for CVS

120
 C- Others
 Prilocaine metabolised mainly in the liver.
 usually by N-dealkylation rather than cleavage of the
amide bond, with phatmacologically active
metabolites.
 Benzocaine is an unusual local anesthetic of very low
solubility
 is used as a dry powder to dress painful skin ulcers.
 Slowly released and produces long-lasting surface
anesthesia.

121
4. Analgesics (Pain Killers)
 Pain (hyperalgesia or allodynia) &
Analgesia
 Pain: unpleasant sensory due to tissue
damage.
 Acute Pain is a symptoms with biological
function…Hazard (minimize injury).
 Chronic pain describe as a disease and not
symptoms.

122
Pain pathway
 Tissue injury leads to cellular change and chemical
release (Histamine) that quicken the neuronal
impulses which interpreted as pain sensation.
 pain-producing mediators are released: Leukotrienes,
prostaglandin E, and histamine sensitize the
nociceptors
 Bradykinin is release due to blood clotting activation.
  

123
124
 Most tissues & organs innervated by sensory
receptors (Nocieptors) connected to 1o afferent nerve
fiber that terminate in the dorsal horn of the spinal
gray matter, then via neurons in the thalamus to the
sensory cortex.
 Various N.T that found in the dorsal horn may involve

in pain modulation (glutamate, GABA, NE, 5HT and

certain peptides (Opioids)).
 Opioids peptides are found centrally & peripherally in

high conc. (Limbic system, Brain stem & Spinal cord).

125
  Endorphins are the natural ligand for Opioids that
mediate their analgesic effects.
 Tissue injury lead to cellular change involving chemical
release (e.g: Histamine) that quicken neuronal impulses
(interpreted as pain).

1- Pain from peripheral reached CNS via 1o afferent (activated
by noxious stimulation) to dorsal horn (spinal cord).
 2o neuron cross the spinal cord and ascend to thalamus

& cerebral cortex and other sites.

 2- Central mechanism by which the afferent input generates a
pain sensation.

126
 3- A descending system pathways such
as:
 1.Opioids (endorphins & enkephalins)
 2.5HT (from raphe nuclei)
 3.Noradrenergic (from locus ceruleus)
 Lessen afferent signal

127
128
 Substantia gelatinosa (short inhibitory interneuron
projection to lamina I & V).
 It regulates transmission at 1rst synapse of the
noceptive pathway between the 1o afferent fiber & the
spinothalamic tract transmission neuron.
 It acts as gate keeper … gate control theory (1965).
 It postulates (when the pain modulation system is
active, noxious stimuli produce less activity in the pain
transmission pathway)
 Noxious stimuli sensitivity increased by pain itself.

129
 Analgesia
 It refers to pain removal process.
 Descending pathway from midbrain and brain stem
exert a strong effect on dorsal horn transmission.
 Electrical stimulation of the (midbrain periaquenductal
grey area) causes analgesia.
 The descending inhibition is mediated mainly by
enkephalins, 5HT, NA and Adenosine. All are
activated by Opioids peptides by lessen the afferent
signals.

130
 Pain sensation can be influenced or modified as follows:
 1.Elimination of the cause of pain.
 2.lowering of the sensitivity of noci-ceptors (antipyretic analgesics,
local anesthetics)
 3.interrupting nociceptive conduction in sensory nerves (local
anesthetics)
 4.suppression of transmission of nociceptive impulses in the spinal
medulla (opioids)
 5.inhibition of pain perception (opioids, general anesthetics)
 6.Altering emotional responses to pain, i.e., pain behavior
(antidepressants as “co-analgesics”).

131
  Many types of agents act in the pain pathway
such as:
 1- Opioids (Narcotic) e.g morphine: Those cause
analgesia by:
 a. Activating the descending pathway.
 b. Inhibiting transmission in dorsal horn.
 c. Inhibiting excitation of peripheral noceptives.
 Suitable for moderate to severe pain

particularly of visceral origin.

132
 2- Non-Opioids (Analgesic antipyretics):
 Suitable for pain in musculoskeletal conditions

 NSAIs (Aspirin) & Acetaminophen

(Paracetamol).
 3- Anaesthetics: Suitable for surgical conditions.
 May be Local or general.

 4- Others: TCA, Tramadol (metabolite of trazodone).

 Most of Antiepileptic drugs.

133
 Pain managements:
 Acute pain (noxious stimulation: injury) is self-limiting and can be
managed by Analgesic drugs.
 Chronic pain which has lasted for 6 month or more:

1. Need comprehensive ttt.

2. May involve clinics, hospices … medical & behavioral aspects.
3. Underlying disease … causative factor.
4. Non-drug ttt (TENS) transcutanous electrical nerve stimulation,
Acupuncture & massage .
5. Invasive procedures (neurosurgery, neurolytic nerve block).
6. Non-medical ttt: Physical therapy & psychological techniques (cognitive,
relaxation training or hypnosis).
7. The use of Analgesic agents.
  

134
A-Narcotic Analgesics
 They also called Opioids analgesics.
 Relief pain by narcosis (CNS depression).
 Relief pain without loss of consciousness.
 It may be natural or synthetics.
 Opium has been used in the past for many reasons
(pain, diarrhea, vomiting … etc).
 It refers to (God's own medicine)…. STD agonist.

135
 Can be classify as:
 1- Opiates: Natural alkaloids … (Opium).
 2- Synthetics: chemically …….. (Pethidine).
 3- Opiopeptides: Endogenous peptides (Endorphins &
Enkephalins).
 Opioids produce v. complicated pharmacological
picture due to their receptors specificity & efficacy
variations.
 Some act as agonist on one receptor and as
antagonists or partial agonists at another one.

136
 Opioids drugs was categorized as:
 1- Pure (Full) agonists: High efficacy or
strong agonists
 Include most of typical Morphine - like drugs.
 Have higher affinity to µ-receptors & lower for δ & κ-
sites
 Codeine, methadone and Dextropropoxyphene are
referred as week agonists due to their less analgesic and
unwanted effects than Morphine and do not cause
dependence.

137
 2- Partial agonists & mixed agonist –
antagonists:
 Nalorphine & Pentazocine.
 Can evoke agonist effects but may also displace full
agonists from its binding sites and decrease their
biologic effects.

138
 Pentazocine is antagonist at µ-receptors & partial
agonist on δ & κ- receptors.
 Most of it tends to cause dysphoria rather than
euphoria.
 It is effect mediated by κ -receptors or non-opioid σ
-receptors.
 3- Antagonists: e,g: Naloxone &
Naltrexone.
 Produce v. little effects alone, but block Opioids effects.

139
Administration & Ph. kinetics:
 Well absorbed from S.C, I.M & Mucosal membrane.
 Rapid GIT absorption, Morphine has 1rst pass
metabolism.
 Metabolize by glucoronyl conjugation.
 Excreted through Kidney or bile.
 Fentanyl (power full N.A) store in adipose tissue,
others in liver, kidney, spleen, lung and skeletal muscle
(main storage site).
 Pethidine & Heroine (ester) go hydrolysis then phase
II.

140
 Ph. dynamics:
 1- Site of action (Opioids receptors):
 There are different receptors for Opioids.
 These receptors found at high level
endogenous peptides (Endorphins(β) &
Enkephalins), at Substantia gelatinosa in the
Limbic system.
 They are G-protein-coupled receptors.

141
  Each one is responsible for certain effects:
 1- µ: Suprospinal analgesia, Euphoria,
respiratory depression & physical dependence.
 µ1 & µ2 are the subtype.
 2- κ: Spinal analgesia, Myosis & sedation.
 3-σ: Dysphoria, hallucination& cardiac
stimulant effect.
 4- δ: vary in individual drug.
 These receptors can be blocked competitively.

142
 Table: Receptor subtype activity of some
representative Opioids
Class Drug Receptor subtype
Mu Delta Kappa
Opioids peptides Enkephalins Agonist Agonist
Β-Endorphin Agonist Agonist
Dynorphin Week agonist Agonist
Agonists Codeine Week agonist Week agonist
Etorphine Agonist Agonist Agonist
Fentanyl Agonist
Meperidine Agonist
Methadone Agonist
Morphine Agonist Week agonist Week agonist
Butorphanol Ant. or part. Agonist
Partial agonists- Buprenorphine Part.Agonist
antagonists
Dezocine Part.Agonist Agonist
Nalbuphine Antgonist Agonist
Pentazocine Ant. or part. Agonist
Antagonists Naloxone Antagonist Antagonist Antagonist

143
 2- Mechanism of action:
 Opioids agonists produce analgesia by
binding to specific receptors, located in
the brain & spinal cord regions involve
in the transmission and pain
modulation.

144
145
 Opioids activate 7TM-GPCRs located pre and post
synaptically along pain transmission pathway.
 Enhancement of neuronal K+ efflux (less respond to
stimuli) and inhibit Ca+2 influx (inhibit release of N.T).
 They are structurally specific … L-isomer is more
active.

146
 1- Cellular effects:
 Inhibit Adenylate cyclase… decrease intracellular cAMP.
 Also exert effects on Ion-channel through direct G-protein
 a. promote K+-channel opening.
 b. Inhibit Ca+2-channel opening.
 These effects reduce both neuronal excitability & transmitters
release….. inhibitory cellular effect.
 Chronic administration… Tolerance & physical dependence
(increase Ca+2 influx).
 So Morphine tolerance is due to cellular adaptation (not kinetic,
but dynamic).

147
 2- Different systems effects:
 1. CNS: Analgesia, Euphoria, dysphoria, Respiratory

depression, Cough suppression, Myosis (blocked by

antagonists), trunk rigidity & vomiting.
 2. CVS: No significant direct effects on HR, rhythm & BP,

but peripheral vasodilatation …. Fall in BP.

 3. Cerebral circulation: increase Co … Respiratory
2
depression.
 Decrease PVR…increase blood flow…increase CSF

pressure…. Increase intracranial pressure (C.I: cerebral

surgery).

148
 4. GIT: constipation (local &central effect), decrease
gastric motility and secretion.
 Small intestine increase tone, large one increase H2O
absorption.
 5. G.U.T: depress renal functions due to decrease
renal blood flow (in man) & due to increase ADH (in
animal).
 6. Uterus: decrease tone …. Colon labor.

149
 7. Endocrine: increase ADH, Somatotrophine &
decrease LTH.
 It is effects mediated by endogenous peptides under
control of hypothalamus.
 8. Others: flushing, hitching, sweating, worm skin,
exocrine secretion, hyperventilation, hyperthermia,
vomiting, diarrhea & Anxiety (All withdrawal
symptoms was produce by Antagonists).

150
 Clinical uses:
 A .Indications:
 Narcotic analgesic…. Used for severe pain
 Acute pulmonary odema.
 As antitussive.
 Antidiarrhea.
 Pre & post anaesthetic medications.

151
 B .Adverse effects:
 Restlessness, Hyperactivity, tremor, Respiratory
depression Nausea, Vomiting, Increase I.C pressure,
Orthohypotension, Hypovolemia, urinary retention
hitching around the nose (due to Histamine release).

152
 C .Contraindications:
 Pure & mixed not used together.
 Head injury pnt.
 Pregnancy ….. decrease uterus tone.
 Impaired hepatic functions.
 Endocrine disease pnt.
 D .Anti dot:
 Over dose was ttt by Naloxone I.V.
 In comatose pnt start with small dose then high ones.
  

153
 B-Non-Opioids (Analgesic antipyretics)
NSAIDs, Selective cyclooxganse-2 inhibitors &
Acetaminophens

 NSAIDs have good analgesic efficacy (> opioids)

 Relatively rapid onset of action
 Cause GIT bleedings, H2O and salts disturbance
 All acts through decreasing prostanoids biosynthesis
via COX inhibition.

154
 Prostanoids
 Encompasses both Prostaglandins & Thromboxanes.
 1- Prostaglandins
 They are a family of naturally occurring unsaturated fatty
acids.
 Discovered firstly as vaso active substance in seminal fluid that
contracts the uterus and furtherly as inflammatory mediator.
 The term is due to its origin (Prostate gland).
 Member are: PGE1, PGE2, PGI2 (Prostacycline), PGD2, PGF2α
while PGA & PGB are stable …. Artifacts).
 They modulate inflammation, body temperature, Pain
transmission, Platelets aggregation ……..etc.
 Not stored, synthesized & release on demand.

155
 2- Thromboxane A2
 Platelets aggregator
 Broncho & vaso constrictor.
 Biosynthesis & degradations
 The initial rate – limiting step is liberation of arachidonate from phospholipids in
one or two steps by one or more lipases enzymes.
 This process was stimulated by:
 1-Thrombine (Platelets)
 2- C5a (neutrophils)
 3- Bradykinin (fibroblast)
 4- Antigen-Antibody reaction (mast cell)
 5- General cell damage.
 6- Heat, Toxins and Trauma.

156
  The arachidonic acid is oxygenated by 4 separate routes one is
 1- Cyclooxygenase (COXs) Isozymes: to give PGs, TXAs & PCs
 There are two types :
 1- COX-1: found as constitutive enzyme in mast cell
(constitutively expressed)
 Widely distributed
 Possess housekeeping functions.
 2- COX-2: inducible (stimuli dependent)
 Induced in inflammation.
 Is an immediate response gene product.
 Both Isozyme promote uptake of two O2 molecules by cyclization of
arachidonic acid to give end peroxide (PGG2) which react with peroxidase
moiety to give PGH1 & PGH2 that give the three compounds above.

157
158
How Anti-inflammatory drugs Acts?
 1- Glucocorticoids:
 Inhibit COX induction.
 Stimulate production of PLA2 inhibitors (Lipocortin)
 2- NSAIDs:
 Inhibit the action of COXs
 Traditional NSAIDs inhibits both COX-1 & COX-2 isoforms,
newer are selective COX-2 called (coxibs) with same efficacy
and controversial side effects.
 The selectivity ability due to amino acid difference in position
523
 The mechanism of action of Acetomiophen is uncertain, but
thought to be through CNS effects.

159
 Table. Cyclo-oxygenase-inhibitory specificity of some
common non-steroidal anti-inflammatory drugs and coxibs

Examples Description  
Ketorolac Highly COX-1-selective  
Flurbiprofen Very COX-1-selective  
Indometacin, aspirin , naproxen, ibuprofen Weakly COX-1-selective
 

Fenoprofen Non-selective; full inhibition of both

enzymes  

Salicylate Non-selective; incomplete inhibition of both

enzymes  

Diflunisal, piroxicam, meclofenamate, Weakly COX-2-selective

sulindac, diclofenac, celecoxib
 

Valdecoxib, etoricoxib Very COX-2-selective  

Rofecoxiba Highly COX-2-selective

160
 Paracetamol
 called acetaminophen is one of the most commonly
used non-narcotic analgesic-antipyretic agents
 Is a component of many over-the-counter proprietary
preparations.
 it has excellent analgesic and antipyretic activity,
which can be traced to inhibition of CNS prostaglandin
synthesis,
 it has weak anti-inflammatory activity (except in
some specific instances)

161
 Does not share the gastric or platelet side effects of the other
NSAIDs. For this reason, paracetamol is sometimes not classified as
an NSAID at all.
 A potential solution to this puzzle was supplied by the observation
that a further COX isoform, COX-3 (an alternate splice product of
COX-1) existed predominantly in the CNS of some species, and that
paracetamol, as well as some other drugs with similar properties
(e.g. antipyrine and dipyrone), were selective inhibitors of this
enzyme
 This elegant idea is still under investigation.
 Alternative explanations for the ability of paracetamol selectively to
inhibit COX in the CNS alone have been provided by Ouellet &
Percival (2001) and Boutaud et al. (2002).

162
Pharmacokinetic
 Paracetamol is given orally and is well
absorbed, with peak plasma concentrations
reached in 30-60 minutes.
 The plasma half-life of therapeutic doses is 2-

4 hours, but with toxic doses it may be

extended to 4-8 hours.
 Paracetamol is inactivated in the liver, being

conjugated to give the glucuronide or sulfate.

163
Unwanted effects
With therapeutic doses, side effects are
few and uncommon,
 Although allergic skin reactions

sometimes occur.
 It is possible that regular intake of large

doses over a long period may cause

kidney damage.

164
 Aspirin
 Aspirin (acetylsalicylic acid) is the oldest non-steroidal anti-
inflammatory drug.
 It acts by irreversibly inactivating both cyclo-oxygenase (COX)-1
and COX-2
 In addition to its anti-inflammatory actions, aspirin inhibits
platelet aggregation, and its main clinical importance now is in
the therapy of myocardial infarction.
 It is given orally and is rapidly absorbed; 75% is metabolised in
the liver.
 Elimination follows first-order kinetics with low doses (half-life 4
hours), and saturation kinetics with high doses (half-life over 15
hours).

165
Unwanted effects
 with therapeutic doses: some gastric bleeding (usually slight and
asymptomatic) is common
 with large doses: dizziness, deafness and tinnitus ('salicylism');
compensated respiratory alkalosis may occur
 with toxic doses (e.g. from self-poisoning): uncompensated
respiratory acidosis with metabolic acidosis may occur,
particularly in children
 aspirin has been linked with a postviral encephalitis (Reye's
syndrome) in children.
 If given concomitantly with warfarin, aspirin can cause a
potentially hazardous increase in the risk of bleeding.

166
 C- Anaesthetics
 Go to topic No. 3
 D- Others
 Triptan: sumtriptan
 NE & 5HT-reuptake inhibitors: TCA

167
 6-Anti-diabetic drugs (Endocrine)
 Pancreas
 scattered clusters endocrine cells called islets of Langerhans
 3types:
 α-cells: produce glucagon
 β-cells: produce Insulin
 δ-cells: produce Somatostatin (Inhibit both above)
 ↑Blood glucose level (after meals) regulate the status of ( ↓Glucagon & ↑insulin)
 Insulin, when released, the main effect is to lower blood glucose levels by
enhancing the utilization and uptake of glucose.
 Glucagon directly counters the effects of insulin by decreasing glucose utilization
and uptake as well as by stimulating the formation of new glucose from glycogen
and amino acids.
 The major target tissues for insulin and glucagon are liver, skeletal muscle and
fat.

168
 Diabetes mellitus
(Other is Diabetes inscipedus??)
 mellitus is the most common endocrine disorder.
 The prevalence of diabetes is 8.2% among all men and women
in the United States.
 The frequency of the disease increases to 18.4% in individuals
65 years of age or older.
 Some risk factors for diabetes mellitus are: Obesity, Familial
history of diabetes mellitus, Increasing age , Ethnicity (High risk
groups include African–Americans, Hispanics and native
Americans) and Dietary factors
 D.M; is caused by relative or absolute lack of insulin.
 Is a chronic heterogeneous group of disorders.

169
 Type I diabetes mellitus
(insulin-dependent diabetes) -juvenile

 Etiology:
 Cause appears to be a progressive autoimmune
destruction of the pancreatic cells.
 Most instances of autoimmune pancreatic
destruction are idiopathic, but some may occur
following viral infections.
 Little or no insulin secretion occurs.
 Movie entitled: mechanism of insulin

170
 Manifestations
 Hyperglycemia, Weight loss, and the three
“polys” [polydypsia: increased thirst,
polyphagia: increased appetite & polyuria:
increased urine output].
 Weakness and fatigue due to poor energy
utilization and skeletal muscle catabolism
 Diabetic keto-acidosis: Accumulation of acidic
ketone bodies in the blood due to a lack of
insulin-stimulated fatty acid utilization

171
172
Management strategy
 Life-long ttt with exogenous insulin to control glucose
level and to prevent short and long-term macro &
micro-vascular complications.
 Nephropathy, neuropathy, retiopathy, and CV
disorders.
 Dietary managements.
 Oral hypoglycemic agents are ineffective in type –I,
because functionality of β-cell are required.

173
 Type II diabetes mellitus
(non-insulin-dependent diabetes)
 Greater prevalence than type I diabetes.
 Etiology:
 The exact etiology of the insulin resistance is unknown
but may be linked to abnormalities of insulin receptors,
intracelluar signaling pathways or glucose transporters.
 Insulin resistance may be related to increased levels of
free fatty acids (FFA) that stimulate insulin secretions
and inhibit glucose uptake by tissues
 FFAs are elevated in obese individuals with a
predisposition to type II diabetes.

174
 Obesity appears to be an important contributing
factor to development of type II diabetes.
 Tissues (liver, fat and muscle) in obese individuals
have an altered responsiveness to the effects of
insulin.
 A strong genetic component is also present.
 Insulin secretion may be normal or even elevated at
the time of diagnosis.
 The continued overproduction of insulin by the cells
can eventually lead to β-cell “burnout” and destruction

175
Manifestations
 The primary manifestation is “insulin resistance”, which
is a lack of responsiveness by tissues and the pancreas
itself to insulin.
 Manifestations of type II diabetes may include many of
those seen in type I diabetes including 3polys, fatigue
and weakness.
 Other manifestations of type II diabetes tend to be
more generalized: Hyperinsulinemia, Visual changes,
Parasthesias (abnormal sensations such as tingling or
burning, often occur in the extremities), Recurrent
infections, Ketoacidosis is rare with type II diabetes

176
Management strategy
 Weight loss has been reported to improve insulin sensitivity in
obese individuals with type II diabetes.
 Exercise may enhance glucose utilization and improve glucose
control in patients with type II diabetes, thus reducing the risk of
diabetic complications.
 Dietary management.
 Oral hypoglycemic drugs.
 Insulin-replacement may be necessary during later stages of the
disease when cells are destroyed in order to maintain normal
metabolic function

177
Anti-diabetic agents

178
 1- Insulin
 Produce, secret and store by pancreatic β-cells.
 Parent protein (preproinsulin)…smaller (Proinsulin)…. insulin +
peptide C.
 Secretes after meals due transient glucose level elevation.
 Insulin is the body key to use glucose
 It promote glucose, FFAs and aminoacids by target cells (Liver,
Adipose tissue and Skeletal muscles)
 Without insulin glucose cannot cross cell membrane leading to
metabolic cascade events: (e.g. gluconeogensis)
 Movie entitled: Blood Sugar Regulation in Diabetics

179
Insulin therapy:
 Is the sole therapy for type –I D.M.
 Can be used for type-II, poorly controlled by diet and
other
 Stimulate CHO metabolism, aid in transferring glucose
to cardiac and skeletal muscles and adipose tissue.
 Converted glucose to glycogen
 Stimulate lipogenesis and protein synthesis.
 Reduce serum K & Mg level.

180
Ph. Kinetics
 Not used orally (protein)
 Given S.C or I.V in emergency.
 It is absorption depend on many factors: site of
injection, temperature, physical activity and dose.
 Insulin preparation differ in dose, onset, duration
(Zinc) and origin
 Biosynthetics & semi-synthetic human
 Human insulin (least antigenic and more soluble)
 Beef & Pork (replaced by human)

181
Side effects:
 Main and serious one is hypoglycemia
 Autonomic symptoms (sweating, trembling, worm)
 Neuroglycopenic (confusion, weakness, drowsiness)
 Hunger, tachycardia, coma.

182
2-Oral Hypoglycemic agents

183
Pharmacodynamics
 Acts mainly by stimulating insulin secretion by β-cells.
 Enhancing β-cells sensitivity to glucose
 Reducing glucagon release.
 They work only if β-cells are functioning.
 If therapy failure other will added & not dose will
increased.

184
 Indications
 Best for after 40 years age and less than 5
years, ideal body weight and fasting glucose
level > 180 mg/dl.
 Side effects
 Hypoglycemia, weight gain, GIT effects,
allergy, hepatotoxicity, hypothyroidism,
disulfram effects (older).

185
 B- Biguanides
 The available one is metformin.
 Used as initial monotherapy for with other or insulin in type-II
for seconerly sulfonylureas failure.
 Pharmacodynamics:
 Decrease blood glucose by:
 1- Reducing hepatic glucose production.
 2- Reducing hepatic glycogen metabolism.
 3- Improving insulin resistance by enhancing insulin-
mediated glucose uptake

186
 It decreases TG and cholesterol levels.
 Increases HDL level & causes weight loss.
 Indications
 Ideal for overweight hyperlipedemic pnt.
 Side effects
 Hypoglycemia occur only when used with insulin or others
 GIT –related.
 rare lactic acidosis (inhibit lactate conversion), affect renal,
hepatic and CVS disorders.

187
C- Thiazolidinedione derivatives
 They are relatively new drugs.
 Rosiglitazone, Pioglitazone
 Use as monotherapy or in combination.
 Mechanism of action
 Reduce hyperglycemia and hyperinsulineamia by decreasing
insulin resistant (via enhancing insulin-mediated glucose uptake)
peripherally and at liver site, complished by selective binding to
peroxisomes at adipose tissue, skeletal muscle and liver.
 Receptor activation modulates many insulin-responssive genes
tha regulates glucose and level metabolism.

188
 Basis of action is postulated that: type-II have too much
insulin with liver resistance to it, so only increasing
sensitivity to exising insulin is required instead for
producing more.
 Reduce TG & HDL, LDL level
 Side effects
 Troglitazone (withdrawn) cause hepatotoxicity.
 Other are devoid from hepatotoxicity, but precaution
should be considered
 Heamatologic effects, hypoglycemia and edema.

189
 7-Antibacterial and antimalarial drugs
(chemotherapy)

 Selected topics includes:

1. Principles of Antimicrobial therapy
2. Antibiotics
3. Antimalarial drugs????

190
 Chemotherapy: is the use of drugs that are
'selectively toxic' to invading micro-organisms while
having minimal effects on the host or the use of drugs
that target tumors.
 Chemotherapeutic agents: are chemicals that are
intended to be toxic for the pathogenic organism (or
cancer cells) but innocuous to the host.
 Antibiotic: chemical substance that produce by M.O
that kill others (Bactria) in low concentrations.
 Selective –toxicity (magic pallets): Ability of
Antimicrobial agent to kill the M.O without affecting
the host (Human/animal).
191
192
 Infectious disease: When a bacterial penetrate body tissues
and the body succeeds in removing the invaders, without outward
signs of disease, by mounting an immune response.
 If bacteria multiply faster than the body’s defenses can destroy
them, infectious disease develops with inflammatory signs.
 Antimicrobial agent selection:
 It depend on many factors:
1. M.O identity & Sensitivity
2. Infection site.
3. Safety
4. Patient factors
5. Therapy cost.

193
 Empirical therapy and best guess: in critical ill patient where the
time factor is fetal immediate use of antibiotic before sensitivity is
preferable.
 Broad spectrum one are used.
 Chemotherapeutic spectra: refers to the species of M.O affected by
the drug.
 May be narrow (limited), extended (G +ve + large G-ve) or broad spectrum
(wide species variety).
 Resistance: is the loss of drug efficacy
 - Bacterial resistance to an antimicrobial agent is attributable to three
general mechanisms:
 1- The drug does not reach its target.
 2- The drug is not active.
 3- The target is altered.

194
195
 Antibiotic therapy complications:
includes:
1. Hypersensitivity reactions
2. Direct toxicity (ototoxicity)
3. Superinfections (oppertunistic)

196
 Can be classify based on different aspects such as
1- Bactericidal (Kill the M.O) & bacteriostatic (arrest the growth)

197
198
199
1- Cell wall synthesis inhibitors
 Members include: β-lactam (Penicillins, Cephalosporins),
cycloserine, vancomycin, and bacitracin.
 They inhibit bacterial growth by interfering with the
transpeptidation reaction of bacterial cell wall synthesis.
 The cell wall is a rigid outer layer unique to bacterial species.
 The cell wall is composed of a complex cross-linked polymer of
polysaccharides and polypeptides, peptidoglycan (murein,
mucopeptide).
 Cross-links give the cell wall its structural rigidity.
 Penicillin-binding protein (PBP, an enzyme) - the active site -
removes the terminal alanine in the process of forming a cross-
link with a nearby peptide.

200
 This inhibits the transpeptidation reaction, halting
peptidoglycan synthesis, and the cell dies.
 The final bactericidal event is the inactivation of an
inhibitor of autolytic enzymes in the cell wall, leading to
lysis of the bacterium.
 Also Agents that act directly on the cell membrane of
the M.O, increasing permeability and leading to leakage
of intracellular compounds, including detergents such
as polymyxin; polyene antifungal agents (nystatin and
amphotericin B) which bind to cell-wall sterols.

201
Clinical uses of the penicillins:
 Penicillins are given by mouth or, in more severe
infections, intravenously, and often in combination with
other antibiotics.
 Uses are for sensitive organisms and may include:
1. Bacterial meningitis (e.g. Caused by neisseria meningitidis,
streptococcus pneumoniae): benzylpenicillin, high doses
intravenously.
2. Bone and joint infections (e.g. With staphylococcus aureus):
flucloxacillin
3. Skin and soft tissue infections (e.g. With strep. Pyogenes or
staph. Aureus): benzylpenicillin, flucloxacillin; animal bites:
co-amoxiclav

202
1. Pharyngitis (from strep. Pyogenes): phenoxylmethylpenicillin
2. Otitis media (organisms commonly include strep. Pyogenes,
haemophilus influenzae): amoxicillin
3. Bronchitis (mixed infections common): amoxicillin
4. Pneumonia: amoxicillin
5. Urinary tract infections (e.g. With escherichia coli): amoxicillin
6. Gonorrhea: amoxicillin (plus probenecid)
7. Syphilis: procaine benzylpenicillin
8. Endocarditis (e.g. With strep. Viridans or enterococcus faecalis)
9. Serious infections with pseudomonas aeruginosa: ticarcillin, piperacillin.

203
Adverse effects
 Penicillins are relatively free from direct toxic effect.
 The main unwanted effects are hypersensitivity reactions caused
by the degradation products of penicillin, which combine with host
protein and become antigenic.
 Skin rashes and fever are common; a delayed type of serum
sickness occurs infrequently.
 Much more serious is acute anaphylactic shock, which although
fortunately very rare, may in some cases be fatal.
 When given orally, penicillins, particularly the broad-spectrum
type, alter the bacterial flora in the gut.
 This can be associated with gastrointestinal disturbances and in
some cases with suprainfection by other, penicillin-insensitive,
micro-organisms.

204
Resistance
 Resistance to penicillins and other β-lactams
is due to one of four general mechanisms:
 Inactivation of antibiotic by β-lactamase.
 Modification of target PBPs.
 Impaired penetration of drug to target PBPs.
 Efflux.
 β-Lactamase production is the most common
mechanism of resistance (Clavulonic Acid)

205
Clinical uses of the Cephalosporins
 Cephalosporins are similar to penicillins, but more
stable to many bacterial β-lactamases and therefore
have a broader spectrum of activity.
 Different generations with different indications are
exists:
 1st : Oral drugs (Cephalexin, cephradine, and
cefadroxil ) may be used for the treatment of
urinary tract infections, for staphylococcal, or for
streptococcal infections including cellulitis or soft
tissue abscess.
 Cefazolin (parenteral) is a drug of choice for
surgical prophylaxis
206
 2nd : (Cefaclor, cefuroxime axetil, cefprozil) are active against β-
lactamase-producing H influenzae or Moraxella catarrhalis and
have been primarily used to treat sinusitis, otitis, or lower
respiratory tract infections, in which these organisms have an
important role.
 Because of their activity against anaerobes (including B fragilis),
cefoxitin, cefotetan, or cefmetazole can be used to treat mixed
anaerobic infections such as peritonitis or diverticulitis.
 Cefuroxime is used to treat community-acquired pneumonia
because it is active against b-lactamase-producing H influenzae
and penicillin-resistant pneumococci.

207
 3rd: used to treat a wide variety of serious infections caused by
organisms that are resistant to most other drugs.
 Third-generation cephalosporins should be avoided in treatment
of enterobacter infections (even if the clinical isolate appears
susceptible in vitro) because of emergence of resistance.
 Ceftriaxone and cefotaxime are approved for treatment of
meningitis, including meningitis caused by pneumococci,
meningococci, H influenzae.
 Ceftriaxone and cefotaxime are the most active cephalosporins
against penicillin-resistant strains of pneumococci and are
recommended for empirical therapy of serious infections that
may be caused by these strains.

208
 4th : Cefepime is an example of a so-called fourth-
generation cephalosporin.
 It is more resistant to hydrolysis by chromosomal b-
lactamases (eg, those produced by enterobacter).
 It has good activity against P aeruginosa,
Enterobacteriaceae, S aureus, and S pneumoniae.
 Cefepime is highly active against haemophilus and
neisseria.

209
Unwanted effects
 Hypersensitivity reactions, very similar to those seen
with penicillin, may occur, and there may be some
cross-sensitivity; about 10% of penicillin-sensitive
individuals will have allergic reactions to
cephalosporins.
 Nephrotoxicity has been reported (especially with
cefradine), as has drug-induced alcohol intolerance.
 Diarrhoea can occur with oral cephalosporins and
cefoperazone.

210
 Cephalosporins that contain a methylthiotetrazole
group (eg, cefamandole, cefmetazole, cefotetan,
cefoperazone) frequently cause hypoprothrombinemia
and bleeding disorders.
 Administration of vitamin K1, 10 mg twice weekly, can
prevent this.
 Drugs with the methylthiotetrazole ring can also cause
severe disulfiram-like reactions; consequently, alcohol
and alcohol-containing medications must be avoided.

211
Vancomycin:
 The clinical use of vancomycin is limited mainly to
pseudomembranous colitis , and the treatment of
some multiresistant staphylococcal infections
 Adverse Reactions:
 Vancomycin is irritating to tissue, resulting in
phlebitis at the site of injection.
 Chills and fever may occur.
 Ototoxicity is rare and nephrotoxicity uncommon with
current preparations.

212
 However, administration with another ototoxic or
nephrotoxic drug, such as an aminoglycoside,
increases the risk of these toxicities.
 Among the more common reactions is the so-called
"red man" or "red neck" syndrome.
 This infusion-related flushing is caused by release of
histamine.
 It can be largely prevented by prolonging the infusion
period to 1-2 hours or increasing the dosing interval.
 Other cell wall inhibitors: Bacitracin , Cycloserine.

213
2-Protein synthesis inhibitors
 Agents that disrupt function of 30S or 50S
ribosomal subunits to reversibly inhibit protein
synthesis, which generally are bacteriostatic (e.g.
chloramphenicol, the tetracyclines, erythromycin,
clindamycin, streptogramins, and linezolid).
 Movie entitled: from RNA to protein

 Agents that bind to the 30S ribosomal subunit

and alter protein synthesis, which generally are
bactericidal (e.g., the aminoglycosides).

214
 A- Tetracyclines
 Tetracyclines are broad-spectrum bacteriostatic antibiotics.
 The group includes tetracycline, oxytetracycline, doxycycline
and minocycline.
 Mechanism of action
 Tetracyclines enter microorganisms in part by passive diffusion
and in part by an energy-dependent process of active transport.
 Susceptible cells concentrate the drug intracellularly.
 Once inside the cell, tetracyclines bind reversibly to the 30S
subunit of the bacterial ribosome, blocking the binding of
aminoacyl-tRNA to the acceptor site on the mRNA-ribosome
complex .
 This prevents addition of amino acids to the growing peptide.

215
Pharmacokinetics
 can be given orally, parenterally (doxycycline) and
topically (tetracycline , oxytetracycline).
 Absorption occurs mainly in the upper small intestine
and is impaired by food (except doxycycline and
minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or
Al3+; by dairy products and antacids, which contain
multivalent cations; and by alkaline pH.
 Tetracyclines are distributed widely to tissues and
body fluids except for cerebrospinal fluid

216
 Tetracyclines cross the placenta to reach the fetus
and are also excreted in milk.
 As a result of chelation with calcium, tetracyclines
are bound and damage growing bones and teeth.
 Tetracyclines are excreted mainly in bile and urine
except doxycycline, which is excreted in the feces. .
 Some of the drug excreted in bile is reabsorbed from
the intestine (enterohepatic circulation) and may
contribute to maintenance of serum levels.

217
Clinical uses:
 Uses (sometimes in combination with
other antibiotics) include:
 Rickettsial and chlamydial infections,
brucellosis, anthrax and Lyme disease
 Cholera Doxycycline (300 mg as a single
dose) is effective in reducing stool volume
and eradicating Vibrio cholerae from the stool
within 48 hours.
 Acne

218
Unwanted effects
 The commonest unwanted effects are gastrointestinal
disturbances caused initially by direct irritation and later by
modification of the gut flora.
 Vitamin B complex deficiency can occur, as can suprainfection.
 Suprainfection can cause Pseudomembranous colitis caused by
overgrowth of Clostridium difficile is a potentially life-
threatening complication.
 Because they chelate Ca2+, tetracyclines are deposited in
growing bones and teeth, causing staining and sometimes
dental hypoplasia and bone deformities.

219
 They should therefore not be given to children, pregnant
women or nursing mothers.
 Another hazard to pregnant women is hepatotoxicity.
 High doses of tetracyclines can decrease protein synthesis in
host cells-an antianabolic effect that may result in renal
damage.
 Long-term therapy can cause disturbances of the bone marrow.
 Phototoxicity (sensitisation to sunlight) has also been seen,
particularly with demeclocycline.
 Minocycline can produce dose-related vestibular disturbances
(dizziness and nausea).

220
Resistance
 Three mechanisms of resistance to
tetracycline analogs have been
described:
 Impaired influx or increased efflux by an active
transport protein pump.
 Ribosome protection due to production of
proteins that interfere with tetracycline binding
to the ribosome.
 Enzymatic inactivation.

221
 B-Chloramphenicol
 Chloramphenicol acts primarily by binding reversibly
to the 50S ribosomal subunit and inhibit peptide
bond formation.
 Chloramphenicol has a wide spectrum of
antimicrobial activity.
 It is bacteriostatic for most organisms but kills
H.influenzae.
 Resistance, caused by the production of
chloramphenicol acetyltransferase , is plasmid-
mediated.

222
Clinical uses of chloramphenicol
 Chloramphenicol should be reserved for serious infections in
which the benefit of the drug outweighs its uncommon but
serious haematological toxicity. Such uses may include:
 infections caused by Haemophilus influenzae resistant to other
drugs
 meningitis in patients in whom penicillin cannot be used.
 It is also safe and effective in bacterial conjunctivitis (given
topically).
 It is effective in typhoid fever, but ciprofloxacin or
amoxicillin and co-trimoxazole are similarly effective and
less toxic.

223
Unwanted effects

224
 Chloramphenicol should be used with great care in
newborns, because inadequate inactivation and
excretion of the drug can result in the 'grey baby
syndrome'-vomiting, diarrhoea, flaccidity, low
temperature and an ashen-grey colour-which carries
40% mortality.
 Hypersensitivity reactions can occur with the drug, as
can gastrointestinal disturbances secondary to
alteration of the intestinal microbial flora.

225
Drug Interactions
 Chloramphenicol inhibits hepatic
cytochrome P450 isozymes (CYPs) and
thereby prolongs the half-lives of drugs
that are metabolized by this system,
including warfarin, dicumarol,
phenytoin, chlorpropamide,
antiretroviral protease inhibitors,
rifabutin, and tolbutamid.
226
 The macrolides are a group of closely related
compounds characterized by a macrocyclic
lactone ring to which deoxy sugars are
attached.
 The prototype drug, erythromycin, was
obtained from Streptomyces erythreus.
 Clarithromycin and azithromycin are
semisynthetic derivatives of erythromycin.

227
Mechanism of action
 Inhibition of protein synthesis occurs via
binding to the 50S ribosomal RNA,
which blocks the aminoacyl
translocation reaction.

228
 Erythromycin
 The antimicrobial spectrum of erythromycin is very
similar to that of penicillin, and it has proved to be a
safe and effective alternative for penicillin-sensitive
patients.
 Erythromycin is effective against Gram-positive
bacteria and spirochaetes but not against most
Gram-negative organisms, exceptions being N.
gonorrhoeae and, to a lesser extent, H. influenzae.
Mycoplasma pneumoniae, Legionella sp. and some
chlamydial organisms are also susceptible

229
Clinical Uses
 An erythromycin is a drug of choice in corynebacterial
infections (diphtheria, corynebacterial sepsis).
 In respiratory, neonatal, ocular, or genital chlamydial
infections.
 in treatment of community-acquired pneumonia.
 whooping cough.
 Erythromycin is also useful as a penicillin substitute in
penicillin-allergic individuals with infections caused by
staphylococci (assuming that the isolate is
susceptible), streptococci, or pneumococci.

230
Adverse Reactions
 A. gastrointestinal effects
 Anorexia, nausea, vomiting, and diarrhea occasionally
accompany oral administration.
 Gastrointestinal intolerance, which is due to a direct stimulation
of gut motility, is the most common reason for discontinuing
erythromycin and substituting another antibiotic.
 B. liver toxicity:
 Erythromycins, particularly the estolate, can produce acute
cholestatic hepatitis (fever, jaundice, impaired liver function).

231
Drug interactions
 Erythromycin metabolites can inhibit
cytochrome P450 enzymes and thus increase
the serum concentrations of numerous drugs,
including theophylline, oral anticoagulants,
cyclosporine, and methylprednisolone.
 Erythromycin increases serum concentrations
of oral digoxin by increasing its bioavailability.

232
 Clarithromycin
 Clarithromycin is derived from erythromycin by addition of a
methyl group and has improved acid stability and oral
absorption compared with erythromycin.
 Its mechanism of action is the same as that of erythromycin.
 Clarithromycin and erythromycin are virtually identical with
respect to antibacterial activity except that clarithromycin is
more active against Mycobacterium avium complex.
 The longer half-life of clarithromycin (6 hours) compared with
erythromycin permits twice-daily dosing.

233
 The advantages of clarithromycin compared
with erythromycin are lower incidence of
gastrointestinal intolerance and less frequent
dosing.
 Clarithromycin 500 mg, in combination with
omeprazole, 20 mg, and amoxicillin, 1 g, each
administered twice daily for 10 to 14 days, is
effective for treatment of peptic ulcer disease
caused by H. pylori

234
Azithromycin:
 Its spectrum of activity and clinical uses are virtually
identical to those of clarithromycin.
 Azithromycin differs from erythromycin and
clarithromycin mainly in pharmacokinetic properties.
 azithromycin penetrates into most tissues (except
cerebrospinal fluid) and phagocytic cells extremely
well, with tissue concentrations exceeding serum
concentrations by 10- to 100-fold.
 The drug is slowly released from tissues (tissue half-
life of 2-4 days) to produce an elimination half-life
approaching 3 days.

235
 These unique properties permit once-daily dosing and
shortening of the duration of treatment in many cases.
 Azithromycin is rapidly absorbed and well tolerated orally.
 It should be administered 1 hour before or 2 hours after meals.
 Aluminum and magnesium antacids do not alter bioavailability
but delay absorption and reduce peak serum concentrations.
 Azithromycin does not inactivate cytochrome P450 enzymes and
therefore is free of the drug interactions that occur with
erythromycin and clarithromycin.

236
Resistance:
 Three mechanisms have been identified:
 1- Reduced permeability of the cell membrane or
active efflux.
 2- Production (by Enterobacteriaceae) of esterases
that hydrolyze macrolides.
 3- Modification of the ribosomal binding site (so-
called ribosomal protection) by chromosomal
mutation or by a macrolide-inducible or
constitutive methylase.

237
Clindamycin:
 It is a congener of lincomycin.
 Clindamycin is active against Gram-positive
cocci, including many penicillin-resistant
staphylococci and many anaerobic bacteria
such as Bacteroides species.
 Mechanism of action:
 Its mechanism of action involves inhibition of
protein synthesis through an action similar to
that of the macrolides and chloramphenicol .
238
Clinical uses:
 In addition to its use in infections
caused by Bacteroides organisms, it is
used to treat staphylococcal infections
of bones and joints.
 It is also given topically, as eye drops,
for staphylococcal conjunctivitis.

239
Unwanted effects:
 Unwanted effects consist mainly of gastrointestinal
disturbances, and a potentially lethal condition,
pseudomembranous colitis, may develop.
 This is an acute inflammation of the colon caused by
a necrotising toxin produced by a clindamycin-
resistant organism, Clostridium difficile, which may
form part of the normal faecal flora.
 Vancomycin, given orally, and metronidazole are
effective in the treatment of this condition.

240
Aminoglycosides
 The aminoglycosides are a group of
antibiotics of complex chemical
structure, resembling each other in
antimicrobial activity, pharmacokinetic
characteristics and toxicity.
 The main agents are gentamicin,
streptomycin, amikacin,
tobramycin and neomycin.
241
Mechanism of action

242
Pharmacokinetics:
 The aminoglycosides are polycations and therefore highly polar.
 They are not absorbed from the gastrointestinal tract and are
usually given intramuscularly or intravenously.
 They cross the placenta but do not cross the blood-brain barrier,
penetrate into the vitreous humour of the eye or into most other
secretions or body fluids, although high concentrations can be
attained in joint and pleural fluids.
 Elimination is virtually entirely by glomerular filtration in the kidney,
50-60% of a dose being excreted unchanged within 24 hours.
 If renal function is impaired, accumulation occurs rapidly, with a
resultant increase in those toxic effects (such as ototoxicity and
nephrotoxicity) that are dose-related.

243
Clinical uses:
 Aminoglycosides are mostly used against gram-negative enteric
bacteria, especially when the isolate may be drug-resistant and when
there is suspicion of sepsis.
 Streptomycin is mainly used as a second-line agent for treatment of
tuberculosis.
 Gentamicin is used mainly in severe infections (eg, sepsis and
pneumonia) caused by gram-negative bacteria that are likely to be
resistant to other drugs, especially pseudomonas, enterobacter,
serratia, proteus, and klebsiella.
 Creams, ointments, and solutions containing 0.1-0.3% gentamicin
sulfate have been used for the treatment of infected burns, wounds, or
skin lesions and for treatment of ocular infections.
 Gentamicin is used as eye drops for treatment of ocular infections.

244
Unwanted effects:
 Serious, dose-related toxic effects, which may increase as treatment
proceeds, can occur with the aminoglycosides, the main hazards being
ototoxicity and nephrotoxicity.
 Ototoxicity and nephrotoxicity are more likely to be encountered when
therapy is continued for more than 5 days, at higher doses, in the
elderly, and in the setting of renal insufficiency.
 Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or
other nephrotoxic antimicrobial agents (eg, vancomycin or
amphotericin) can potentiate nephrotoxicity and should be avoided if
possible.
 Ototoxicity can manifest itself either as auditory damage, resulting in
tinnitus and high-frequency hearing loss initially, or as vestibular
damage, evident by vertigo, ataxia, and loss of balance.

245
Mechanisms of resistance:
 Three principal mechanisms have been
established:
1. production of a transferase enzyme or enzymes
inactivates the aminoglycoside by adenylylation,
acetylation, or phosphorylation.
2. There is impaired entry of aminoglycoside into
the cell.
3. The receptor protein on the 30S ribosomal
subunit may be deleted or altered as a result of
a mutation.

246
 N:B: Rest (Antibiotics) topics include:
 3- Agents that affect bacterial nucleic acid metabolism, such as the
rifamycins (e.g., rifampin and rifabutin), which inhibit RNA
polymerase, and the quinolones, which inhibit topoisomerases.
 4- The antimetabolites, including trimethoprim and the
sulfonamides, which block essential enzymes of folate metabolism. 
 &&&&&&&&&
 ‫ ومامن كاتب االسيفنى ** ويبقى الدـهر ماكتبت يـداه‬،‫كتبت‬
 ‫فـالتـكتب بيـدك غـير شــــئ ** يسرك فى القيــامة ان تراه‬
 $$$
 Omdurman, 23. April.2013, at 10:17 p.m.
  

247