Revision for Final Exam, June 2014

Dr. Ahmed Abdelrahman1

:MCQ

Subjects Chapter1 -First and zero order kinetics.

2-Bioavailability.3- Factors affecting oral absorption.

4--Effect of pH on oral absorption and renal excretion.5--Factors affecting dose and action of drugs.

6-Types of Tolerance (described within the factors affecting dose and action).7-Adverse drug reactions.

8-Types of Antagonism (described within Drug Interactions).

1-General Pharmacology

1-Parasympathomimetics: -Anticholinesterases (Reversible and Irreversible)2-Sympathomimetics: -Adrenaline (Uses)-Dopamine- Amphetamine (Uses).

3-Sympathetic Depressants:-Selective alpha1 blockers (Prazosin).

-Central alpha2 agonists: Alpha methyldopa-Clonidine.-Beta Blockers.

2-A.N.S.

All except Anti-arrhythmic drugs. 3-C.V.S.Thiazides-Loop diuretics-Potassium sparing diuretics. 4-Diuretics

1-Bronchial asthma.2-Acetylcysteine (Mucolytic).

5-Respiration

1-Antihistaminics.2-Serotonin agonists and antagonists.

3-Prostaglandins.

6-Autacoids

1-Anticoagulants.2-Antiplatelets.

3-Antihyperlipidemics (Statins-Fibrates).

7-Blood

1-Peptic ulcer.2-Antiemetics and Prokinetics.

3-Physical purgatives: Bulk and Lubricant.

8-G.I.T.

1-Opioid Analgesics: Morphine-Codeine-Meperidine-Fentanyl.2-NSAIDs: Salicylates-Paracetamol.

3--Gout.4- Benzodiazepines

5-Antiparkinsonians: L-dopa-Bromocryptine.6-Antiepileptics: Phenytoin-Carbamazepine-Valproate.

9-C.N.S.

1-Glucocorticoids.2-Antidiabetics.

3-Oral Contraceptives.4-Antithyroid drugs.

10-Endocrine

1-B-Lactam Antibiotics:-Penicillins-Cefalosporins-Monobactams-Carbapenems. 2-Protein synthesis inhibitors: Aminoglycosides -Macrolides-Clindamycin-

Tetracyclines-Chloramphenicol- Fusidic acid.3- Quinolones.

4-Metronidazole.

11-Chemotherapy

MCQ :

Subjects Chapter1-Pharmacokinetics:

-Transmembrane movement of drugs.-Factors affecting absorption.

-Metabolism (Biotransformation).-Excretion.

2-Pharmacodynamics.

1-General:

1-Parasympathomimetics:Choline esters-Pilocarpine.

2-Parasympatholytics: Atropine-Atropine substitutes-Hyoscine.3-Sympatomimetics: Noradrenaline-Isoprenaline-Ephedrine-Vasopressors-Nasal

decongestants-B2 agonists4-Sympatholytics: Non-selective alpha blockers-Yohimbine.

2-A.N.S.:

Cough therapy. 3-Respiration:Histamine-Leukotrienes-Ergot alkaloids and Migraine. 4-Autacoids:

--------------------------------------------------------------------------------------------------- 5-Diuretics:Anti-arrhythmic drugs. 6-C.V.S.:

1-Fibrinolytics.2-Drugs used to treat bleeding (hemostatics and coagulants).

7-Blood:

1-Bz receptor agonists-Buspirone-Chloral hydrate.2-Opioid analgesics: Semisynthetic-Methadone-Propoxyphene-Mixed agonist antagonists.

3-NSAIDs other than Salicylates and Paracetamol.4-Antiepileptic drugs: Ethosuximide.

5-Antiparkinsonian drugs: MAO-B inhibitors-COMT inhibitors-Amantadine-Anticholinergics-Drugs contraindicated in Parkinsonism.

6-Antidepressants and Lithium7-Antipsychotics.

8-CNS stimulants: Methylxanthines.

8-C.N.S.:

1-Other purgatives.2-Emetics.

3-Treatment of: Ulcerative colitis-Diarrhea-Colics.

9-G.I.T.:

1-Mineralocorticoids-Adrenostatics.2-Calcium homeostasis.

3-Glucagon.4-Sex hormones (Estrogen-Progestogens)-Antiestrogens (SERMs).

5-Thyroid hormones.

10-Hormones:

1-Vancomycin. 2-Teicoplanin.3-Sulfonamides-Trimethoprim-CoTrimoxazole.

4-Anti-T.B. drugs. 5-Antiviral drugs. 5-Antifungal drugs. 6-Praziquantel.

11-Antibiotics:

:

Day 1 (4 June): General Pharmacology Clinical Pharmacology.Day 2 (5 June): CNS.

Day 3 (6 June): Hormones.Day 4 (7 June): Antibiotics.

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Day 5 (8 June): Blood- GIT.Day 6 (9 June): CVS-Diuretics

Day 7 (10 June): ANS-Respiration-Autacoids.Day 8 (11 June): Revision of CNS, GIT, and General.

Day 9 (12 June): Revision of Hormones, Blood, ANS, and Respiration.Day 10 (13 June): Revision of Antibiotics, CVS, Diuretics, and Autacoids.

14 and 15 June: Clinical pharmacology + MCQ revision.

Important notes:1-This is not an obligatory schedule, you can make your own schedule.

2-In any schedule you should leave the last 2-3 days for revision.3-The most important chapters in the final ESSAY AND MCQ exams-according to the marks are

CNS, CVS, CHEMOTHERAPY, and ENDOCRINE.4-Do not forget that there will be a 10 mark question about GENERAL PHARMACOLOGY in

paper 1 (essay exam).5-Try to READ the MCQs in the departments book after studying each chapter, especially in

second term chapters (about 70-80% of MCQs will be about second term chapters; mainly on CNS, Chemotherapy, and Endocrine).

6- Please DO NOT TEST YOURSELF, JUST READ AND UNDERSTAND THE ANSWERS.7-In paper (1) take good care of the time, each of the 8 questions should not take more than 15

minutes.8-The form of your exam is very similar to the exams of the last 3 years, so please take a look

at these exams in the department book of MCQ (Question Bank).

.

General Pharmacology1-Effect of pH on oral absorption and renal excretion

The presence of acidic drugs as salicylates and barbiturates- in acidic medium as the stomach and urine increases the unionized form of the drug which is lipid soluble (lipohilic), but the

presence of acidic drugs in alkaline medium as the small intestine increases the ionized form which is lipid insoluble (hydrophilic) leading to "ion trapping".

On the other hand; the presence of basic drugs as ephedrine and amphetamine- in acidic medium increases the ionized form (ion trapping) and their presence in alkaline medium

increases the unionized form. 1-Gastric acidity increases oral absorption of acidic drugs as salicylates (aspirin) and barbiturates

(phenobarbitone).2-Intestinal alkalinity increases oral absorption of basic drugs as ephedrine and amphetamine.3-Acidifation of urine (e.g. by ammonium chloride or vitamin C) increases excretion of basic

drugs (ion trapping) but reduces excretion of acidic drugs.4-Alkalinization of urine (e.g. by sodium bicarbonate) increases excretion of acidic drugs (ion

trapping) but reduces excretion of basic drugs.

2-First order and Zero order Kinetics

Zero order kinetics First order kinetics1-A constant amount (number of moles) is

eliminated / unit time.

2-The rate of elimination is not proportional to the concentration of the drug.

3-Drug disappearance curve is non-linear.

4- t1/2 is variable, it increases with the dose (plasma concentration of the drug).

5-AUC is not proportional to the drug concentration.

6-The drug does not necessarily reach Css after 4-5 t1/2, the drug may cumulate leading to toxicity.

7-Saturation of enzymes or carriers responsible for drug elimination.

8-Examples: large doses of aspirin, phenytoin, and alcohol.

1-A constant percent (proportion-fraction) of the drug is eliminated / unit time.

2-The rate of elimination is proportional to the drug concentration.

3-Drug disappearance curve is linear.

4- t1/2 is constant whatever the dose (plasma concentration of the drug).

5-Area under the plasma concentration/ time curve (AUC) is proportional to the drug concentration.

6-Steady state concentration (Css) is reached after 4-5 t1/2 of repeated drug intake at regular intervals.

7-No saturation of enzymes or carriers responsible for drug elimination.

8-Examples: all drugs, including small doses of aspirin, phenytoin, and alcohol.

3-Factors affecting oral absorption:A-Factors related to the drug:

1-Lipid solubility (lipid/ water partition coefficient): the higher the lipid solubility (the higher the lipid/ water partition coefficient) the more the absorption of the drug.

2-Degree of ionization: the more the unionized form of the drug (lipophilic form) the more the absorption.

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3-Valency: Ferrous salts are better absorbed than the Ferric salts.4-Nature of the drug: inorganic drugs are better absorbed than organic.

5-Drug formulation: Paracetamol has a rapid rate of dissolution and is rapidly absorbed.

B-Factors related to the patient:1-Surface area of absorbing surface: drugs are mainly absorbed from the small intestine due to

very large surface area (1000 times that of stomach due to the presence of microvilli).2-Vascularity of absorbing surface: drugs are mainly absorbed from the small intestine due to

very high vascularity.3-State of general circulation: drug absorption is impaired in shock.

4-State of health of absorbing surface: oral drug absorption is reduced in gastritis and malabsorption syndrome.

5-Gut motility and rate of drug dissolution: prokinetic drugs as metoclopramide increase gut motility and accelerate gastric emptying and accordingly increase absorption of rapidly

disintegrated drugs as paracetamol but decrease absorption of slowly disintegrated drugs as digoxin. Atropine slows gut motility and delays gastric emptying and has opposite actions

compared to metoclopramide. 6-Gut pH : acidic drugs: weak acidic drugs as aspirin and barbiturates are better absorbed in the

acidic medium of the stomach, whereas weak basic drugs as ephedrine and amphetamine are better absorbed in the alkaline medium of the small intestine.

7-Gut contents: Food decreases absorption of some drugs as ampicillin-Ca2+ in milk and dairy products and in some antacids decreases absorption of tetracyclines-Al3+ and Mg2+ salts in antacids decrease absorption of tetracyclines and fluoroquinolones-Tetracyclinesdecrease absorption of Ca2+ and iron-Grape fruit inhibits P-glycoprotein leading to increase in oral

absorption-Tea contains tannic acid which decreases oral iron absorption and may lead to iron-deficiency anemia.

8-First pass effect:a-Gut first pass effect: gastric acidity destroys some penicillins as benzyl penicillin G (acid-

sensitive penicillins)-Proteolytic enzymes destroy polypeptide hormones as insulin-Gut mucosa metabolizes some drugs as chlorpromazine and alpha-methyl dopa.

b-Hepatic first pass effect: Propranolol and nitroglycerin are extensively metabolized by the liver, this can be avoided by increasing the oral dose (oral dose is much higher than dose given

IV or SL).Lidocaine (antiarrhythmic) is almost completely metabolized by the liver, so it is given only IV

in treatment of ventricular arrhythmias.9-Specific factors: intrinsic factor is essential for oral absorption of B12.

4-Bioavailability:Definition: the fraction (percent or proportion) reaching the systemic circulation

chemically unchanged following administration by any route.Factors affecting oral bioavailability: = Factors affecting oral absorption.

Calculation of oral bioavailability: AUCoral

Oral Bioavailability= X 100 AUCIV

N.B.: IV bioavailability = 100%, but oral bioavailability is variable.(Bioequivalence and Therapeutic equivalence: see Applied Medical Pharmacology book).

5-Adverse and toxic effects of drugs including types of Tolerance

See "Applied Medical Pharmacology" book, volume I.

6-Factors affecting the dose and action of drugsSee "Applied Medical Pharmacology" book, volume I.

7-Types of AntagonismSee Drug Interactions ((DI) in Applied Medical Pharmacology book, volume I.

Autonomic Nervous System

ParasympathomimeticsAnticholinesterases

1-Organo-Phosphorous Compounds (OPC) Poisoning7

Causes:1-Occupational: inhalation or skin contamination during spraying insecticides as parathion and

malathion by farmers.2-Accidental ingestion of insecticides or contaminated fruits and vegetables.

3-Suicidal ingestion of insecticides.4-Exposure to war gases as sarin, tabun, and soman.

Mechanism of OPC:OPC bind to the esteratic site of acetylcholinesterase, first by a loose bond, but soon the bond

becomes covalent causing irreversible inhibition of the enzyme (aging of the enzyme), leading to accumulation of endogenous acetylcholine. Acetylcholine over-activates cholinergic receptors

(Muscarinic and Nicotinic) both peripherally and centrally.Clinical Manifestations:

1-Muscarinic effects: bradycardia-hypotension-increased bronchial secretion-bronchospasm-salivation-lacrimation-excessive sweating-miosis-abdominal cramps, colics, diarrhea-involuntary

passage of stools and urine.2-Nicotinic effects: twitches and fasciculations of skeletal muscles followed by flaccid paralysis

of skeletal muscles which may cause death due peripheral respiratory failure.(N.B.: stimulation of sympathetic ganglia may lead to tachycardia and hypertension in some

cases).3-CNS effects: headache, dizziness, tremors, anxiety, confusions, convulsions, coma, and death

due to depression of R.C. (central respiratory failure).Treatment:

A-General supportive treatment:1-Endotracheal intubation and oxygen.

2-Position: comatose patient is kept in lateral position, head down, and neck extension.3-Decontamination:

In case of skin contamination: remove contaminated clothes and wash the skin with soap and water.

In case of oral ingestion: gastric lavage within 1-2 hours of ingestion, and activated charcoal to adsorb the poson and reduce systemic absorption.

N.B.: decontamination is performed after the patient is fully stabilized and not immediately after admission.

B-Specific antidotal treatment:1- AtropineIV (bolus followed by infusion):

Atropine is a competitive antagonist with acetylcholine at M-receptors (not N-receptors) both peripherally and centrally. Atropine is given until the following

target end-points are achieved:Tachycardia: heart rate over 80 beats / minute.

Mydriasis (dilted pupils). Sweating (dry axillae).

A.B.P. (diastolic BP over 80 mmHg.).Bronchial secretions (clear chest with absence of wheezes).

2-Oximes (cholinesterase reactivators):Pralidoxime is the most commonly used oxime.

Oximes bind to the anionic site of cholinesterase and attract OPC leading to free enzyme.Oximes should be given early before aging of the enzyme.

The main advantage over atropine is restoration of skeletal muscle strength and improvement of diaphragmatic weakness.

3-Benzodiazepines: Diazepam IV and other benzodiazepines are given to control CNS stimulation as convulsions

(seizures) due to OPC or sometimes due to atropine therapy.

2-Reversible Anticholinesterases (Carbamates)

2- Neostigmine 1- PhysostigmineSynthetic.

Carbamate-quaternary ammonium.

-Poorly absorbed orally.-Poorly passes B.B.B.

-As physostigmine.

As physostigmine.

-Muscarinic actions (by accumulated acetylcholine).

-Nicotinic actions (by accumulated acetylcholine).

-Direct skeletal muscle stimulation.-No CNS actions.

1-Diagnosis and treatment of Myasthenia gravis (atropine should

be given before neostigmine).2-Treatment of poisoning by curare

and other competitive neuro-muscular blockers (atropine should

be given before neostigmine).3-Treatment of peripheral

symptoms of acute atropine poisoning.

4-Non-obstructive post-operative urine retention.

5-Non-obstructive post-operative paralytic ileus.

6-PAT.7- Glaucoma.

Natural: plant origin.Carbamate-Tertiary amine.

-Well absorbed orally.-Penetrates B.B.B.

-Hydrolyzed by (substrate of) cholinesterase.

Binds reversibly to both anionic and esteratic sites of cholinesterases

preventing hydrolysis of endogenous acetylcholine.

-Muscarinic actions (by accumulated endogenous acetylcholine).

-Nicotinic actions (by accumulated endogenous acetylcholine).

-CNS action: stimulation, which may lead to convulsions.

1-Local uses in the eye:- Glaucoma.

- To counteract mydriatics-Alternatively with mydriatics to cut

recent adhesions in iritis.2-Treatment of acute atropine poisoning

especially if CNS manifestations are present (however physostigmine may be dangerous as it causes CNS stimulation

itself).3-Treatment of Alzheimer's disease

(dementia).

1-Source:2-Chemistry:

3-Pharmacokinetics-Absorption:

-Distribution:-Fate:

4-Mechanism of action:

5-Pharmacological actions:

6-Therapeutic uses:

9

As physostigmine but no CNS

manifestations.

As physostigmine (except parkinsonism).

Manifestations: as physostigmine except CNS Treatment: stomach

wash and atropine.

Bradycardia-hypotension -bronchospasm and bronchial secretion- HCl secretion.-CNS

stimulation (convulsions).

Bradycardia-hypotension-bronchial asthma-peptic ulcer-hyperthyroidism-

parkinsonism.

Manifestations:-Muscarinic: bradycardia-hypotension,

bronchospasm, miosis.-Nicotinic: twitches of skeletal muscles.

-CNS: convulsions, coma, death to depression of R.C

Treatment:1-Stomach wash.

2-Artificial respiration.3-Specific antidote= atropine.

4-Anticonvulsants.

7-Adverse effects:

8-Contraindications:

9-Acute toxicity:

Sympathomimetics1-Adrenaline (Epinephrine)

*Mechanism of action:Direct agonist that stimulates (activates) all types of adrenergic receptors: all receptors (1, 2,

3), and all receptors (1, 2).*Pharmacological actions:

A-Local actions:

1-Eye: decongestion and reduction of IOP (1), but no mydriasis except in cases of supersensitivity as glaucoma, pancreatitis.

2-Bronchi: bronchodilatation (2) and decongestion (1).3-Skin and mucous membranes: decongestion, hemostatsis, and prolongation of the duration of

local anesthesia and decrease of systemic effects. All these actions are due to V.C. (1).B-Systemic actions:

I-CVS:1-Heart: adrenaline increases all cardiac properties (1) including: heart rate (positive

chronotropic)-conductivity (positive dromotropic)-contractility (positive inotropic)-excitability-rhythmicity. Adrenaline also increases cardiac output and myocardial oxygen

demands.2-Blood vessels: V.C. of blood vessels of skin and mucous membranes (1) but vasodilatation of

coronary blood vessels and skeletal muscle blood vessels (2)3-Arterial blood pressure (ABP): adrenaline elevates ABP (pressor effect)

elevates systolic BP due to increase in cardiac output mainly-the effect on diastolic BP is variable: in small doses there is reduction in DBP due to vasodilatation of skeletal muscle

blood vessels, but with higher doses there is vasoconstriction especially in skin and mucous membrane blood vessels and DBP may rise-finally adrenaline markedly increase

pulse pressure.Adrenaline reversal: adrenaline elevates ABP but when given after alpha blockers as

phentolamine, adrenaline decreases ABP. This is due to the unopposed action of adrenaline on 2 receptors leading to vasodilatation and hypotension.

II-Smooth muscle fibers:1-Bloov vessels: see before.

2-Eye: active mydriasis due to stimulation of 1 receptors in dilator pupillae muscle.3-Bronchi: bronchodilatation (2).

4-GIT: relaxation of the wall ( and ) and contraction of sphincter (1).5-Urinary bladder: relaxation of the wall=detrusor muscle (2) and contraction of the sphincter

and trigone (1) leading to urine retention.6-Male sex organs: ejaculation of semen (1).

7-Uterus: variable action but adrenaline relaxes the uterus in human females in late pregnancy and during labor (2).

8-Pili-erector muscle: contraction (1).9-Nictitating membrane in cats: contraction (1).

III-Exocrine glands:

1-Salivary glands: thick viscid saliva.2-Sweat glands: adrenaline increases sweating from apocrine (non-thermoregulatory) sweat

glands in palm and sole (1), but has no effect on eccrine (thermoregulatory) sweat glands which contain M3 receptors and not 1.

IV-CNS: adrenaline poorly penetrates BBB so it causes mild CNS stimulation causing tremors, irritability, and anxiety (1).

V-Metabolic actions: 1-Calorigenic action: adrenaline increases BMR, oxygen consumption, and heat production.

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2-Hepatic glycogenolysis leading to hyperglycemia (2).3-Skeletal muscle glycogenolysis leading to increase in blood lactate (2).

4-Hypokalemia due to increase in K+ uptake by skeletal muscles (2).5-Lipolysis and elevation of free fatty acids in blood (1 and 3).

VI-Skeletal muscles:Vasodilatation, glycogenolysis, increased K+ uptake, and tremors (all action are mediated by 2

stimulation).VII-Anti-allergic action:

Adrenaline is the physiological antagonist of histamine; that is why adrenaline is life saving in anaphylactic shock.

Contraindications Adverse Effects1-Tachyarrhythmia.

2-Pulmonary embolism.3-Thyrotoxicosis.

4-With halothane.

5-With digitalis.6-Angina pectoris (ischemic heart

disease=coronary heart disease).7-Hypertension.

8-Severe hypertension if adrenaline is given with non-selective blockers as

propranolol.

9-Gangrene if added to L.A. in fingers and toes, and during circumscision.

10-With MAO inhibitors, ganglion blockers, cocaine, guanethidine, and

reserpine.11-Hemorrhagic shock.

1-Tachycardia, palpitations, and arrhythmia (treated by blockers as propranolol). These adverse effects are particularly more dangerous

in thyrotoxicosis, pulmonary embolism, and when adrenaline is given with digitalis or with halothane (an inhalation general anaesthetic

which sensitizes the heart to catecholamines) as serious ventricular arrhythmias may occur as ventricular fibrillation (V.F.).

2-Increased cardiac work and precipitation of anginal attacks.

3-Elevation of A.B.P. and may cause cerebral hemorrhage in hypertensive patients.

4-Gangrene if added to L.A. in fingers and toes, and during circumscision (treated by 1 blockers).

5-Weak CNS stimulation: anxiety, headache, and tremors.

6-Lacrimation, irritation, and pigmentation of the eye when applied locally for long time.

7-Supersensitivity occurs with MAO inhibitors, ganglion blockers, cocaine, guanethidine, and reserpine.

*Drug interactions:1-With general anesthesia as halothane sensitization of the heart to catecholamines

arrhythmias (treated by -blockers).2-With LA as procaine prolongation of action of L.A., reduction of systemic toxicity of LA as

convulsions, and hemostasis.3-With cocaine severe V.C. which may lead to gangrene.4-With LA in fingers, toes, and circumscision gangrene.

5-With non-selective -blockers as propranolol severe hypertension due to unopposed 1 stimulation by adrenaline.

6-With digitalis ventricular arrhythmia which may be fatal.7-With MAOIs, reserpine, guanethidine supersensitivity.

*Therapeutic Uses (Indications):A-Local uses:

1-With LA: to prolong the action and reduce systemic toxicity of LA (except in fingers, toes, and circumscision).

2-Open angle glaucoma: adrenaline is given as eye drops to reduce I.O.P., but Dipivefrin (prodrug converted into adrenaline) is preferred as it more lipophilic, more diffusible, and

less toxic.3-Hemostatic as in cases of epistaxis, given as nasal pack (except in hypertension).

4-Decongestion of mucous membranes of eyes and nose.

B-Systemic uses: 1-Anaphylactic shock: SC adrenaline is life-saving and the drug of choice due to its anti-allergic

action (adrenaline is the physiological antagonist of histamine).2-Cardiac arrest: adrenaline is given intra-cardiac for cardiac resuscitation.

3-Contraction ring of the uterus (B2 agonists as Ritodrine and Isoxsuprine are preferred).4-Acute bronchial asthma: adrenaline is given S.C. (SABA as Salbutamol and Terbutaline are

preferred).5-Hypoglycemic coma: adrenaline is given S.C. (I.V. glucose 50 mL 50% is preferred).

2-DOPAMINE.*Pharmacokinetics:

1-Absorption: not absorbed orally, given by I.V. drip.2-Distribution: poor passage across B.B.B.

3-Fate: metabolized by COMT and MAO (mainly) into homovanilic acid (HVA) which is excreted in urine.

*Pharmacodynamics:-Mechanism of action: direct stimulation of specific dopaminergic (D1) receptors, 1-receptors,

and 1-receptors according to the rate of infusion.- Pharmacological actions: depend on the rate of infusion as follows:

1-Slow rate of infusion (2.5-5 g/kg/minute): dopamine stimulates D1-receptors in blood vessels leading to V.D. especially renal, mesenteric, and coronary blood vessels, which increases blood

flow to the vital organs as the kidney.2-Moderate rate of infusion (5-10 g/kg/minute): dopamine stimulates cardiac 1-receptors

leading to increase in COP.3-Rapid rate of infusion (> 10 g/kg/minute): dopamine stimulates 1-receptors leading to V.C.,

increase in TPR and ABP.(Renal V.C. leads to acute renal failure and death).

*Therapeutic uses:1-Shock (hypovolemic, cardiogenic, and endotoxic): dopamine is given at a slow-moderate rate

to increase tissue perfusion and blood flow to vital organs as the kidney, and to increase COP and accordingly urine output and ABP especially systolic - increase.

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Blood volume should be corrected, e.g. by blood transfusion, before administration of dopamine "fill up then open up".

2-Heart failure: especially acute and resistant heart failure, dopamine is given in a moderate infusion rate.

*Adverse effects:1-Tachycardia, palpitation, arrhythmias (ventricular), and anginal pains due to direct and reflex

1-stimulation (treated by 1- blockers).2-Hypertension if given with MAO inhibitors or in rapid infusion rate due to 1-stimulation

(treated by 1- blockers).3-Nausea and vomiting (due to stimulation of D2-receptors in C.T.Z.)

4-weak CNS actions as headache and anxiety.*Important notes:

1-Dopamine is not effective in treatment of Parkinsonism as it cannot pass B.B.B., but its precursor L-dopa can pass easily and is converted into dopamine by dopa decarboxylase in CNS.

2-Dopamine receptor subtypes are D1, D2, D3, D4, and D5 (see CNS).3-To antagonize the pharmacological actions of dopamine we have to block the following

receptors:-D1- receptors: by dopaminergic antagonists as "haloperidol".

-1- receptors by: 1-blockers as" propranolol".-1- blockers by: 1-blockers as "phentolamine".

4-The dose of dopamine should be reduced in patients treated with MAO inhibitors to avoid elevation of ABP (explain).

5-Precautions during infusion: monitor heart rate by ECG -monitor ABP and urine volume -replace fluids before dopamine -avoid extravasation-stop infusion gradually.

3-DobutamineSource: synthetic. Chemistry: catecholamine.

Pharmacokinetics: Given by I.V.infusion-Does not cross BBB-metabolized by MAO. Pharmacodynamics:

1-Direct selective B1 agonist.2-Positive inotropic with much less increase in heart rate (more inotropic than chronotropic).

3-Almost no effect on T.P.R., i.e. no vasoconstriction (no action on alpha1) or vasodilatation (no effect on D1).

Therapeutic uses:1-Cardiogenic shock as due to acute myocardial infarction.

2-Acute heart failure (especially with hypotension).Adverse effects:

1-Tachycardia, palpitation, arrhythmia, angina pains if given in large doses (less than dopamine).2-Nausea and vomiting.

Summary of Catecholamines:Isoprenaline Dobutamine Dopamine Noradrenalin

e Adrenaline

Synthetic. Synthetic. Natural. Natural. Natural. Source:

as adrenaline. as adrenaline. as adrenaline. as adrenaline. *Catechol.*L-isomer is more active.

*Unstable.

Chemistry

as adrenaline. as adrenaline. as adrenaline. as adrenaline. *Not absorbed.*Poor passage

across BBB.*Metabolism by

MAO and COMT-uptake.

Kinetics:

1-S.L.2-Inhalation.

3- I.V. infusion (drip).

I.V. infusion (drip).

I.V. infusion (drip).

I.V. infusion (drip).

1-S.C.2-Inhalation.3-Eye drops.

4-Nasal pack.5-Intracardiac.

Route(s):

1,2,3 no selective 1no D or .

1, 1.D1, Mainly 1 weak 1 no 2.

All and . Agonist on:

H.R.both directly and

reflexly-A.B.P. (diastolic-

variable effect on systolic-

pulse pressure).

Minimal effect(more ino- than chrono- and no effect on blood

vessels).

H.R. (slow-moderate rate)-

A.B.P (rapid rate).

H.R. (reflex)-A.B.P. (both

systolic and diastolic-no

effect on pulse pressure-

abolished after -blockers).

H.R. -A.B.P.(systolic-

variable effect on diastolic-pulse

pressure-reversed after -blockers).

Action on H.R. and

A.B.P.:

1-AV block.2-Asthma.

1-Cardiogenic shock (due to

myocardial infarction).

2-Heart failure.

1-Shock.2-Heart failure.

To elevate A.B.P. in severe

hypotension.

1-Anaphylactic shock.

2-Cardiac resuscitation.3-With L.A.

4-Decongestant5-Hemostatic.

6-Asthma.7-Glaucoma.

8-Contraction ring of uterus.

Uses:

Comparison between adrenaline and Amphetamine:Amphetamine Adrenaline

Chemistry: Non-catecholamine.Mechanism of action:

Indirect acting sympathomimetic by releasing noradrenaline from adrenergic neurons.

*Therapeutic Uses (Indications):

Chemistry: Catecholamine.Mechanism of action:

Direct acting sympathomimetic by stimulation of all adrenergic receptors (Beta1,2,3 and Alpha1,2).

*Therapeutic Uses (Indications):

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Uses are due to its CNS actions:I-Psychic:

1-Delays mental and physical fatigue.2-Elevates mood in psychic depression, Parkinsonism,

alcohol withdrawal in chronic alcoholism.3-Lightens sleep in narcolepsy and nocturnal enuresis.4-Attention Deficit Hyperkinetic Disorder in children

(ADHD) to calm the patient and increase attention span.II-Anorexigenic: in treatment of obesity (not preferred due

to liability to addiction.III-Analeptic: to stimulate vital medullary centers (R.C.

and V.M.C) in cases of acute toxicity by morphine or barbiturates.

Adverse effects and Toxicity: As adrenaline+ psychic and physical dependence

(addiction) + Marked CNS manifestations as insomnia, anxiety, psychosis (schizophrenia), and anorexia + Acute

toxicity: Manifestations: hypertension (treated by alpha blockers as

phentolamine)-psychosis (treated by antipsychotics as chlorpromazine) and

convulsions (treated by anticonvulsants as diazepam)

Contraindications:As adrenaline + CNS symptoms as insomnia, anxiety,

psychosis, and anorexia.

A-Local uses:1-With LA: to prolong the action and reduce systemic toxicity of LA (except

in fingers, toes, and circumscision).2-Open angle glaucoma: adrenaline is given as eye drops to reduce I.O.P.,

but Dipivefrin (prodrug converted into adrenaline) is preferred as it more lipophilic, more diffusible, and less toxic.

3-Hemostatic as in cases of epistaxis, given as nasal pack (except in hypertension).

4-Decongestion of mucous membranes of eyes and nose.B-Systemic uses:

1-Anaphylactic shock: SC adrenaline is life-saving and the drug of choice due to its anti-allergic action (adrenaline is the physiological

antagonist of histamine).2-Cardiac arrest: adrenaline is given intra-cardiac for cardiac resuscitation.3-Contraction ring of the uterus (B2 agonists as Ritodrine and Isoxsuprine

are preferred).4-Acute bronchial asthma: adrenaline is given S.C. (SABA as Salbutamol

and Terbutaline are preferred).5-Hypoglycemic coma: adrenaline is given S.C. (I.V. glucose 50 mL 50% is

preferred).Adverse effects:

1-Elevation of arterial blood pressure which may lead to cerebral hemorrhage in hypertensive patients.

2-Gangrene if given with L.A. in fingers and toes, and during circumscision.3-Cardiac manifestations: tachycardia, arrhythmia, palpitations, and angina

pains in patients with ischemic heart disease.4-Cardiac arrhythmias (ventricular arrhythmia up to V.F.) if given with

general anesthesia (G.A.) as halothane (treated by beta blockers).5-Weak CNS manifestations as irritability, tremors and insomnia.

6-Exaggerated action if given in thyrotoxic patients, with MAO inhibitors or sympatholytics.

Contraindications:1-Hypertension.2-Angina pectoris 3-Arrhythmia.4-Thyrotoxicosis.5-With: L.A. in fingers, toes,

circumscision- halothane-sympatholytics-MAOIs.

Sympathetic Depressants (Sympatholytics)I-Central Alpha2 Agonists

1-Clonidine*Pharmacokinetics:

- Well absorbed orally. Clonidine can be given as a transdermal patch.- Passes B.B.B.

- Partly metabolized and partly excreted unchanged in urine.*Pharmacodynamics:

-Mechanism of action: direct agonist on 2-receptors centrally and peripherally (presynaptic).-Pharmacological actions:

1- Stimulation of central 2-receptors inhibition of V.M.C and C.A.C.

sympathetic outflow from CNS V.D. (and decrease in TPR) and bradycardia (and decreased C.O.P.) and accordingly decrease ABP.

2- Stimulation of presynaptic 2-receptors release of noradrenaline from adrenergic neurons V.D. and decrease in TPR, Heart rate and COP (bradycardia is due to reduced

sympathetic tone and predominance of vagal tone).3-Stimulation of 2 receptors in kidneyRenin release.

Both central and peripheral actions decrease A.B.P.4-blocks postsynaptic 1 receptors on blood vessels V.D.

5-Anti-serotonin action.*Therapeutic uses:

1- Treatment of hypertension, including hypertension with renal impairment (clonidine increases renal blood flow) and high renin hypertesion.

2- Prophylaxis of migraine headache.3- Control of withdrawal symptoms in morphine and nicotine addicts.

4- Analgesic (given intrathecal).*Adverse effects:

1- Rebound hypertension if clonidine is stopped suddenly. This is due to upregulation of 1-receptors with chronic use of clonidine, it may be accompanied by tachycardia (due to

upregulation of 1-receptors). Rebound hypertension can be treated by re-administration of clonidine (to reduce noradrenaline release) or by 1-blockers -blockers but never use non-

selective -blockers without 1-blockers to avoid more hypertension by unopposed 1-stimulation.

2- Sedation and drowsiness due to decreased sympathetic activity.3- Dry mouth (may be due decreased acetylcholine release from cholinergic neurons to salivary

glands).4-Bradycardia (see before).

*Drug interaction:Tricyclic antidepressants (TCAs) inhibit neuronal reuptake of noradrenaline (cocaine-like action)

and antagonize the effect of clonidine.

N.B. Apraclonidine and brimonidine are 2 agonists used in treatment of glaucoma (as eye drops), whereas tizanidine is a central 2 agonist used as central skeletal muscle relaxant.

2-Alpha-Methyl Dopa* Pharmacodynamics:

Mechanism of action: 1-Alpha-methyl dopa competitively inhibits dopa decarboxylase enzyme leading to inhibition of

synthesis of noradrenaline (from dopamine) in adrenergic neurons.2-Alpha- methyl dopa itself is converted-by dopa decarboxylase-into alpha-methyl dopamine

then into alpha-methyl noradrenaline. Alpha-methyl noradrenaline acts as 2-agonist, stimulating 2-receptors both centrally and peripherally.

Pharmacological actions:I-CVS:

1-Stimulation of central 2-receptors decreases sympathetic discharge from CNS leading to vasodilatation and TPR (due to inhibition of VMC), bradycardia and COP, both

actions ABP.

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2-Stimulation of peripheral pre-synaptic 2-receptors leading to decrease in release of noradrenaline release from adrenergic neurons, and this also leads to vasodilatation and

TPR, bradycardia and COP, both actions ABP.

3-Stimulation of 2-receptors in JGA in the kidney decreases renin release and further ABP.4-Vadodilatation of renal blood vessels and increase in RBF.

II_CNS:1-Inhibition of VMC.

2-Sedation and drowsiness.3-Night mares and psychic depression (due to synthesis of serotonin, noradrenaline and

dopamine).4-Iatrogenic Parkinsonism may occur with large doses (due to synthesis of dopamine in basal

ganglia).5-Hyperprolactinemia (due to synthesis of dopamine in hypothalamus).

III-Parasympathetic predominance:1-Bradycardia COP.

2-Increase in GIT secretion and motility leading to diarrhea.3-Miosis and IOP.

*Adverse effects:I-CNS:

1-Sedation, drowsiness, night mares, depression (due to deficiency of monoamines). 2-Hyperprolactinemia (gynecomastia in males, galactorrhea-amenorrhea in females).

3-Parkinsonism.II-Sympatholytic actions and parasympathetic predominance:

1-Postural (orthostatic) hypotension (due to venodilatation).2-Nasal congestion (stuffiness).

3-Bradycardia.4-Diarrhea and colics.

III-Hypersensitivity (Type II) reactions:1-Hepatitis and hepatotoxicity.

2-Hemolytic anemia (diagnosed by positive Coomb's test).3-Bone marrow depression.

IV-Others: Fever (Type I hypersensitivity reaction)-Salt and water retention.*Contraindications:

1-Hypersensitivity (allergy).2-Liver diseases.3-Parkinsonism.

4-Psychic depression.5-Bradycardia.

*Indications: Treatment of mild and moderate hypertension especially in pregnancy (drug of choice) and in hypertension with renal impairment (as it RBF).

It can be also given IV in emergency hypertension.II-Selective 1-blockers (Prazosin)

Mechanism of action:1-Competitive selective 1-blocker.

2-Inhibits phosphodiesterase enzyme (PDE) both c-AMP (which causes V.D. and tachycardia) and c-GMP (which causes V.D. and bradycardia).

Pharmacological actions:1- V.D. of both arteries (TPR= afterload) and veins (venous return= preload) by blocking post-

synaptic 1 receptors, and increase c-AMP and c-GMP. V.D. leads to A.B.P.2- No (or minimal) reflex tachycardia because:

-No 2-blocking action and no increase in noradrenaline release from adrenergic neurons innervating the heart.

-Inhibition of PDE leading to increase in both c-AMP ( heart rate) and c-GMP (heart rate). 3- Relaxation of urinary bladder sphincter.

Therapeutic uses: 1-Treatment of essential (primary) hypertension (a diuretic may be added on prolonged use).

2-Treatment of congestive heart failure (CHF) as it reduces both preload due to venodilatation and afterload due to arteriodilatation. This increases COP in these patients.

3- P.V.D. as Raynaud's disease.4- Secondary hypertension due to pheochromocytoma (beta blockers may be added)..

5- BPH (Tamsulosin is better because it is a selective 1A blocker ).6-Other use: Rebound hypertension after sudden clonidine cessation-

Hypertensive crisis in depressed patients treated by MAO inhibitors (cheese reaction)-Severe V.C. if extravasation of noradrenaline occurs during IV infusion.

Adverse effects: 1-"First dose phenomenon": severe postural hypotension after the first dose due to potent

venodilatation. It can be prevented by starting treatment with a small dose given at bed time, and then the dose is gradually increased.

2- Nasal congestion.3- Failure of ejaculation.

4- Na+ and water retention due to decreased RBF, corrected by adding a diuretic.5-Headache and dizziness (due to cerebral V.D.).

Question: How to correct hypotension induced by -blockers as phentolamine?Answer: Angiotensin II given by IV infusion (physiological antagonism). Alpha agonists as

phenylephrine and noradrenaline will not effective because alpha receptors are blocked, whereas adrenaline is dangerous because it will stimulate 2-receptors leading to V.D. and more

hypotension.III-eta Adrenoceptor Antagonist s (-Blockers )

*Classification:A-Classification according to selectivity:

1- Non-selective -blockers= First generation -blockers:- They block both 1- and 2-receptors.

- Examples: Propranolol, Pindolol, Oxprenolol, Nadolol, Sotalol, and Timolol.2- Cardioselective -blockers= Selective 1-blockers= Second generation -blockers:

- They block 1-receptors (but if given in large doses or for long periods, they can block 2-receptors because "selectivity is not absolute").

- Examples: Atenolol, Metoprolol, Acebutolol, Bisoprolol, and Esmolol.3--Blockers with additional action= Vasodilator -blockers= Third generation -blockers:

- Labetalol and Carvedilol: they block 1, 2, and 1-receptors. Carvedilol has also an antioxidant action.

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- Celiprolol: blocks 1-receptor and is an agonist (or partial agonist) on 2-receptors.- Nebivolol: blocks 1-receptor selectively and acts as a 2-agonist, and releases nitric oxide (NO)

causing vasodilatation. It is known as "nitrogenic -blocker".- Medroxalol.- Bucindolol.

4- Selective 2-blocker: Butoxamine which has no clinical uses and used only experimentally.B-Classification according to degree of lipid solubility:

Most -blockers are lipophilic drugs, and a few -blockers are hydrophilic drugs as Nadolol, Atenolol, Sotalol.

The differences between lipophilic and hydrophilic -blockers are shown in this table: Hydrophilic -Blockers Lipophilic -Blockers

Incomplete (poor-delayed) oral absorption.

Poorly penetrates B.B.B.weak CNS actions.

Less bound to plasma proteins and less liable to drug interactions.

Mainly excreted slowly unchanged in urine less liable to drug interactions, but we should adjust the dose according

to renal function.

Long, given as single daily dose good compliance.

Nadolol-Atenolol-Sotalol.

Well absorbed orally.

Passes easily B.B.B.marked CNS actions.

Highly bound to plasma proteins drug interactions.

Mainly rapidly metabolized by hepatic microsomal enzymes (HME) drug interactions with HME inducers and

inhibitors. Metabolism is slow in cases of decreased hepatic blood flow, liver

diseases, and if given with HME inhibitors.

Short, requires frequent daily doses poor compliance.

Propranolol-Oxprenolol-Pindolol-Timolol-Metoprolol.

1-Absorption:

2-Distribution:

3-Plasma protein binding:

4-Fate:

5-Duration and t1/2:

6-Examples:

C-Classification according to "Membrane Stabilizing Activity"(MSA):1-Some -blockers have the ability to block Na+ channels leading to an additional antiarrhythmic

action known as "quinidine-like action", and local anaesthetic action. Examples: Propranolol-Metoprolol.

2- Other -blockers do not block Na+ channels and have no MSA. Examples: Nadolol-Atenolol.D-Classification according to "Intrinsic Sympathomimetic Activity"(ISA):

1-Most -blockers are "pure antagonists", i.e. they block -receptors without initial stimulation. Examples: Propranolol- Atenolol- Metoprolol- Nadolol.

2-Few -blockers have partial agonistic activity (P.A.A.), i.e. they stimulate -receptors before blocking them, and are said to have intrinsic sympathomimetic activity (I.S.A.). Examples:

Pindolol- Oxprenolol- Acebutolol.

PROPRANOLOL*Pharmacodynamics:

A-Mechanism of action: Competitive non-selective -antagonist. Propranolol is a pure antagonist (no ISA).

Propranolol also blocks Na+ channels = MSA = L.A. action and antiarrhythmic action (quinidine-like action).

B-Pharmacological actions:1-CVS:

Heart: blocking of 1-receptors leads to:- automaticity= negative chronotropic action (heart rate and may cause bradycardia). The

effect of -blockers on heart rate is more marked during exercise than during rest.-conductivity=negative dromotropic action (conductivity all over the heart including AV

conduction).-excitability.

- myocardial contractility= negative inotropic action.-COP.

-myocardial O2 requirements.-The anti-arrhythmic action of propranolol is due to: 1-blocking action (decreases excitability,

automaticity, and conductivity) + membrane stabilizing activity (MSA) due to Na+-channel block (quinidine-like).

Blood vessels: blocking of 2-receptors in blood vessels leads to initial V.C. especially in skeletal muscles, coronary, and hepatic blood vessels.

ABP:-At the start of treatment of hypertensive patients with propranolol; ABP is not reduced although

propranolol COP, because it causes initial V.C. especially in skeletal muscle blood vessels by blocking 2-receptors.

-After continous treatment with propranolol (at least for 4 weeks); ABP is reduced due to the following mechanisms:

1- COP.2- renin release by blocking 1-receptors in juxta-glomerular apparatus in kidney.

3- noradrenaline release from adrenergic neurons by blocking pre-synaptic -receptors.4- sympathetic outflow from CNS by blocking central 1-receptors (propranolol is "lipophilic").

5- Re-setting of baroreceptors.6- Stimulation of synthesis of vasodilator prostaglandins, as prostacyclin (PGI2) and PGE2.

N.B.: Propranolol and all non-selective -blockers "abolish" the hypotensive action of isoprenaline and "augment" the hypertensive (pressor) action of adrenaline (they have no effect

on the hypertensive action of noradrenaline).2-Bronchi:

Propranolol and all non-selective -blockers induce bronchospasm by blocking 2-receptors in bronchial smooth muscles. This is very dangerous in asthmatic patients as it may precipitate

attacks of asthma.Cardio-selective -blockers are less dangerous but remember that "selectivity is not absolute".

3-Metabolic actions:- lipolysis by blocking 1and 3-receptors and reduces free fatty acids.

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- glycogenolysis by blocking 2-receptors in liver and skeletal muscles. This may be dangerous in case of insulin-induced hypoglycemia.

-Long-term (chronic) use of propranolol may induce atherosclerotic changes as it increases VLDL and LDL and decreases HDL (this is less marked with -blockers having ISA, and with

cardio-selective -blockers).- uptake of K+ by skeletal muscles, and may lead to "hyperkalemia", by blocking 2-receptors in

skeletal muscles.Important Notes:

1- Hypoglycemia=stress sympathetic activity tachycardia and palpitation (1-stimulation), Glycogenolysis and increased blood glucose (2-stimulation), and increased sweating (M3-

stimulation in thermoregulatory sweat glands).2-Propranolol will mask the symptoms of hypoglycemia except sweating (why?). This may lead

to "silent hypoglycemia" and coma in diabetic patients receiving overdoses of insulin or oral hypoglycemic drugs.

4-Eye:- Formation of aqueous humor by blocking -receptors (2 mainly) in ciliary body, and

accordingly decrease IOP.- No change in the size of the pupil and no action on the ciliary muscle.

- Local application of timolol may lead to systemic actions as bradycardia and bronchospasm (how?).

5-CNS actions:- Reduces anxiety by blocking 1-receptors in CNS.

- Reduces tremors mainly by blocking 2-receptors in skeletal muscles and mainly by CNS action (propranolol is lipophilic).

6- Liver:-V.C. of hepatic blood vessels and decreases portal pressure in cases of portal hypertension due

to liver cirrhosis.-Reduction of hepatic blood flow reduces HME activity leading to "non-specific" or "indirect"

HME inhibition which may decrease hepatic metabolism of drugs.

*Thearpeutic Uses of -Blockers:CVS:

1- Prophylaxis of angina pectoris (ischemic heart disease), useful in stable angina and in unstable angina as it decreases cardiac work and myocardial oxygen requirements, but it is

contraindicated in variant=Prinzmetal angina=vasospastic angina which is due to sudden coronary V.C. (due to supersensitive 1-receptors in coronary blood vessels) as it leads to more

V.C. due to "unopposed 1 effect.2-Treatment of essential hypertension (propranolol decreases ABP after prolonged use).

3-Treatment of supra-ventricular tachycardia (as PAT) and ventricular arrhythmias (due to general anaesthesia, digitalis, 1agonists as adrenaline and isoprenaline, acute myocardial

infarction, thyrotoxicosis, and cardiac surgery). (-blockers are "Class II" antiarrhythmic drugs).

4-After acute myocardial infarction (AMI) to decrease size of infarction, treat arrhythmias, decrease cardiac work and myocardial oxygen requirements, and increase survival (decrease

mortality rate).5-Acute dissecting aortic aneurism (with sodium nitroprusside).

6-Obstructive hypertrophic cardiomyopathy= chronic hypertrophic subaortic stenosis (it may increase COP in this case by reducing cardiac muscle spasm).

7-Some -blockers as metoprolol, carvedilol, and bisoprolol are given in small doses (then the dose is very gradually increased) in congestive heart failure. However; -blockers are

contraindicated in "compensated" heart failure when COP is dependent on sympathetic drive on the heart (see CVS pharmacology) and should never be given suddenly or in large doses.

An additional benefit is by renin release and ABP.Liver:

8-To reduce portal pressure in portal hypertension due to bilharzial or alcoholic cirrhosis.Eye:

9-Teatment of glaucoma: Timolol, Betaxolol, Levobunolol, and Carteolol are used. (Timolol may induce bradycardia and bronchospasm in asthmatic patients although it is given as eye drops,

how?).Endocrine:

10- To control CVS symptoms (tachycardia, angina, and arrhythmia) and CNS symptoms (anxiety, tremors and insomnia) of thyrotoxicosis.

Propranolol is the drug of choice because:-Has no ISA.-Passes B.B.B.-Decreases conversion of T4 (active) into T3 (more active), i.e. it

inhibits peripheral deiodination.-Can be given orally (in chronic cases) and I.V. (in thyrotoxic crisis).

11-Treatment of pheochromoctoma but should be combined with 1-blockers, non-selective -blockers should never be used alone (why?).

CNS:12- Prophylaxis of migraine headache.13- Treatment of "situational anxiety".

Skeletal Muscles:14- To control tremors (as essential tremors in old age and Parkinsonism).

Contraindications Adverse Effects1-Bradycardia.

2-AV block.

3-Hypotension.

4-Bronchial asthma.

1-Bradycardia (treated by atropine).

2-Decreases AV conduction and may cause AV block (treated by atropine).

3-Hypotension (no postural hypotension, WHY?).

4-Bronchospasm especially in asthmatics (treated by antimuscarinic drugs as Ipratropium).

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5-Peripheral vascular diseases (PVD) as Raynaud's disease.

6-Prinzmetal (variant or vasospastic) angina.

7-Never use non-selective -blockers ALONE in these conditions (combine with -blockers, or use drugs

blocking both -and -receptors as labetalol).

8-Severe heart failure or if the case is compensated by sympathetic stimulation.

9-Use non-selective -blockers "cautiously"in diabetics treated by insulin or oral hypoglycemics.

10-Severe depression.

11-Never Stop -Blockers Suddenly (Abruptly).

5-Cold extremities, claudication, and fatigue (due to V.C.).

6-V.C. of coronary blood vessels especially in variant angina.

7-Unopposed -effect if propranolol is used alone in pheochromocytoma, rebound hypertension due to sudden

clonidine withdrawal, and cheese reaction more hypertension.

8-Decrease myocardial contractility and may precipitate heart failure.

9-Aggravate insulin-induced hypoglycemia and mask the symptoms=silent hypoglycemia (except sweating).

10-Sexual dysfunction in males (decrease sexual desire due to central effect).

11-Increse in LDL and decrease in HDL causing atherosclerosis (non-selective blockers mainly).

12-Hyperkalemia especially in renal impairment.

13-CNS manifestations: sedation, sleep disturbances, depression (lipophilic blockers).

14-"Rebound" angina, arrhythmia, and even infarction if suddenly stopped after chronic use, due to up-regulation

(and supersensitivity) of 1-receptors.

*Drug Interactions of Propranolol (-Blockers):A-Pharmacokinetic Interactions:

1-Propranolol (and other lipophilic -blockers) are highly bound to plasma proteins and can displace other drugs as digitalis leading to "digitalis toxicity".

2-Propranolol decreases hepatic blood flow and indirectly decreases activity of HME, thus reducing its own hepatic metabolism and of other drugs as lidocaine.

3-HME inducers as nicotine and phenytoin increase hepatic metabolism of propranolol thus reducing its activity (the dose of propranolol should be increased).

4-HME inhibitors as cimetidine decrease hepatic metabolism of propranolol and may lead to marked adverse effects (the dose of propranolol should be reduced).

B-Pharmacodynamic Interactions:

1-Propranolol + digitalis severe bradycardia and AV block.2-Propranolol + verapamil or diltiazem (Ca2+-Channel blockers) severe bradycardia and AV

block.3-Propranolol augments the hypertensive action of adrenaline.

4-NSAIDs as aspirin antagonize the anti-hypertensive action of propranolol because they reduce synthesis of vasodilator prostaglandins and also cause Na+ and water retention.

5-Propranolol augments the insulin-induced hypoglycemia and masks the symptoms.6-Propranolol augments rebound hypertension due to sudden clonidine withdrawal if used alone

(without -blocker).

Cardio-Selective -Blockers:Advantages over non-selective blockers:

1-Allowed in variant angina.2-Allowed in P.V.D.

3-Allowed in bronchial asthma.4-Allowed in D.M. treated by insulin or oral hypoglycemics.

5-Less liable to cause hyperlipidemia.6-Less liable to cause hyperkalemia.

REMEMBER: selectivity is not absolute and it is lost with large doses or long-term therapy.Atenolol:

Similar to nadolol and sotalol:Hydrophilic.No ISA.No MSA.

Metoprolol:Similar to propranolol:

Lipophilic.No ISA.Has MSA.Acebutolol:

Similar to oxprenolol:Lipophilic.Has ISA.Has MSA.

Esmolol:Metabolized very rapidly by RBC esterase, so it has very short duration (ultra-short), given by

IV infusion in emergency arrhythmias.Has no ISA, and no MSA.

-and -Blockers:1 -Labetalol:

Blocks - and 1-receptors in a ratio of 3:1.Less potent than propranolol as -blocker, and less potent than phentolamine as 1-blocker.

Decreases ABP by decreasing both COP and TPR.It causes V.D. and hypotension without reflex tachycardia (why?).

Used in: 1-Essential hypertension, including emergency hypertension.2-Pheochromocytoma (it is used alone).

2-Carvedilol:As labetalol: and 1 blocker + Antioxidant.

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Autacoids: AntihistaminicsNon-Sedating (2nd generation)

Loratadine-Fexofenadine-Cetrizine

Sedating Antihistaminics (1st generation)

Diphenhydramine-Promethazine-Dimenhydrinate-Cyclizine-Meclizine-Clemastine-Hydroxyzine-

CyproheptadinePoor passage across BBB.

As sedating antihistaminics.Pass BBB.

Competitive antagonists with histamine atH1 receptors.

1-Passage across BBB:2-Mechanism of action:

Long duration: 12-24 hours.

1-Antihistaminic and Antiallergic action (as 1st generation).

No (or less) sedation.No antimuscarinic action.

No antiemetic action.

No antiparkinsonian action.No antiserotonin action.

No antiarrhythmic action.No alpha blocking action.

Treatment of allergic reactions (as 1st generation).

Short duration: 4-6 hours.

1-Antihistaminic and Antiallergic action: antagonize the actions of histamine mediated through H1 receptors

on the skin, blood vessels, and smooth muscles.2-Sedating action.

3-Antimuscarinic action (atropine-like action).4-Antiemetic action by blocking H1 and M-receptors in

medullary vomiting center.5-Antiparkinsonian action by blocking M-receptors in

basal ganglia.5-Antiserotonin action by Cyproheptadine.

6-Antiarrhythmic action (Na+ channel block by Antazoline).

7-Alpha blocking action.

1-Treatment of allergic reactions as urticaria, rhinitis, conjunctivitis, common cold (chlorpheniramine), atopic dermatitis, angioedema, and anaphylaxis.

2-Antiemetics in all causes of vomiting including motion sickness (promethazine-diphenhydramine-

dimenhydrinate-cyclizine-meclizine).3-OTC Sleep aids in situational insomnia.

4-Parkinsonism (e.g. diphenhydramine).

1-Sedation and dizziness, excitation may occur and is more common in children.

2-Atropine-like manifestations: dry mouth, constipation, urine retention, IOP.

3-Teratogenicity (Cyclizine and Meclizine are teratogenic in experimental animals as rodents, but not

proved in humans).4-Allergy.

BPH-Glaucoma-Pregnancy-Driving.

3-Duration:

4-Pharmacological actions:

4-Therapeutic uses:

5-Adverse effects:

6-Contraindications:NSAIDs Prostaglandins (PGs)

1-CNS: Analgesic-Antipyretics2-Anti-inflammatory.

3-Iatrogenic Peptic ulcer.

4- RBF Na+ and water retention, and may lead to nephropathy.

5-Antiplatelet action by Aspirin (pediatric dose) by inhibition of

TXA2 synthase.

1-CNS: Algesia-Pyrexia.2-Inflammation.

3-GIT: protect the stomach and duodenum by HCl, mucus, HCO3 (PGE2).4-Renal V.D. and RBF.

5-V.D. by PGI2 and PGE2 or V.C. by PGF2 and TXA2.

6- Platelet aggregation by PGI2 or platelet aggregation by TXA2.

7-Oxytocic action (PGF2 and PGE2).

Actions:

27

6-Tocolytic action.

7-Bronchoconstriction due to shift of arachidonic acid into LT pathway.

8-Premature closure of DA if given in late pregnancy.

8-Bronchodilatation by PGD2 and PGE2, or bronchoconstriction by PGF2

9-Maintain the patency of Ductus Arteriosus (DA) in fetus by PGE2.

10-Induction of ovulation and enhance erection.11- IOP (PGF2).

1-Analgesic in superficial pains2-Antipyretic (non-specific).

3-Antiinflammatory in acute gouty arthritis, rheumatic fever, rheumatoid

arthritis.4-Prophylaxis of thrombo-embolism

by aspirin.5-Tocolytics in premature labor and

dysmenorrhea.6-Obliteration of patent ductus arteriosus (by Indomethacin).

1-Prophylaxis and treatment of iatrogenic ulcer (Misoprostol).

2-Antiplatelet (Epoprostenol).3-Induction of labor and abortion, and to control post-

partum hemorrhage (Carboprost-Dinaprostone).4-Treatment of erectile dysfunction (Alprostadil).

5-Maintain the patency of DA before surgical treatment of congenital heart diseases (Alprostadil).

6-Glaucoma (Latanoprost).

Therapeutic uses:

1-Allergy.2-Peptic ulcer (iatrogenic).

3-Asthmatic attacks in bronchial asthma.

4-Bleeding.5-Teratogenicity.

6-Premature closure of ductus arteriosus.

7-Delayed labor and increase post-partum hemorrhage.

1-Diarrhea and colics, bone pains (Misoprostol).2-Anaphylactic shock and CVS collapse (Carboprost

intra-amniotic for induction of abortion).3-Abortion (Misoprostol in peptic ulcer).

4-Short duration.5-Expensive.

Adverse effects:

1-Allergy.2-Peptic ulcer.

3-Bronchial asthma.4-Bleeding disorders.

5-Pregnancy (early and late).

Misoprostol in treatment of peptic ulcer is contraindicated in pregnancy.

Contraindications:

Serotonin agonists and antagonistsSerotonin Antagonists Serotonin agonists

1) 5-HT2 Antagonists:Cyproheptadine-Methysegide-Pizotifen-Ketotifen:

Used in:1-Prophylaxis of migraine headache.

2-Carcinoid tumor.3-Appetite stimulants (except methysergide).

4-Cyproheptadine has also antihistaminic action and is used in treatment of allergic conditions.

Adverse effects:

1-Buspirone:5-HT1A agonist.

Non-Benzodiazepine anxiolytic (anxio-selective).Used in generalized anxiety disorder, but has slow onset of action.

2-Triptans: Sumatriptan-Zolmitriptan:5-HT1D agonists,

Cause vasoconstriction of cranial, coronary, and systemic blood vessels.

Methysergide causes fibrosis of serous membranous leading to retro-peritoneal fibrosis.

2) 5-HT3 Antagonists: Ondansetron-Granisetron:Block 5-HT3 receptors in medullary C.T.Z.

Used as antiemetics in nausea and vomiting due to cancer chemotherapy and post-operatively.

Used in acute attacks of migraine headache, given orally 2 doses / day.

Adverse effects:1-Tingling, numbness, cold hands.

2-Elevation of blood pressure.3-Anginal pains.

4- Abortion due to their oxytocic action..5-Dizziness and neck pain.

Contraindications:1-Hypertension.

2-Angina pectoris.3-Peripheral vascular disease.

4-Pregnancy.3-Metoclopramide and Itopride:5-HT4 agonists in enteric ganglia.

Prokinetics: stimulate release of acetylcholine from cholinergic nerves in GIT leading to increase in tone of lower esophageal

sphincter and accelerate gastric emptying.Used in GERD and gastroparesis.

4-D-Fenfluramine:Appetite suppressant (anorexigenic) in obesity,

5-SSRIs: Fluoxetine-Fluvoxamine:Antidepressants used in treatment of psychic depression.

Drug Therapy of Migraine:

Drugs used in Prophylaxis Drugs used in Acute Attacks1-Propranolol: the most commonly used.

2-Serotonin antagonists:Methysergide.

Clonidine.Pizotifen.

Cyproheptadine.3-TCAs as Amitriptyline.

4-Valproic acid.5-CCBs as Flunarizine: blocks selectively Ca2+ channels in

cranial blood vessels without affecting Ca2+ influx in the heart or smooth muscles.

Mild attack:1-Analgesics as Paracetamol or NSAIDs as Aspirin.

2-Antiemetics as Metoclopramide or Domperidone may be added in case of migraine-induced vomiting.

Severe attacks:1-Ergot alkaloids:

A-Ergotamine:-Given orally but poorly absorbed, also given S.L., I.M, I.V.,

inhalation, suppository-Passes BBB-Metabolized by liver and excreted in urine.

-Pharmacodynamics:Partial agonist on alpha1 and 5-HT2 receptors leading to vasoconstriction-Spasmogenic on

smooth muscles including uterus (oxytocic)-CNS actions: stimulation of CIC leading to bradycardia and CTZ causing

nausea and vomiting.-Adverse effects: elevation of ABP-anginal pain-cold hands,

29

tingling, numbness, and may be gangrene-nausea and vomiting-bradycardia-abortion.

-Contraindications: Hypertension-angina-PVD-pregnancy-liver and kidney diseases-old age.

B-Dihydroergotamine: less toxic than ergotamine.C-Cafergot (Caffeine + Ergotamine): caffeine improves oral

absorption of ergotamine and causes cranial vasoconstriction.2-Triptans as Sumatriptan and Zolmitriptan:

-Given orally.-5HT1D agonists leading to vasoconstriction.

-Adverse effects: elevation of ABP-anginal pain-cold hands, tingling, numbness-abortion

Contraindications: Hypertension-Angina-PVD-Pregnancy-With ergotamine within 24 hours.

Respiration*Drug Therapy in Bronchial Asthma:

A-Bronchodilators (Short-term asthma relievers):1-Sympathomimetic 2-Agonists.

2-Methylxanthines.3-Antimuscarinic drugs (Anticholinergic drugs-Muscarinic antagonists).

B-Anti-inflammatory drugs (Long-term asthma controllers):1-Glucocorticoids (Corticosteroids).

2-Leukotriene antagonists=Leukotriene inhibitors=Leukotriene modifiers=Antileukotrienes: LT receptor antagonists (Montelukast and Zafirlukast) and LT synthesis inhibitors (Zileuton) which

inhibits5-lipooxygenase enzyme.

3-Degranulation inhibitors = Mast cell stabilizers.N.B.:

Anti-inflammatory drugs are not bronchodilators and are not used in acute attacks of bronchial asthma, but used for prophylaxis.

NSAIDs except Paracetamol-are contraindicated in bronchial asthma (why?).

A-Bronchodilators:I-2-Agonists:

Pharmacodynamics : Stimulation of 2-receptors activation of adenylate cyclase synthesis of c-AMP

bronchodilatation + mast cell stabilization and inhibition of release of bronchoconstrictor mediatorsfrom mast cells + reduction of mucus secretion + increase muco-ciliary clearance +

decrease microvascular leakage (capillary permeability).Classification:

A-Selective 2-Agonists: They are the most important drugs in treatment of bronchial asthma, they include:

1-Short-acting 2-agonists=Asthma relievers: Salbutamol and Terbutaline given by inhalation in acute attacks duration 3-4 hours.

2-Long-acting 2-agonists=Asthma controllers: Salmeterol, Formoterol by inhalation, and Bambuterol given orally-duration 12 hours.

Role in bronchial asthma:1-The drugs of choice in acute attacks: SABA are given by inhalation.

2-LABA are given for long-term prophylaxis with inhaled steroids.3-Salbutamol is given by inhalation (nebulizer) or IV in severe acute asthma (status asthmaticus).

Adverse effects:1-Tremors of the skeletal muscles.

2-Tachycardia (mostly reflex due to V.D. and hypotension, but may be due to direct stimulation of cardiac 1 receptors especially with repeated doses because selectivity is not absolute).

3-Tolerance (due to down-regulation of 2-receptors, corrected by corticosteroids).4-Nervousness Tension.

5-Hypokalemia.6-Hypotension-Headache-Flushing.

7-LABA increase the risk of asthma-related death if used alone in patients with ischemic heart disease or arrhythmia, that is why they should be combined with inhaled corticosteroids (ICS).

B-Non-Selective -Agonists:They are not commonly used because of cardiac adverse effects as tachycardia,

palpitation,arrhhythmia and anginal pains due to 1-stimulation. Examples:1-Adrenaline (inhalation and S.C.).

2-Isoprenaline (inhalation and S.L.).

II- Methylxanthines:Theophylline and Aminophylline (theophylline ethylene diamine).

Pharmacodynamics:Mechanism of action:

1-Inhibit phosphdiesterase type 4 intracellular c-AMP bronchodilatation + mast cell stabilization and inhibition of release of bronchoconstrictor mediatorsfrom mast cells + reduction

of mucus secretion + increase muco-ciliary clearance + decrease microvascular leakage (capillary permeability) .

2-Block of adenosine receptors bronchodilatation + decrease histamine release..3-Improve diaphragmatic contractions.

4-Inhibition of PDE-4 in inflammatory cells reduces the release of cytokines and reduces cell migration.

The Role of Methylxanthines in Bronchial asthma:

31

1-Aminophylline may be given very slowly IV (250-500 mg.) in acute attacks (asthma reliever) if there is no response to inhaled selective 2- agonists. This may be dangerous especially if

aminophylline is rapidly injection as it may lead to arrhythmia and severe hypotension (velocity reaction).

2-Theophylline is given as sustained release tablets or capsules in prophylaxis of bronchial asthma (asthma controller).

Aminophylline may be also given as rectal suppositories (500 mg.).3-Aminophylline is given by IV infusion in life-threatening asthma (status asthmaticus =severe

acute asthma).Adverse effects:

-Theophylline and Aminophylline have low therapeutic index and the plasma level should be measured to avoid toxicity.

-Therapeutic plasma concentration of theophylline: 5-20 mg / L (5-20 g / mL) and the toxic level > 20 mg / L.

-Adverse effects include:1-CNS manifestations: nervousnss, insomnia, headache, and seizures (convulsions).

2-CVS manifestations: tachycardia, palpitations, arrhythmias, anginal pains, and hypotension.3-GIT manifestations: anorexia, nausea, vomiting, ulceration, and proctitis (rectal suppository).

4-Thrombophlebitis (IV injection).Symptoms of toxicity may start at plasma level of 15 mg/L.

Seizures and arrhythmia occur at plasma levels above 40 mg/L.

Drug interactions:A-The clearance of theophylline is reduced by:

1-HME inhibitors as: Erythromycin (Macrolide antibiotics)-Fluroquinolones-Chloramphenicol-Cimetidine-Contraceptive pills.

2-Hepatic cirrhosis.3-Heart failure (decreases COP and so decreases hepatic blood flow).

In these conditions the dose of theophylline should be reduced to avoid toxicity.2-The clearance theophylline is increased by:

-HME inducers as: Phenobarbitone- Phenytoin-Rifampicin Cigarette smoking (nicotine).The dose of theophylline should be increased in these conditions to achieve therapeutic levels.

III- Anti-Muscarinic Drugs:Atropine was previously used in prophylaxis of bronchial asthma but is now replaced by

synthetic substitutes.Examples: Ipratropium -Oxtropium Tiotropium.

Mechanism of action:They are competitive antagonists that block muscarinic receptors in bronchi by competition with

acetylcholine released as a result of vagal stimulation.Role of Antimuscarinic Drugs in Bronchial asthma:

1-They are given by inhalation in prophylaxis of bronchial asthma (the response varies according to degree of vagal stimulation on bronchi).

2-They are used as alternatives to LABA patients who are intolerant to LABA as in cases of arrhythmia or ischemic heart diseases.

3-They may be added to LABA to achieve synergism.4-They are the drugs of choice in asthmatic attacks precipitated by non-selective beta antagonists

as propranolol.5-Chronic obstructive pulmonary disease (COPD).

Advantages of Synthetic substitutes:Advantages of Ipratropium Disadvantages of Atropine

1-Quaternary ammonium-given by inhalation.2-Minimal systemic anticholinergic actions.

3-No CNS (cannot penetrate BBB).4-Little effect on bronchial secretion.

5-No effect on muco-ciliary clearance.

1-Tertiary amine-given orally-Passes BBB.2-Systemic anticholinergic actions: dry mouth constipation-urine retention-tachycardia-blurred

vision and elevation of IOP.3-CNS actions.

4-Causes dryness of bronchial secretion leading to thick viscid sputum.

5-Decreases muco-ciliary clearance.

B-Anti-inflammatory Drugs:I- Corticosteroids (Glucocorticoids):

Mechanism of action:1-Anti-inflammatory action by inhibition of phospholipase A2 leading to inhibition of synthesis

of arachidonic acid, leukotrienes and prostaglandins.2-Anti-inflammatory action by inhibition of synthesis of cytokines as interleukins (IL1,2,3,4) and

tumor necrosis factor (TNF).3-Potentiate the effects of 2-agonists (by upregulation of receptors) thus prevent tolerance.

4-Inhibit IgE antibody synthesis and antigen-antibody reaction.Corticosteroids are not bronchodilators and are not used in acute attacks.

The Role of Corticosteroids in Bronchial asthma:

1-Inhaled corticosteroids (ICS) as Beclomethasone, Fluticasone, Triamcinolon, Budesonide, are used in prophylaxis of bronchial asthma. This is the preferred route to avoid the serious

adverse effects of systemic steroids (immunosuppression-osteoporosis-edema-hypertension-ulcer).

2-Systemic steroids as Hydrocortisone sodium succinate or methylprednisolone IV is the drug of choice in status asthmaticus (200 mg. / 4-6 hours for 24 hours).

This is followed by oral prednisolone for 7-10 days then gradually withdrawn to avoid acute adrenocortical insufficiency.

33

3-Systemic steroids as predisolone orally are used only in severe persistent asthma not responding to other anti-asthmatic drugs (see later).

Adverse effects of Inhaled steroids:1-Oro-pharyngeal candidiasis (moniliasis): prevented by mouth wash after corticosteroid

inhalation, and treated by oral Nystatin.2-Dysphonia (voice abnormality, e.g. weakness and hoarseness).

3-Systemic adverse effects may occur on prolonged use, e.g. growth retardation in children and osteoporosis in females

II- Mast Cell stabilizers = Degranulation Inhibitors:Cromolyn (Disodium cromoglycate) and Nedocromil.

Mechanism of action:Inhibition of the release of allergic mediators from mast cells and other inflammatory

mediators by stabilizing the cell membrane by altering the permeability of chloride channels.They are not bronchodilators and are not used in acute attacks.

Role of Mast Cell stabilizers in Bronchial asthma:1-Used only for prophylaxis and given by inhalation, either in the form of solution (inhaler) or in

the form of powder (by spinhaler).2-They are used before exposure to allergen (environmental asthma), before exposure to industrial fumes (occupational asthma), and before exercise (exercise-induced asthma).

3-They decrease: bronchial hyper-responsiveness, the need bronchodilators, and the severity of symptoms.

4-They may be used with ICS.Other uses:

1-Allergic rhinitis (given as nasal drops or nasal spray).2-Allergic conjunctivitis (given as eye drops).

Adverse effects:Bronchospasm, cough, chest tightness, throat irritation, dry mouth, and anaphylaxis (rare).

III- Leukotriene Modifiers:Mechanism of action:

1-Inhibition of 5-Lipooxygenase and inhibition of leukotrienes synthesis by Zileuton (not commonly used as it may cause hepatotoxicity).

2-Competitive antagonists of cysteinyl leukotriene receptors (LTD4 mainly): by Montelukast and Zafirlukast.

Role in Bronchial asthma:They are given for prophylaxis against bronchial asthma.

They have the following advantages: 1-Montelukast is safely used in children (as young as 6 months) 2-easy administration as they are given orally.

New Drugs in Treatment of Bronchial Asthma:1-Omalizumab: anti-IgE monoclonal antibody

Synthesized by recombinant DNA technology.Mechanism of action: binds to IgE thus prevents binding of IgE to its receptors on mast cells,

and inhibits degranulation and release of allergic mediators.It is given SC in severe persistent asthma not controlled by other drugs as ICS and LABA (see

later).2-Calcium channel blockers.

3-Potassium channel openers as cromokalim.4-Prostaglandin E2.

5-Nitric oxide donors.Drugs Contraindicated in Bronchial Asthma:

1-NSAIDs (except paracetamol=acetaminophen).2-Non-selective -Blockers (Propranolol-Nadolol-Timolol-Sotalol-Oxprenolol-Pindolol).

3-ACE inhibitors as Captopril.4-Morphine (depresses R.C., cough centre, and releases histamine).

5-Muscarinic agonists = Parasympathomimetics (Carbachol-Bethanechol-Pilocarpine-Physostigmine-Neostigmine).

6-Other drugs: Histamine liberators as morphine-curare-trimetaphan-Histamine like drugs as phentolamine and tolazoline-Barbiturates (due to depression of R.C.).

Cough TherapyAcetylcysteine:

Pharmacodynamics:1-Mucolytic: by splitting the disulfide bonds of mucoproteins of respiratory secretion. This leads

to reduced viscosity and tenacity of mucus.2-Acetaminophen (Paracetamol) antidote: by normalizing hepatic glutathione (SH donor) which

binds to the hepatotoxic metabolite of acetaminophen (NABQ) and protects liver cells.3-Antioxidant.

Therapeutic uses:1-Mucolytic: used as adjuvant in treatment of acute and chronic respiratory diseases as bronchial

asthma, T.B., pneumonia, cystic fibrosis-also used to clear the airways as in bronchoscopy.2-Treatment of acute acetaminophen toxicity, considered as its antidote

DiureticsK+ Sparing diuretics

(Spironolactone)Loop diuretics Thiazides and Thiazide-like

diureticsOral only.Very slow.

Long.Distal part of DCT.

Weak.

1-Diuretic.2-Spironolactone and Eplerenone reduce mortality in Heart failure.

1-Edema due to hyperaldosteronism.2-Edema: with thiazides or loop.

3-Hypertension: with thiazides or loop.4-Heart failure (class IV).

Oral and IV.Rapid.Short.

Loop of Henle.Potent.

1-Diuretic.2- RBF.

3-Antihypertensive.4-Hyperuricemia.5-Hyperglycemia.

1-Edema: acute and resistant.2-Hypertension; emergency-severe-and with renal impair.

3-Acute renal failure.4-Hypercalcemia.

Oral only.Delayed.

Long.Proximal segment of DCT.

Moderate.

1-Diuretic (mainly by V.D.).2-Antidiuretic in nephrogenic diabetes insipidus by RBF.

3-Antihypertensive.4-Hyperuricemia.5-Hyperglycemia.6-Hyperlipidemia.

1-Edema due to: Heart failure-Renal-Hepatic.

2-Hypertension.3-Nephrogenic diabetes insipidus.

4-Idiopathic hypercalciuria.5-Pre-menstrual tension.

1-Routes:2-Onset:

3-Duration:4-Site of action:

5-Potency:

6-Actions:

7-Uses:

35

1-Hyperkalemia.2-Acidosis.

3-Gynecomastia and sexual disturbances (by Spironolactone due to

steroid structure).4-Gut upset.

5-CNS disturbances.6-Allergy.

7-Hypocalcemia.

1-Renal impairment (to avoid hyperkalemia).

2-With ACEIs or ARBs (to avoid hyperkalemia).

3-Allergy.

Aldosterone antagonists: Spironolactone, Eplerenone. Non-

aldosterone antagonists: Amiloride-Triamterene.

1-Hypokalemia.2-Hyponatremia.

3-Hypomagnesemia.4-Hypochloremic alkalosis.

5-Hypovolemia and dehydration.

6-Hypotension.7-Hypocalcemia.

8-Hypersensitivity.9-Hyperuricemia.

10-Hyperglycemia.11-Ototoxicity.

12-Teratogenicity.

1-Allergy.2-Digitalis toxicity.

3-With Lithium lithium toxicity.

4-With Aminoglycosides.5-Diabetes mellitus.

6-Gout.7-With Steroids.

8-Pregnancy.Frusemide-Bumetanide-

Torsemide-Ethacrynic acid.

1-Hypokalemia.2-Hyponatremia.

3-Hypomagnesemia.4-Hypochloremic alkalosis.

5-Hypovolemia and dehydration.6-Hypotension.

7-Hypocalcemia.8-Hypersensitivity.

9-Hyperuricemia.10-Hyperglycemia.11-Hyperlipidemia.

12-Teratogenicity.

1-Allergy.2-Digitalis toxicity.

3-Renal insufficiency.4-Hepatic insufficiency.

5-Diabetes mellitus.6-Gout.

7-With Steroids.8-Pregnancy.

Thiazides: Chlorothiazide-Hydrochlorothiazide.

Thiazide-like: Indapamide-Chlorthalidone-Metolazone.

8-Adverse effects:

9-Contraindications:

10-Examples:

How to avoid hypokalemia caused by Thiazides or Loop diuretics:1-Adding a K+-sparing diuretic as spironolactone, amiloride, or triamterene.

2-Adding ACEI as captopril or ARB as losartan.3-K+ syrup or SR potassium tablets (irritant and should be avoided in peptic ulcer).

4-Dietary potassium supplementation.5-Intermittent use of K+ losing diuretics.

Drug Interactions:K-sparing diuretics (Spironolactone)

Loop diuretics (Frusemide) Thiazides (Hydrochlorothiazide)

1-Hyperkalemia antagonizes the action of digoxin.

2-Spirnolactone + Thiazide synergism and correction

of serum K+.3-Spironolactone + loop

diuretics synergism and correction of serum K+.

4-Spironolactone + ACEIs severe hyperkalemia.

5- Spironolactone + ARBs

1-Hypokalemia induced by thiazide may precipitate digoxin toxicity.

2-Thiazides + loop diuretics severe hypokalemia.

3-Frusemide + K+ sparing diuretics as spironolactone, amiloride, or triamterene

synergism and correction of serum K+.4-Frusemide + ACEIs as captopril

synergism in treatment of HF and hypertension and correction of serum K+.

5- Frusemide + ARBs as losartan

1-Hypokalemia induced by thiazide may precipitate digoxin toxicity.

2-Thiazides + loop diuretics severe hypokalemia.

3-Thiazides + K+ sparing diuretics as spironolactone, amiloride, or triamterene

synergism and correction of serum K+.4-Thiazides + ACEIs as captopril

synergism in treatment of HF and hypertension and correction of serum K+.

5- Thiazides + ARBs as losartan

severe hyperkalemia. synergism in treatment of HF and hypertension and correction of serum K+.6-Frusemide + corticosteroids severe

hypokalemia.7-Frusemide antagonizes the hypoglycemic

action of insulin secretagogues as sulfonylureas (less than thiazides).

8-Frusemide antagonizes the uricosuric action of uricosuric drugs as probenicid.9-NSAIDs antagonize partially effect of

frusemide on RBF.10-Probenicid decreases tubular secretion

of frusemide and antagonizes their diuretic action.

11-Cross allergy between most most loop diuretics except ethacrynic acid-and

sulfonamides.12-Frusemide displaces warfarin from

plasma proteins and may lead to bleeding.13-Frusemide decreases renal clearance of

lithium and may lead to lithium toxicity.14-Frusemide should never be given with

Aminoglycosides as streptomycin because both are ototoxic.

synergism in treatment of HF and hypertension and correction of serum K+.

6-Thiazides + corticosteroids severe hypokalemia.

7-Thiazides antagonize the hypoglycemic action of insulin secretagogues as

sulfonylureas.8-Thiazides antagonize the uricosuric

action of uricosuric drugs as probenicid.9-NSAIDs antagonize partially the

diuretic and antihypertensive actions of thiazides.

10-Probenicid decreases tubular secretion of thiazides and antagonizes their diuretic

action.11-Cross allergy between thiazides and

sulfonamides.

CVSAnti-Anginal Drugs

Summary of anti-anginal drugs:CCBs: Verapami and

Diltiazem (non DHP)

CCBs: Nifedipine (DHP)

Nitrates Beta Blockers

Atreriodilatation and afterload (much less than

nifedipine).

Almost no venodilatation.

V.D. (much less than nifedipine).

Bradycardia.

Potent arteriodilatation and

afterload.

Almost no venodilatation.

V.D. of normal sub-endocardial vessels "coronary steal"

phenomenon.

Reflex tachycardia.

Arteiodilatation and afterload.

Potent venodilatation and preload.

V.D of big epicardial vessels redistribution

of blood into ischemic areas.

Reflex tachycardia.

No vasodilatation.

No venodilatation.

Non-selective BB may cause V.C. due to

unopposed effect.

1-Effect on arteries and afterload (TPR):

2-Effect on veins and preload (EDV):

3-Effect on coronary blood vessels:

37

Decrease.

Decrease by cardiac properties (mainly) +

afterload.

Beneficial in long-term prophylaxis.

Beneficial.

Not used because they should not be combined with BB to avoid severe

bradycardia and AV block.

Decrease.

Decrease by afterload.

1-Beneficial in long-term prophylaxis.

2-May be used S.L after crushing the

capsule.

Beneficial.

Beneficial.

Decrease (systolic > diastolic).

Decrease by preload (mainly) and afterload.

1-Beneficial in acute attacks (S.L.).

2-Beneficial in immediate prophylaxis

(S.L.).3-Beneficial in long-

term prophylaxis (SR oral preparations).

Beneficial.

Beneficial.

Bradycardia.

Decrease.

Decrease by cardiac properties and ABP.

Beneficial in long-term prophylaxis.

Contraindicated.

Beneficial.

4-Effect on hear rate:

5-Effect on ABP:

6-Effect on cardiac work and myocardial oxygen

needs:

7-Role in stable angina:

8-Role in variant angina:

9-Role in unstable angina:

1--Blockers:All -blockers both selective and non-selective- are useful in prophylaxis of stable angina

because they decrease heart rate, contractility, and ABP leading to decreased cardiac work and myocardial oxygen demands.

Non-selective -blockers are contraindicated in variant angina because they lead to "unopposed 1-action" causing more vasospasm.

Cardio-selective -blockers are used with great caution and are better avoided in variant angina because selectivity is not absolute.

In unstable angina: -blockers without ISA are used (in addition toI.V. nitroglycerin, nifedipine(CCB), heparin and antiplatelet drugs as aspirin).

Adverse effects and contraindications: see ANS,But remember that they should never be stopped suddenly.

N.B.:1-The dose of -blockers is adjusted according to the heart rate, which should not exceed 50-60

beats/minute at rest, and 100-120 beats/minute during exercise.2--blockers decrease heart rate prolongation of diastole increased end-diastolic volume

(EDV) and ejection time increased cardiac work and oxygen consumption which partially antagonizes their beneficial effect in angina. This can be corrected by co-administration of

nitrates (nitrates increase heart rate reflexly and shorten diastole).

2-Nitrates and Nitrites:Organic Nitrates:

1-Nitroglycerin (Glyceryl Tri-Nitrate =GTN).2-Isosorbide Dinitrate.

3-Isosorbide Mononitrate. *Pharmacodynamics:Mechanism of action:

1-The molecule is "de-nitrated" in the tissues, i.e. a nitrite ion is released by glutathione -S-transferase which requires sulfhydryl group.

2-Nitrite molecule is converted into "Nitric Oxide" (N.O.) which stimulates guanylyl cyclase and increases synthesis of c-GMP which in turn leads to smooth muscle relaxation particularly blood

vessel and mainly veins(by dephosphorylation of myosin light chain kinase). Pharmacological actions:

I-CVS:1-Nitrates and nitrites are mainly venodilators more than arteriodilators.

*2-Venodilatation decreases venous return (pre-load) which decreases end-diastolic volume (EDV). This leads to reduction of COP and consequently cardiac work and myocardial oxygen

demands are decreased. Reduction of COP decreases systolic BP.-Venodilatation causes postural hypotension.3

*4-Arteriodilatation decreases TPR (after-load) which leads to reduction of cardiac work and myocardial oxygen demands. Reduction of TPR decreases both systolic and diastolic BP.

(they decrease systolic BP more than diastolic, why?). 5-Reduction of ABP causes reflex sympathetic stimulation causing increased heart rate (reflex

tachycardia) and myocardial contractility, which increases cardiac work and myocardial oxygen demands. Tachycardia also shortens diastole and decreases coronary perfusion (filling of the

coronaries occurs during diastole). To correct these unwanted effects of nitrates they are combined with -blockers (or verapamil).*6-V.D. of normal epicardial coronary vessels leads to opening of collaterals and re-distribution

of blood into the ischemic areas.(Remember that atherosclerotic vessels can not be dilated).

7-V.D. of cutaneous blood vessels causes flushing.8-V.D. of meningeal blood vessels causes "throbbing" (pulsating) headache.

*Indicates the beneficial actions of nitrates in angina.II-Platelets: Nitrates inhibit platelet aggregation by stimulating synthesis of c-GMP in platelet.

III- Other smooth muscle fibres: nitrates cause smooth muscle relaxation of bronchi, GIT, uterus, and ureters.

IV-Methemoglobinemia : nitrites -and to a much less extent nitrates- oxidize ferrous iron of hemoglobin into ferric iron. This is especially dangerous in IHD as it causes more hypoxia.

However; methemoglobinemia is useful in treatment of cyanide poisoning (see Pharmacology of Respiration).

*Therapeutic uses:1-Angina pectoris: nitrates are useful in all types of angina (stable, variant, and unstable) and all

conditions of angina (acute attacks, immediate prophylaxis, and long-term prophylaxis).The aim of therapy with nitrates in stable and unstable angina is to reduce cardiac work and myocardial oxygen demands and not to dilate the coronaries, whereas the aim of the aim of

therapy in variant angina is to dilate the coronaries. They are given S.L. or by buccal spray in

39

acute attacks and immediate prophylaxis, and are given orally, as skin ointment, and as transdermal patch for long-term prophylaxis. Nitroglycerin is given by IV infusion in unstable

angina.2-Heart failure: they reduce pre-load mainly and after-load to a lesser extent. Nitroglycerin is

given by IV infusion in acute heart failure. Reduction of pre-load in patients with heart failure improves myocardial contractility and increases COP (but in patients without heart failure COP

is reduced due to reduction of venous return and EDV).3-Emergency hypertension: nitroglycerin IV infusion is used.

4-Acute myocardial infarction: nitroglycerin IV infusion decreases cardiac work, dilates the coronaries, and decreases pulmonary congestion. It may also reduce the size of infarction.

5-Nitrit