***II- 4 PRocesses relevent to drug Therapy :Pharma/PK./PD

-x matter—-> X inosage Form 
in all area of person Life as well as wider implication for soceity
-Physical -Vommiting/sweating/Diarrhea
-Psychological= Depression /anxiety!
Cost Tax MoneY

^^Drug phase: 
a) Phase 1(pharmaceutical phase): drug taken orally becomes sol. So it can pass through biologic membrane. In subcutaneous, IM, IV there is no pharmaceutical phase. 
b) Phase 2 (pharmacokinetic phase): absorpyion (through snall intestines), distribution, metabolisim (biotransformation through liver) and excretion. 
c) Phase 3 (pharmacodynamic phase) biologic or physiologic response.

^^Pharmaceutics phase: (dissolution) 
is the first stage of drug action. And can be of two stages:
Disintegration: the breakdown of tablets into smaller particles.
Dissolution: is dissolving of the smaller particles into GI fluids before absorbtion.
Generally, drugs are better disintegrated and absorbed in acidic medium than alkaline. It’s important to know that coated drugs are resistant to disintegration in gastric acid of the stomach and therefore they do not disintegrate until they reach the alkaline medium of the small intestines.

^^PK phase:
process of drug movment which can be:
– Passive
– Active
– Pinocytosis

****3-Principle of Rational Drug Use and their application:

-Apporpriate X to their clinical needs
-Doses that meet their individual requirments 
f-Adequate Period of time
-Lowest cost ot them and community

^^Principles of rational drug use
1) Rely on accurate diagnosis in treatment planning,
2) Determine the right drug, right dose, right time, and the correct way of the application,
3) Assess the success of treatment, side effects and compliance,
4) Predict the interactions in use of multiple drug,
5) Assess the practicability and the cost of treatment.


-Advertisement= media, informative videos, newspaper
– Training= physicians, pharmacists, health care personal
– Guidelines=for diagnosis and treatment of diseases
-Legislation= Regulation and Promotional Activities of Medicinal 
-Drug boxes= Big font size on the direction for use
-Monitoring and evaluation= Surveys for physicians, pharmacists, nurses and public

***IV-Pharmcogenetics + Phamargenomics

-Study of individual carition in DNA sequeence Related to ZX absorption+ disposition!
1-polymorphic variation in genes
3-metabolising enzymes
4-receptos+ others

(Dose Admninistered)—–(Abosrption)—-)[C] in systeic circulation
(A)—>[C] sita of action—->Pharma effect( toxicity + efficacy)
(B)—–(Distribution)—–>X i tissue of disturbtuion
(C)—-(elimination)—–metabolism and or excretion!

^^Determines efficaty and toxicity:

PK factorsPD factors
-Tareget Protiens
-downstream messengers!

Study of variable of expression of individual to disease susceptiblit as well as X Response at cell, Tissue,Idnivdual  Level !

***5-ADR:Epidemiology Data+ classificaton…

-Response to a X that is noxious and unintended and that occurs at doses used in humena Prophylaxis /dx/Tx
-excludes Tx Failures/Overdose/X Abuse/non compliance!

^^Epidemiological Data:
-substantial morbidity and mortality
– estimates of incidence study methods and population
– 4sth to 6th leading cause of death among hospitalized patients
– 6.7% incidence of serious ADRs
– 0.3% to 7% of all hospital admissions
– 30% to 60% are preventable
-$3.5 billion is spent on extra medical costs of ADEs annually


Acute(60 min)
-Anaphylactic shock
no change in Tx

Type A:
-Extension of Pharma ffect
-Predictable dose Dep

Sub Acute:
-1-24 H
-serum sickness
-change in tx
-additional Tx
Type B:
-immunological Rc
—>2  days
(eczamatous Eruptions, Dyskinesia)
disabiling/life thrreatning
(QT interval up)
(kidney failure)

1-subjective report(pts complaint)
2-Objective Report
( directo bservation)
(abnormal findings, physical exam, lab test,Dx procedure)

iti s related with detectioj/assement/understanding/ Prevention of ADR!

^^Aim of pharmacovigilance:
-imp patient care and safety
-imp public health and safety
– assessment of benefit, harm, effectiveness and risk of medicines
– promote education and clinical training
– promote effective communication to the public
– promote rational and safe use of medicines

****6- Drug Interaction : epidemiolgoical data /classification

X interaction:
effect of 1 X is changed by Effect of Another!

^^Epidemiological Data:
-Incidience of ADR btwn 30% in hospitalzied pts
-Incidence 70% in ambulatory
-adverse ADR lo <1% it still a problem and risk!

1-PK—> absroption/distribution/metabolism/ excretion of X affected by another X
( Renal excretionof Digoxin altered by amiodaron)
2-PD —>X may have addivtive or synergitic/antagonistic affect
(ex= NSAID (-) Antihypertensive of ACE(-)
—-> X and idetayr supplements!,Food beverages 
(vitmine K in vwfieis promotes Clotting factors ,(-) effect of anti Cogaltant)

^^Cliniocal significant X interaction:

X interactionMechanismoutcomes
Warfrin -aspirin
-displace of warfarin from plasma\

-(-) Warfarin metabolism
serious GI bleeding
(-) Cytochrome p450
 ↑ Phenytoin [C]
↓ Carbamezapine [C]
ACEI (-)-PotassiumLowered LAdosterone
Elevatred Serum K+
(-) ACE result!
(-) of Renal
(-) digoxin clearance
Digoxin tocivity!
Increases Risk of Methotrazate toxicity!
(Leukopenia/T penia/Anemia)

^^clinically insignificant Drugs interactions:
-Grapefruits—-> enzymatic(-)—>effect C Blocker/carbameapine
-Soya—–>Enzyme(-) —>Effect warfarin/Haloperidol/Olanzapine
-Garlin—>(+)antiplatlet acitvity–>Effect:anticoagulats/aspirin!

***7 X use in children,eldery…Kindey injur/Liver Injury:

-Children response to X is different!
-esp in neonates the doses should always be calculate with care
-Avoid IM injection as they are painful!

-based on body weight
-or based on ranges
(i1 year infant)
(1-5 years)

-have reduced renal pclearance
-take more tiem to excrete
-Susceptible for nephrotoxic X
-acute illness cna lead ↓  Renal clearance!

-Liver Disease may effect metabolism
\-X should be to minum 
-Main problem is Ascites,evidence of encephalopathy!

IV- Impaire metabolism:
-metabolism is doene by liver
-Hypoalbumenia in severe liver disease
-due to ↓ prt protduction

2- ↓ Clotting:
 ↓synthesis of clotting factors ,
– prothrombin tim
– ↓ (S) off  OP anticoagulants!

3-Fluid overload:
are worsened by X

4-Heptatoxic X:
-Dose ewlated/unpredictable!
-X tht cuase Problem with lvier should be avoided!

5-Renal (-):
↓ renal excretion of X
-(S) of X ↑  even is elimintion is N
-Man yADR 
-some X are effective when low renal function

Avoid Intramsular injection as it can be Painful for children!
-But children may require medicine not specifically liced forPediatirc
-medical act does not prohibit unlicensed medicine
-It is recognised that the informed use of unlicensed medicines or of licensed medicines for unlicensed applications (‘off-label’ use) is often necessary in paediatric practice.
doses are based on body weight for:
1- neonates
2-infants (up to one year)
3- 1–5 years 6–12 years

-liver impairment can disturb the response to drugs in many ways including:
I- Impaired drug metabolism:
-Metabolism by the liver is the main route of elimination for many drugs,
-but hepatic reserve is large and liver disease has to be severe before important changes in drug metabolism occur.
-Routine liver-function tests are a poor guide to the capacity of the liver to metabolize drugs, and in the individual patient it is not possible to predict the extent to which the metabolism of a particular drug may be impaired.
-A few drugs, e.g. rifampicin and fusidic acid, are excreted in the bile unchanged and can accumulate in patients with intrahepatic or extrahepatic obstructive jaundice.

II- Hypoproteinaemia The hypoalbuminaemia in severe liver disease is associated with reduced protein binding and increased toxicity of some highly protein-bound drugs such as phenytoin and prednisolone.

III-↓clotting Reduced hepatic synthesis:
of blood-clotting factors, indicated by a prolonged prothrombin time, increases the sensitivity to oral anticoagulants such as warfarin and phenindione.

IV- Hepatic encephalopathy;
In severe liver disease many drugs can further impair cerebral function and
may precipitate hepatic encephalopathy. These include all sedative drugs, opioid analgesics, those diuretics that produce hypokalaemia, and drugs that cause constipation.

V Fluid overload:
-Oedema and ascites in chronic liver disease can be exacerbated
by drugs that give rise to
fluid retention, e.g. NSAIDs and corticosteroids.

VI- Hepatotoxic drugs Hepatotoxicity :
is either doserelated or unpredictable (idiosyncratic). Drugs that
cause dose-related toxicity may do so at lower doses in the presence of hepatic impairment than in individuals with normal liver function, and some drugs that produce reactions of the idiosyncratic kind do so more frequently in patients with liver disease. These drugs should be avoided or used very carefully in patients with liver disease. Where care is needed when prescribing in hepatic impairment, this is indicated under the relevant drug in the BNF.

-The use of drugs in patients with reduced renal function can give rise to problems for several reasons:
– Reduced renal excretion of a drug or its metabolites may cause toxicity;
-Sensitivity to some drugs is increased even if elimination is unimpaired;
-Many side-effects are tolerated poorly by patients with renal impairment;
-Some drugs are not effective when renal function is reduced.

Many of these problems can be avoided by reducing the dose or
by using alternative drugs

***8-Organic Nitrates. Phamrakinetics or Diff ….

Organic nitrates are used in acute angina attacks and it is the
long term management in the prevention of angina attacks. 

^^Short acting: have a rapid onset of action (1-3 mins) and are use:
– sublingually as nitroglycerin (immediate treatment to angina). 
– IV administration is needed when continuous titration is necessary in unstable angina/AHF. 
– Slow releasing transdermal/buccal prep is used for prevention of angina.

^^ Long acting:
-usually taken orally for long term management of angina for the duration of 6-8 hrs.

^^ Monitoring: 
I. Sublingually: drug is rapidly metabolized and therefore effectiveness is subjectively measured .
II. IV: continuous monitoring of BP, HR,SpO2 is recommended.
– Adverse reactions: 
– Dizziness
– Nausea
– Palpitation
– Vertigo
– Headache
– Diaphoresis
– Syncope
– Hypotention (adverse effect of nitroglycerin)

^^ Tolerance: 
• Physiological tolerance: effects due to symp.
Nervous system response and due to compensating response Na,H2O
• Long acting (oral/transdermal) or IV can give tolerance>
• `pharmacological tolerance: to avoid tolerance there should be 10-12hrs nitrate free intervals when possible.

The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbidedinitrate) is very low.
-For this reason, the sublingual route, which avoids the first-pass effect, is preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbidedinitrate both are absorbed efficiently by this route and reach therapeutic blood levels within a few minutes. However, the total dose administered by this route must be limited to avoid excessive effect; therefore, the total duration of effect is brief (15–30 minutes).
oral preparations can be given that contain an amount of drug sufficient to result in sustained systemic blood levels of the parent drug plus active metabolites if a much longer duration is needed.
Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely by way of the kidney.
Because of its rapid onset of action (1–3 minutes), sublingual nitroglycerin is the most frequently used agent for the immediate treatment of angina. Because its duration of action is short (not exceeding 20–30 minutes), it is not suitable for maintenance therapy. 

^^ Effectiveness:
At therapeutic doses, nitroglycerin has two major effects:
• First, it causes dilation of the large veins, resulting in pooling of blood in the veins. This diminishes preload and reduces the work of the heart. 
• Second, nitroglycerin dilates the coronary vasculature, providing an increased blood supply to the heart muscle. Nitroglycerin decreases myocardial oxygen consumption because of decreased cardiac wo

-IV Nitroglycerine is Rapid (minutes) but its Hemodynamic effect are quickly reversed when Indusion Stop!!
…Not Too used in recurrent Rest angina

-Buccal Nitroglycerina  Blod concentration for long periods , but leads ot tolerance!

-Transmdermal Nitroglycerina :  may prodvude Blood level for 24 H  but full effect does not persis  beyond 6-8 H and can develop tolerance… Nitrate free period of leasy8 hours is required between Doses  to prevent Tolerance!

Short ActingLong Acting
(0.15-1.2 mg/ 10-30min)
-Isosorbide dinitritae ,sublingual
(2.5-5mg)(10-60 min)
-Amyl Nitritant, Inhlane

-Nitroglycerin, OP 
-Nitroglycerine 2% .transdermal
-Nitroglycerin Slow-buccal 
1-2mg)(3-6 H)

-Nitroglycerin has 2 major efect:
1-Dialation of Large veins —>↓ Preload + Heart work
2- Dialates coroary vasculature,↑ blood ot heart muscle!

^^toxicity + ttolerance:
-Orthostatic Hypotnesiojn
-HR ↑
-Throbbing headache
Do not Give if Intercranial pressure is High!!
ca be overcome by NitrateFree interncal 
(10-12 Hours)

***9- Beta Adenoreceptor Agonist:

-Beta blockers antagonizr the effect of catecholamine at  B adenoreptor Side!
-Occupy beta Receptor and Competetive ↓ recpeotr occupancy!

-Most are pure antagonist of B recpeotrs
-cause no activation of Receptor
-Mostly B1+b2 receptors!
• First-generation:
(Nonselective β antagonists (e.g. propranolol, Timolol, nadolol)
 Second generation:
(Selective β1 antagonists (e.g. acebutolol, atenolol, metoprolol, and esmolol)
 Third generation:
(selective eg betaxolol and nonselective eg.labetalol)

^^ Properties of beta blockers: 
a) Receptor blockage:
I. Nonselective beta blockage
II. Selective beta blockage
III. Beta and alpha blockage 
b) Intrinsic symptomatic property 
c) Membrane stabilizing action eg. Propranolol.

Nonselective β antagonists (e.g. propranolol, Timolol, nadolol)
1- Selective β1 antagonists
(e.g. acebutolol, atenolol, metoprolol, and esmolol)
-2 Antagonists with partial agonist activity
(e.g. acebutolol, pindolol)
3- Antagonists of both α- and β- adrenoceptors
(e.g. labetalol, carvedilol)

^^ADR( due to selectivelty of B+Alpha adenoreceptors)

non selective B antogonistSlelective B1 antagAntagonist with partial agonistAntogonist of Alpha+Beta
-Cold hand+feet
-Metabolism disturb
-CNS effect
-Cardio specific blocker
-CNS effect
-little effect on pul/peripheral(R)
-Diminishes effect on cardiac rate and cardiac output!

-compared to b blocker without ISA!

-orthostatic Hypotension

^^Recommendations for use
Beta blockers can be used for:
– Hypertension
– Glaucoma
– Migraine
– Hyperthyroidism
– Angina pectoris
– MI

TimololCardioselective beta blockerantagonist with partial agonsit effectantagonist with B and alpha activity!
↓ production of aqous humor in eyes
-chronic open eye glacoma!

-HBP pts+ (-) pul function

-HBP pts +  bradycardai
elderly or black HBP pts!

***10-Ca Channel blockers:


Non Dihydropyridinise
-Verapmil=Carcian and vascular muscle effect
-Dilitazem= effect on carddiac and smooth muscle

-Nifepine ( CVD disease)

-Calcuim CB act selectively on cardiovascular tissues.
-Dihydropyridines are selective vasodilators (with increased affinity for vascular ca channels than cardiac ca channels)
-& non Dihydropyridines are equipotent for cardiac tissue.

^^Short+long acting Formulation:
-most have short hald lives following an oral dose!
-Tx is 3 x a day use
-amiodropine has veyr long hald life!

– Amlodipine 5 mg tablets
– Diltiazem 60 mg tablets
– Adizem-SR (diltiazem SR) 90 mg capsules
– Adizem-XL 120 mg capsules
– Nifedipine 5 mg capsules
– Adlat Retard (nifedipine retard) 10 mg tablets
– Adipine SR (nifedipine SR) 10 mg capsules (SR=slow release)

iconstpitation in 10%
-peripheral edema
-Veramil ( not for Congestive HF)
-Cardiac depression ( if Cablocker in high dose

^^Clinical use:

– Cardiac: HTN, SVTS,AP
– Non cardiac: migraine, raynauds phenomenon, cluster headaches.
– Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities

Angina—–>immediate short actign Calcium Channel  can icnrease risk of Cardiac event and are contraindicated!

***11-Angiostensin Covnerting Enzyme inihibiot(ACE_ and Angio II Blockers:

-Same efficacy in Tx HBP
-Delay progression of CM neuropathy
-Tx of HF
-Angiosten Rector Antogniist less cough 
-ACE(-) , inhibit degradation of substance like bradykinin/substance/enkephalins
-angio Recpetor antagonist is more selectiveBlock of ACE receptor

^^ Adverse reactions:
1. Severe hypotension ( after initial dose )
in patients who are hypovolemic due to diuretics, salt restriction
2. Acute renal failure ( particular in patients with renal artery stenosis)
3. Hyperkalemia ( more common in patients with renal insufficiency or diabetes )
4. Dry cough ( less common in angiotensin receptor blocker)
5. Fetal anuria, hypotension , renal failure (contraindicated in 2nd and 3rd trimester)
6. Alter sense of taste , allergic skin rash 

^^ Practical recommendations for use and monitoring:
-Start with very low dose as possible.
– Be careful if the pts is on diuretics because of risk for hypotension.
– Wait to effect 3-5d, than double the dose. 
– Each change in the dose check for K levels

^^practical recommendation:
-start with lowest dose possibl
-Be careful if pts is on Duiretc( hypotension risk)
-Wait for effect -3-5 Day
-Each change in dose, check K levels!!

***12-Diuretics . Classification/ Monitoring of effectines and Safety !(Possible)

1-Loop Duiretic

3-K Sparing

4-Carbonic Anhydrase

5-osmotic Duretics!
(mannitol /urea)

^^moniterin for Effecitvess – 
-Keep checking BP
-Renal  function( Creatinine, Urea)
-Electrolytes ( Na+ / K+ /Ca2-)
-Wieght  ( for fluid loss)

^^ Monitoring:
Regular monitoring of Na, K, Glu and frequent test on K+ are needed especially in patients with impaired renal function or with renal failure. Along with hypovolemia, all electrolytes and acide base disturbances should be assessed.

^^ Fix Combinations:
 -ACEI + diuretics:
(Captopril-hydrochlorothiazide (very useful in case of cough)
– ARBS + diuretics: Losartan-hydrochlorothiazide
– BB+ diuretics:

^^Benefits of fix dosage combination:
– Help obtain BP control due to different modes of action
– Helps enhance compliance by using a single tablet (one or twice a day)
-Using low doses of 2 different agents minimizes clinical and metabolic effect particulary in patients with target organ failure or sever initial levels of hypertension

***13-Lipid Levering X, Classification Monitering of effectiness!

^^Classification(3 most common)

StatinsNiacinBile-Acid Resins
-Low Cholesterol level by(-) Enzyme HMG-CoA reductase!

-↓ hepatic synthesis of CLDL and LDL
-disrupts bile acid reabospriton 
-Decrease Choldestol Level

-Omega-2 DA

^^ Monitering for effectiness :
-Lipid Panel ( total cholesterol/LDL/HDL/TGL)
-↓ BO

^^Moniter for Safety :
-Rhabdomyolysis( myoglobiuria/serum CK)
-Liver moniterong(AST/ALT/ bilirubin/albumin)

^^Target cholesterol values in CVD pts
total Cholesterol <5.2mmol/L
LDL  <1/8 mmol/L
HDL >1/6mmol/L
TGL <1.7 mmol/L

***14algorythm for HBP :


Diuretics, betablockers, ACEI, ARBS are suitable for initiation and maintenance of therapy. The choice depends on patient’s:
-previous experience,
– cost
–  risk factors
–  target organ damage,
– DM 

-can either be started as monotherapy with a single drug or combination therapy.
-A goal BP of 140/90 is appropriate for general prevention of CV events
-and for CV risk reduction. 
Patients with diabetes are at high risk of CV events. They are recommended with ACEI/ARBS Typically in combo. 

***15 NSAID  X , MOA ,ADR!

^^MOA :
-Differ X difer by their antipyeetic/analgeiscs/anti inflam activity
-They act on (-) cyclooxygenase enzyme which catalyzes Frist step of Prostanoid biosynthesis
-↓ PG’s Synthesis with both beneficial and unwantd effect

^^NSAID Action :

1-Anti-inflammatoy acton:
(be (-) cycylooxygenase ,↓ PG formation)
PG E2 is Sensitive to Bradykinin/Histamine/chemical mediator

2-Analgesic action:
-Prostaglandin E2 (PGE2)
-is thought to sensitize nerve endings to the action
of bradykinin, histamine, and other chemical mediators
-released locally by the inflammatory process.
-Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs
-repress the sensation of pain.

3-Antipyretic :
-Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated.
-This can be caused by PGE2 synthesis, which
is stimulated when an endogenous fever-producing
agent (pyrogen),such as a cytokine, is released from
white cells that are activated by infection, hypersensitivity, malignancy, or inflammation

4-Respiratory action:
-↑ Alveolar vasodialation
-High dose works on Resp Center in medulla=hyperventilation
-At therapeutic doses, aspirin increases alveolar ventilation.
-Higher doses work directly on the respiratory center in the medulla,
–>resulting in hyperventilation and respiratory alkalosis
that usually is adequately compensated for by the kidney

5-Gastrointestinal effect:
Normally, prostacyclin (PGI2) inhibits gastric acid secretion,
0whereas PGE2 and PGF2 stimulate synthesis of protective
mucus in both the stomach and small intestine.
0In the presence of aspirin, these prostanoids are not formed,
resulting in increased gastric acid secretion and diminished mucus protection

6-On Kidney:
 Cyclooxygenase inhibitors prevent the
synthesis of PGE2 and PGI2prostaglandins that are responsible for
maintaining renal blood flow, particularly
in the presence of circulating vasoconstrictors .
Decreased synthesis of prostaglandins can result
in retention of sodium and water and may cause edema and hyperkalemia in some patients. Interstitial nephritis can also occur with all NSAIDs except aspirin


-epigastric Distress ,NAusea+ vommiting
-Caused by Salicylates

-irreversible acetylation of platlet cyclooxygenase—>↓ platlet TXA2 level

-in high [C] Salicylates cause Resp Depression!

4-Hypersensitivity :
-Aspirin Caused:
4-anaphylactic shock!

5-GI ulcer!

^^Classification according to COX-I and COX-II:
1-Selective Cycloxygneare-1 (-)
2-Non Selective Cyclooxygenase(-) 
(Indomethacin , diclofenac)
3-Relative Cyclooxynage-2(-)


^^Rational use:
-For mild pain and dpending on comorbidities as CVD Risk factrors/ GI Risk/ Age/ Renal / Hepatic Function
-Dont give to Childre may cause Reye syndrome!
-Paracetamol – Effective for Acute Pain
-Topical NSAID- good for Acute / chronic LocalPain!
-NSAID are 1st line for Low b ac pain but if C7 can use paracetamol!

***!6: CSD , MOA, comparison , Type of Therapy:

-coritsol is principal human GCD!
-Diurnal production(Pea early morning+decline in afternoon)

– GCF favor gluconeogenesis through increasing AA uptake by the liver & kidney –elevating activities of gluconeogenic enzymes.
-They stimulate protein catabolism (except in the liver) and lipolysis.
-thereby providing the building blocks and energy that are needed for glucose synthesis

2-↑ Stress Resistance:
-↑ Plasma levels of glucose!
-roviudes energy to combat stress 
-modest ↑ in BP by vasoconstirction!

3-After blood cell in plasma:
-↓ in esonophil/ basophils/monocytes/ lymphocuytes reduistructing them from ciruclation to lymph tissue
-↑ level of Hb/RBC/Platlets!

4-Endocrime suystem:
-Feedback (-) of corticotropin production by (+) GCD.
-causes inhibition of further glucocorticoid synthesis
-as well as further production of thyroid-stimulating hormone.
-In contrast, growth hormone production is increased

The comparison is based on classification according to duration of action and potency of different drugs according to cortisol 

Xanti inflamamtoryTopiclDose
short to medium GCD

Intermediate acting

Long acting GCD(36-55H)


^^ Type of therapy:
pulse therapy, high dose, medium dose and low dose therapy, alternative day therapy, replacement therapy
In determining the dosage regimen to be used, the seriousness of the disease should be considered , the amount of drug likely to be required to obtain the desired effect, and the duration of therapy: 
I- In some diseases, the amount required for maintenance of the desired therapeutic effect is less than the dose needed to obtain the initial effect, and the lowest possible dosage for the needed effect should be determined by gradually lowering the dose until a small increase in signs or symptoms is noted.

II-When it is necessary to maintain continuously elevated plasma corticosteroid levels to suppress ACTH, a slowly absorbed parenteral preparation or small oral doses at frequent intervals are required. The opposite situation exists with respect to the use of corticosteroids in the treatment of inflammatory and allergic disorders. The same total quantity given in a few doses may be more effective than that given in many smaller doses or in a slowly absorbed parenteral form.

III-Severe autoimmune conditions involving vital organs must be treated aggressively, and undertreatment is as dangerous as overtreatment. To minimize the deposition of immune complexes and the influx of leukocytes and macrophages, 1 mg/kg/d of prednisone in divided doses is required initially. This dosage is maintained until the serious manifestations respond. The dosage can then be gradually reduced

IV- When large doses are required for prolonged periods of time, alternate-day administration of the compound may be tried after control is achieved. When used in this manner, very large amounts (eg, 100 mg of prednisone) can sometimes be administered with less marked adverse effects because there is a recovery period between each dose. The transition to an alternate-day schedule can be made after the disease process is under control. It should be done gradually and with additional supportive measures between doses

^^ADR+ Prevention:
-osteoporosis( need to take with Vit D)
-Cushing like syndrome- moniter ,stop if needed
-Catract risk
-Hyperglycemia moniter blood glucose level

***Antiarrythmic X: classifcation….

N Channel Blocker
IIBeta adrenedic block
K+ channel block
PRolong repolization
IVCA Chanell blockade

Class I – Na channel blockers
-Block  voltage -senstive NA channels
—>↓ na slows the rate of rise og phase 0
—>↓ in excitiblity and conduction velocity
-↓ slop of phase 0depolaization
-class IA -quininde/procamnide
-clinical use-both atrial and ventircular arrythmia
-Ia Quinide (400mg 2h till max 1200 mg)

Class Ib- Lidocaine, mexiletine
-Clinical use: acute vnetircular arrythmia esp post MI
-Class Ic-propaferone, Flexanidie
-Lidocaine( IV dose 1-2mg/kg)
-clinical use- SVT !/Ventricular aRR

-X : progafenon, flexatuide)
-Tx of A+V arrythmias
-can provoke proaarythmia
-prevent of PAroxysmal A Fibrillaion

Class II-B blockers/ metroprolol
↓ slope of phase 4
-Prlong AC condition ,
-↓ HR and contractility!
-↓ SA+ AV node activity 
-↓ HR and contractility!
-clinical use : SVT/A Fib/A flutter!
-X :Metoprolol!

Class III
-K+ channel blockers!
-prolong duration of AP
-X:amiodorone , sotalol 
-clinical use: A fib/A flutter/ VT
-Tx of Sevee regfractory Supraventicualr aRR

Class IV:

-X Ca Cannel blocker
-Decrease current in carried by Ca_
-↓ Rate 4 of spontenous DP
-Effective onl for Atrial aRR
-CCB cesopamil dilitazem
-↓ conduction velocity /↑ ERP/↑ PR interval
-clinical use- SVT
-X :Verapamil

^^The goals of antiarrhythmic drugs:
• Discontinuation of arrhtyhmia (atrial or ventricular tachycardia, AF)
• Prevention of recurrent arrhythmia
• Controlling of ventricular rate, if recurrence can’t be prevented.

^^ Other antiarrhythmic drugs:
At high doses, the drug decreases conduction velocity, prolongs the refractory period, and decreases automaticityin the AV node directly slows conduction through AV node.
1.IV adenosine is the drug of choice for  abolishing acute supraventricular tachycardia. 
2.Adenosine has an extremely short duration of action (~ 15 sec).
3,Can provoke proarrhythmic effect, bronchospasm, conduction abnormalities. 

↓ the refractory period in atrial and ventricular myocardial cells while prolonging the effective refractory period &↓ conduction velocity in the AV node. 
Digoxin is used to control the ventricular response rate in atrial fibrillation and flutter. 
-Directly inhibits sodium potassium pump. 
-Digoxin vagal activity and sympathetic activity,  automaticity of myocardium.
-Slowing of AV nodal conduction through increasing of vagal tone slowing of ventricular rate.
Therapeutic use:
•AF, atrail tachycardia

•Atrial paroxysmal tachycardia the most effctive drugs for termination are: verpamil, adenozine.

***18-Antiarrythmic X for terminal and prophylaxis of Acute A fibrillation
^^Acute AF (<48 h):

-Without signs of HF: 

1.Propafenone (dose: 450–900 mg/d q 8 h) for conversion of atrial fib to sinus rhythm
-Effectiveness: individual maintenance. dose: under ECG Bp control
-Safety: not in patients with significant structural heart disease or MI in the last 3 months, uncontrolled cong.HF, sever bradycardia , BBB.
-Amiodarone (dose: p.o → loading doses of 800-1200 mg/d are required for 1 – 3 wk until initial therapeutic response occurs, then 600–800 mg/d for 1 month. Maintenance dose → 100–400 mg/d; i.v → 5–7 mg/kg during 30-60 min., then 20 mg/kg during 24 h (1.2-1.8 g/day)). Always check for edemas, pulmonary toxicity, serum electrolytes.

2.Metoprolol (p.o: 50–200 mg/d; i.v: 1–2 mg/min (total 10-15 mg)
Safety: not in patients with AV block 2nd degree, CHF, clinically relavent bradycardia, astyhma, hypotention or COPD.

-With signs of HF:

^^Prolonged AF (>48 h):

-Anticoagulation therapy 
1.Vit. K antagonists – therapeutic range for 3 weeks prior to cardioversion.
-Amiodarone, beta-blockers, verapamil, digoxin Slowing of ventricular rate.


1-Propafenone → ECG, BP, pulse (particularly at initiation of therapy).
2-Quinidine → 
3-cardiac monitor required during I.V. administration
4-CBC, liver and renal function tests should be routinely performed during long-term administration.
 Metoprolol → monitor ECG and BP.
 Amiodarone → 
5-BP, HR, ECG, and rhythm throughout therapy
6-assess patient for signs of lethargy, edema of the hands or feet, weight loss, and pulmonary toxicity (baseline pulmonary function tests and chest X-ray; continue monitoring chest X-ray annually during therapy)

 Digoxin serum concentrations are monitored because digoxin possesses a narrow therapeutic serum range; the therapeutic endpoint is difficult to quantify and digoxin toxicity may be life-threatening. Digoxin serum concentrations should be drawn at least 6-8 hours after last dose, regardless of route of administration

^^Adverse reactions:
1-Quinidine –
Proarrhythmia, hypotension, hepatotoxicity, GIsymptoms (diarrhea, nausea, vomiting), cinchonism (vertigo, diplopia tinnitus), autoimmune and inflamatory syndromes.
2-Propafenone – 
Conduction abnormalities, proarrhythmia, unusual smell sensation, hepatitis, depression, alopecia, CHF.
Bradycardia, cold extremities, fatigue, nightmares, headache, depression, increase congestive heart failure, transitory male inpotension.
4-Amiodorone – 
Hypothyroidism, hyperthyroidism, asymptomatic corneal microdeposits, pulmonary fibrosis, GI tract intolerance, abnormal liver-function tests, tremor, ataxia, dizziness, lack of coordination, neuropathy, sinus node dysfunction.
5-Digoxin – 
Adverse effects are concentration-dependent.
Loss of appetite, nausea, vomiting, diarrhea, blurred vision, drowsiness, dizziness, depression.

***20-Unfracture Hepatin(indication + method of adm…with bleeding!!
Heparin binds to antithrombin III this heparin- antithrombin III complex inactivates thrombin and clotting factors IX, X, XI, XII.

1. Deep venous thrombosis 
2. Acute pulmonary embolism
3. Acute MI
4. Unstable angina 
5. Prophylaxis to prevent postoperative venous thrombosis

^^Methods of administration: 
-IV: absorbed rapidly from GI and it is the preferred method and it is used if immediate anticoagulant effect is needed.
– Subcutaneous

-Initial dose—> 80 IU/kg (bolus)
-Continuous—-> 18 IU/kg/h (average 20,000-40,000 IU/d).

^^Monitoring of effectiveness:
1. Dosage is considered to be adequate when aPTT reaches therapeutic range.
2. aPTT normal value is 24-40sec
3. aPTT therapeutic range 1.5 – 2 times to the baseline level.
4. In the early stages of treatment aPTT should be determined every 4h.
• Heparin should be administrated until INR is within therapeutic range (INR 2 – 3)

^^ Monitoring of safety:
• Hb, Hct
• signs of bleeding
• fecal occult blood test
• aPTT
• Platelet counts 
should be routinely monitored
Becareful of thrombocytopenia, osteoporosis, hyperkalemia and bleeding.

^^Use of antidote in case of overdose with heparin and bleeding:
• Excessive anticoagulant action of heparin is treated by discontinuance of the drug. 
• If bleeding occurs administration of a specific antagonist protamine sulfateis indicated. 
Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity. 
For every 100 units of heparin remaining in the patient, 1 mg of protamine sulfate is given i.v (1 mg binds 100 IU of heparin). 
The rate of infusion should not exceed 50 mg in any 10-minute period. 
Excess protamine must be avoided; it also has an anticoagulant effect. Dosage for heparin reversal is 1 mg protamine sulfate i.v for every 100 IU of active heparin

***21-Low moleculat weight heparin:

-Drugs: enoxaparin,nadroparin, dalteparin, certopain.
-MOA : They have a preferential inhibitory effect on activated factor Xa rather than thrombin (factor II).


LMWHunfractioned hepatin
Half lifeLongShort
Lab moniteringNonAptt
ADRLess bleedinHigh Risk of bleed

^^ Indications:
• Deep venous thrombosis 
• Acute pulmonary embolism
• Acute MI
• Unstable angina 

^^ Adverse reactions:
1. Bleeding :
-elderly and patients with renal/hepatic insufficiency as well as alcoholics are more prone to hemorrhage.
-Careful monitoring of bleeding time is required to minimize this problem. 
2. Hypersensetivity reactions :
-possible AE includes chills, fever, urticaria, or anaphylactic shock.
-This is mainly because heparin is of animal origin and thus should be used cautiously in patients with allergy.

3. Osteoporosis:
-Long-term heparin therapy (≥ 6 month) is associated with osteoporosis and spontaneous fractures). 

4. Heparin-Induced Thrombocytopenia the risk is lower in those treated exclusively with LMWH.
– LMWH Is administered subcutaneously once every 12-24 hrs. monitoring is not required in majority of patients except for patients with kidney problems ,
burn patients and those who are at the risk of bleeding.
– LMWH has anti Xa activity but PTT is not sensitive enough to pick this up consistently and therefore more sensitive tests are needed.monitoring LMWH with anti Xa is more sensitive but it is not routinely used. Samples should be drawn 4 hours after dosing.

 Transitioning:
Warfarin should be started concomitantly with LMWH for 4-5 days, then when the INR value reach ≥ 2 heparin can be stopped, while warfarin cont.

***22-Vitamin K antagonist-Indication ,dosage…

-Primary/secondar prophylaxis of Arterial TE 
(DVT/E / Cerebrovascular disease/Cardiac disorder/A Fib/ Heart valve )

^^ Dosage :
-Depends on INR value
-can start frm 5-10 mg
-increase or decrease 0.5-3mg
-Therautic range INR2-3

^^ Monitoring of effectiveness and safety
-Prothrombin time, hematocrit; INR (frequency varies depending on INR stability)
– INR (normal value
→ <1.18; therapeutic range → 2.0 – 3.5 
– Prothrombin index (PI; normal value (with SPA reagent)
→ 70-130%, therapeutic range → 15–25%)
– Control – every week during the first month, later every month.

Anticoaulant effect(+)AnC effect(-)
-Vit K

^^Pharmacotherapy in case with vitamin K antagonists overdose and bleeding
I-INR above therapeutic range but < 5
→ dose can be reduced or omitted and resumed at a lower dose

II-INR 5-9, pt is not bleeding
→1 or 2 doses of warfarin can be omitted, and when IR falls into therapeutic range warfarin is cont. at lower dose

III-INR 9-20, pt is not bleeding
→warfarin should be omitted. Vit K 3-5 mg p.o. INR should be monitored and vit K repeated as required.

IV-INR > 20, or serious bleeding
→warfarin should be omitted. Vit K 10 mg by slow i.v infusion. FFP transfusion. Prothrombin complex concentrate.

***23- use of Warfarin Before Surgery :
In patients with previous arterial embolism, only 4 daily doses of warfarin should be withheld preoperatively and the INR should be measured the day before surgery to determine if a small dose of vitamin K is needed to accelerate the reversal of anticoagulation. 

After an acute episode of venous thromboembolism, defer surgery, if feasible, until patients have received at least 1 month, and preferably 3 months of anticoagulation. 

To get acceptable INR for surgery:

I-Management based on risk of Thrombosis:
-Surgery/Procedure to be done in <24h:
-Discontinue warfarin and administer IV vit. K
-If surgery will be performed within 6 hours Octaplex is recommended
– Check INR immediately after product infusion and prior to surgery to document correction. If INR not corrected, consider repeat administration of Octaplex.

II-Surgery/procedure to be done in 23-96h: 
-Discontinue warfarin and administer IV or PO vit. K
-Check INR in 24h. 
-If INR is not corrected after a dose of vit. K, give another dose of IV vit. K and recheck INR in 12h.

III-Elective surgery with planned anticoagulant reversal:
-Patient should be 5 or 6 days warfarin-free prior surgery depending on therapeutic INR range
-Consider need for LMWH bridging therapy.

***24-Interaction of Warfarin:

Hepatic Dysfunction
Vit K

^^ Transition from LMWH use to warfarin therapy:
-Warfarin should be started concomitantly with LMWH for 4-5 days, then the INR value reach >2 heparin can be stopped, while warfarin continues.

***25/26 – New Oral AnC : Diabigation/Rivacarob///

• Reduction of risk of stroke and systemic embolism in non-valvular atrial fibrillation.
• Treatment of DVT and PE (in patients who have been treated with a parenteral anticoagulant for 5-10 days)
• Reduction in the risk of recurrence of DVT and PE

ApTT, PTT are the tests routinely used to check the effectiveness. Another test that specifically shows a linear relationship to drug effectiveness is TCT-thrombin clotting time- but this test is not routinely used.

Renal function should be assessed in patients with creatinin clearance(CrCl) less than 30ml/min (it should be discountinued). In 30-50 dose should be reduced 

With pglycoprotien( p-gp), ketoconazole,cyclosporins,verapmil, amiodrone, rifampicin.

Monitering OF Effectiness & Safety:
1-Activated partial thromboplastic(APIT) :
is sensitive to Dabligatran but it becomes insensitive
APTT of 1.5 besline vvaue wth 150 mg 2x a da !
2-Thrombin time:
-very (S) to dabigatram and Normal TT
-Not usefl for dose adjustment

II-Non-steroidal anti-inflammatory drugs (NSAIDs): Monitor for risks of bleeding if dabigatran used with NSAIDs, especially
those with half-lives greater than 12 hours (e.g. naproxen, piroxicam). NSAIDs with short half-lives less than 12 hours (e.g.
ibuprofen) have not been shown to be associated with increased bleeding risk.

III-Inhibitors of P-glycoprotein efflux transporter: The prodrug dabigatran exilate is a substrate for the P-glycoprotein effluxtransporter. Avoid use in combination with the following inhibitors which may increase the levels of dabigatran.
 azoles (e.g. ketoconazole, itraconazole)
 calcium channel blockers (e.g. diltiazem, nifedipine, verapamil)
 immunosuppressants (e.g. cyclosporine, tacrolimus)
 macrolides (e.g. clarithromycin, erythromycin)
 protease inhibitors (e.g. ritonavir, saquinavir)

***27??-Anti-platlet Drugs(asporin/clopodogrel. Ticagrelor) -Indicuation , dual therpay , monitering of effecitvness and safety !

-Hemoatsis is basic defencem ehcniams  to prevent Blodo loss after injury
-This process depends on :
1-Blood flow dynamics
2-Components of Vessel Wall
3-Platletts and plama protien in Tissues!

-5 days is optimal Time  for aspirin before surgery!

^^Antiplatlet X:
1-COX-1 (-) : NSAID:
2-Membrane Receptor Antagonist :Seortonin , Alpha 2 adrengergic Receptor
3- Thromboxane Receptor Antagonist
4-Receptor Antagonist GP IIB /.IIIa
5-PDE (-)

-As primary prevention in pts with large # of Risk Facotres (RF)
-PTs who have several Risk
-PTs with A-Fib 
-Prior Ischemic HEart Disease
-Acute phase AMI
-Acute coronary syndrome
-Coronary Stending
-To (-) Thrombotic stokr event!

ASpirin : ↓ Platlet Agregation /antipyritic /analgesic/antiinflammatory!

^^Side Effect:

I-The most important interaction of aspirin is with NSAIDs (ibuprofen)
– The effect of aspirin ibuprofen is less when used at the same time as it is also an inhibitor of COX (in this case reversible),
-so that when joined, aspirin can not interact with it. And, as we know, ibuprofen starts before its effect, while the antiplatelet effect of aspirin takes longer to start (first has other effects). 

II-Ticlopidina and clopidogrel are not competitive antagonists.
-They are prodrugs (need metabolically activated). The mechanism of activation is different for these drugs.
-The cytochrome P450 Clopidroguel resulting differences in the rate of metabolism is activated. In the case of prasugrel metabolism it takes place by another mechanism, which produces less variation.

^^Effectiveness: this is measured by PT and INR.
• five days is the optimal time without ASA treatment before surgery.

***28-thrombolytic : comparison of commonly used agents:
The thrombolytic agents share some common features. All act either directly or indirectly to convert plasminogen to plasmin, which in turn cleaves fibrin, thus lysing thrombi 

-Alteplase (tPA)

-Pulmonary embolism with hemodynamic instability 
-Ascending thrombophlebitis 
-Peripheral vascular disease 
-Myocardial infarction 
-Ischemic stroke <3h (only Alteplase)

^^Monitoring of efficacy and safety:
-Efficacy 
a.Pain relief and ST-segment normalization together are highly accurate at predicting reperfusion.

b.As blood reaches ischemic tissue, CK is washed out, causing a dramatic peaking of CK earlier than would be expected.
CK normally elevates four to six hours following infarction, with a peak at 24 hours. When reperfusion occurs, however, CK elevates in minutes, and peaks within a few hours

c.When used for stroke patients, we can check it by physical examination of patient, by examinaing the motor/sensory part in which this part of the brain in charge on

^^Safety 
1.Because the biggest side effect is hemorrhage we need to constant monitor physical state, signs of bleeding, bp , CBC.
2.Because streptokinase has foreign protein ( made from streptococcus) which is antigenic Because most individuals have had a streptococcal infection sometime in their lives, circulating antibodies against streptokinase are likely to be present in most patients. These antibodies can combine with streptokinase and neutralize its fibrinolytic properties. Therefor we need to look for allergic reaction symptoms as fever, rashes and anaphylactic reactions.

^^Comparison of commonly used agents:
1.Alteplase considered as fibrin specific in contrast to streptokinase 
2.Alteplase is superior in dissolving older clots in contrast to streptokinase 
3.Alteplase half-life as very short high life (5min) in contrast to streptokinase in which half life is <30min 
4.Streptokinase causing systemic fibrinolytic state due to its poor specificity 

***29- Treatment of Bronchial obstruction:Sympathomimentic / anticholenierci ////

1- MOA:
Their binding to β receptors—abundant on airway smooth muscle cells—stimulates adenylyl cyclase and increases the formation of intracellular cAMP, therefore, relaxiation of the airway’s smooth muscle and inhibition of the bronchoconstricting mediators from mast cells occurs. They may also inhibit microvascular leakage and increase mucociliary transport. In general, adrenoceptor agonists are best delivered by inhalation. This results in the greatest local effect on airway smooth muscle with the least systemic toxicity.

2. Sympathomimetic agents
a. Epinephrine: is an effective, rapidly acting bronchodilator when injected subcutaneously or inhaled. Maximal bronchodilation is achieved 15 minutes after inhalation and lasts 60–90 minutes. Because epinephrine stimulates α and β1 as well as β2 receptors, some side effects occur such as:
– tachycardia,
–  arrhythmias
– ,and worsening of angina pectoris.
b. Isoproterenol is a potent nonselective β1 and β2 bronchodilator. 
i. Because epinephrine and isoproterenol increase the rate and force of cardiac contraction (mediated mainly by β1 receptors), they are reserved for special situations
c. Ephedrine compared with epinephrine, has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and β2-selective agonists, ephedrine is now used infrequently in treating asthma. When inhaled as a microaerosol from a pressurized canister, isoproterenol causes maximal bronchodilation within 5 minutes and has a 60- to 90-minute duration of action. It is now rarely used for asthma.

d. Beta2-Selective Drugs
i. Most widely used sympathomimetics for the treatment of the bronchoconstriction of asthma. They are effective after inhaled or oral administration and have a longer duration of action than epinephrine or isoproterenol.

ii. Albuterol, terbutaline, metaproterenol, and pirbuterol are available as metered-dose inhalers. Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol. Bronchodilation is maximal within 15 minutes and persists for 3–4 hours. Albuterol and terbutaline are also available in oral form. This route of administration presents no advantage over inhaled treatment and is rarely prescribed.Of these agents, only terbutaline is available for subcutaneous injection. The indications for this route are similar to those for subcutaneous epinephrine—severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective—but it should be remembered that terbutaline’s longer duration of action means that cumulative effects may be seen after repeated injections.

iii. A newer generation of long-acting β2-selective agonists includes salmeterol (a partial agonist) and formoterol (a full agonist). These long-acting β agonists (LABA) are potent selective β2 agonists that achieve their long duration of action (12 hours or more) as a result of high lipid solubility. These drugs appear to interact with inhaled corticosteroids to improve asthma control. Because they have no anti-inflammatory action, they should not be used as monotherapy for asthma. 

iv. Ultralong-acting β agonists, indacaterol, olodaterol, and vilanterol, need to be taken only once a day but are currently FDA-approved only for the treatment of chronic obstructive pulmonary disease (COPD). 

 The three important methylxanthines:
 Theophylline
 Theobromine
 caffeine.
• theses are used best in acute asthma attack (nocturnal asthema attack)and they have long term asthma control.
• They are either taken solo or with inhaled corticosteroids. 
• Theophylline is the most effective bronchodilator. It relieves airflow obstruction in acute asthma and reduces the severity of symptoms in patients with chronic asthma:
1-Improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. 
2- Its use requires occasional measurement of plasma levels; it often causes unpleasant minor side effects (especially insomnia); and accidental or intentional overdose can result in severe toxicity or death.
3- The development of more effective bronchodilators (β2-selective adrenergic agonists) and more effective anti-inflammatory agents (ICS) with fewer adverse effects has resulted in the decline in the clinical use of theophylline. Typically, theophylline is rarely used as monotherapy and, when prescribed, is most commonly used as add-on therapy when treatment with other agents.
• Requires occasional measurement of plasma levels, it often causes unpleasant minor side effects (especially insomnia). 
• Overuse can lead to toxicity and death.
1- Increased effect by smoking,phenytoin, rifampicin
2-Decreased effects by erythromycin,

• ipratropium bromide, tiotropium bromide: produce a slower responce than inhaled sympathomimetics. 
• They are better suited for regular prophylactic use.
• A combination of inhaled ipratropium and beta2 agonist has a longer lasting bronchodialation. 
• Ipratropium appears to be as effective as albuterol in patients with COPD who have at least partially reversible obstruction
• Antimuscarinic agents are effective bronchodilators. Greater bronchodilation, with less toxicity from systemic absorption, is achieved by treatment with a selective quaternary ammonium derivative of atropine, ipratropium bromide. Ipratropium can be delivered in high doses by this route because it is poorly absorbed into the circulation and does not readily enter the central nervous system. 
• Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition.

o Decrease in symptoms
o Improvement in pulmonary function tests
o Serum levels in Theophylline use
 Methylxantines: antagonize Propranolol, potentiate sympathomimetics, additive with diuretics and antibiotics – variable (may also cause precipitation if mixed in same IV line)
 Antimuscarinic drugs: decrease gut motility and delay gastric emptying and therefore may increase the absorption of other medications. The side-effects of antimuscarinic drugs may be exacerbated when given with antihistamines, anti-parkinsonism drugs, monamine oxidase inhibitors or tricyclic antidepressants.

^^Sympathomimentic agents( Beta  blockers):^^

-binding to B Receptors ( abundant in airway SM)
-(+) adenyylyl cyclase 
-↑ formation of intraceelular cAMP
–> relaxing the SM  and(-) bonchoconstirction!

-is effective when injected subcutanously  or inhaled
-15 min post inhlation 
-ADR: HR ↑ / ARR/ Angina Worsening

-Non selective B1+ B2 Bronchodialator!

-Longer Duration /OP / Centrel effect/ Lower potency then epinephjrine!

4- Beta 2 Selective Drugs:
-Inhlaed , short Acting ,1st Line for Athma

-MEtered-Dose inhlaners!
-brronchodialation is within 15min persist 3-4 hours

6-Long acting Salmeterol(partial agonist + Formoterol ( full agonist(

– Important 3 : Therophylline/ theorbromine/ Caffeine!
-greater efficacy for acute asthma!
-narrow theraptuic index…monitering still neccesary

1- Theophylline:
-Most effective Bronchodialator
-improves long term control of asthma when takes as sole maintanceTx
or when with CSF!
-neeeds plasma level measurnent

^^Antumuscaridinic X:
-are effective Bronchodialators!
-Less toxic from systemic absorption
-quaternary ammonium derivative of atropine/ipratropiu bromide/!
-Ipratropium can be delviered in high dses

-Decrease in Sx
-Imrpovement in PFT!
-Serum level og Theuphyllne Use

^^Interaction :
-Methyxantines: anmtagonize propranolol!
-Antimusictic x: ↓ gut motility!+ delay gastric emptying !–> increase Absorption of other X

****30- Tx of bornchial bsturction : X for inflammation!

-Causes Fro Broncho Obst : asthma/COPD!

^^Adrenoreceptor Agonist:

-B receptor abudnant in SM of Airway
(+) adenyl Cyclase & (+) Formation of cAMP
hence relaxing the SM of bronchoconstriction from mast cell

-Best delivered by inhalation
Great Local Effecton airway SM and least toxicity.
Bronchial deposition of aerosol in (+) by slo inhalation

Epinephrine, and isoproterenol because of ADR 
and development of B2 selective agonist
More effective 

ADR esp that activate B1+b2:
1-HR (+)
2-Skeletal muslce tremor
3-(-) in K+

The B2 Selective Adenoreceptor Agonist X , 
Particulary albuterol most widely used Sumpathomimc for Tc 
of Bronchocontstirction of asthma!
very effective after oral administration 

^^inhalation trechnique:
-Aerosolized poweder with spacer holding chamber
-Metered Doser

^^Preventon of ADE:
-combotherapy to allow lowe dose of X such as GC
-Long term therapy With B2 agonist( increase death in asthma pts)
-PRevent tolerance of B2 agonist by admnister GC
-bornchial obstruction is controled ,doses are adjusted to lower effect to prevent ADR!!
-Albuterol, terbutaline, metaproterenol, and pirbuterolare available as metered-dose inhalers.
Given by inhalation, these agents cause bronchodilation
equivalent to that produced by isoproterenol. Nebulized
therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler

^^Methylxanthine rugs:
the 3 Important imp X are: 
At High [C] can (-) several Phosphodiesterase
cAMP and in Some tissue ,cGMP cyclic AMP regulates many cellular function!
including buyt not limited to (+) cardiac function/ Relaxated SM/(-) in immune
& inflammatory function

^^Antimuscarinic agents
Antimuscarinic agents are effective bronchodilators.
Even when administered by aerosol, the bronchodilation achievable with atropine,
the prototypic muscarinic antagonist,
is limited by absorption into the circulation and across the BBB
. Greater brdialator  with less toxicity from systemic absorption,
is achieved by treatment with a selective quaternaryammonium
derivative of atropine, ipratropium bromide.


-They do not relax airway smooth muscle directly but (-) bronchial hyperreactivity.
Their most important action is (-) of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells.
-Inhalational treatment is the most effective way to avoid the systemic adverse effects of corticosteroid therapy. 
-The introduction of ICS such as beclomethasone, budesonide, ciclesonide,flunisolide, fluticasone, mometasone, and triamcinolone has made it possible to deliver corticosteroids to the airways with minimal systemic absorption. A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis.
-Side effects from inhaled corticosteroids are minor when the proper amount is taken:
1- Cough
2-  hoarseness or husky voice
3-  sore throat or thrush (a yeast infection)
4-  Patients can protect against these discomforts by rinsing their mouth, gargling with water and spitting out, to remove any medicine left in the mouth.

^^ Treatment of COPD:
-COPD is characterized by airflow limitation that is not fully reversible with bronchodilator treatment.
Despite the differences between COPS and asthma, the approaches to treatment are similar,
although the benefits expected (and achieved) are less for COPD than for asthma. 
– For relief of acute symptoms, inhalation of a short-acting β agonist (eg, albuterol),
of an anticholinergic drug (eg, ipratropium bromide), or of the two
in combination is usually effective. For patients with persistent symptoms of
exertional dyspnea & limitation of activities, regular use of a long acting bronchodilator,
whether a long-acting β agonist such as salmeterol or a long-acting anticholinergic (eg, tiotropium)
is indicated.
– For patients with severe airflow obstruction or with a history of prior exacerbations, regular use of an inhaled corticosteroid reduces the frequency of exacerbations. 
o Theophylline may have a particular place in the treatment of COPD, as it may improve contractile function of the diaphragm, thus improving ventilatory capacity. 
The major difference in treatment of these conditions centers on management of exacerbations. The use of antibiotics in this context is routine in COPD, because such exacerbations involve bacterial infection of the lower airways far more often in COPD than in asthma.

o Some drugs may increase the effects of oral beta-2 agonists, including certain antidepressants, thyroid drugs and, other bronchodilators (oral or inhaled).
o If the patient is taking methylxanthines for long-term control, he may feel more of the effects on his heart.
o Beta blockers can decrease the effect of beta-agonist..
o Oral beta-2 agonists, in turn, can interfere with drugs that reduce blood pressure and with digitalis drugs, used to treat congestive heart failure and very rapid heartbeat.
o There is a fatal drug interaction between isoniazid and theophylline which may be due to convulsions that trigger a shock lung syndrome.
o Antimuscarinic agents may interact with:
o MAOIs: dry mouth, blurred vision, urinary hesitancy, urinary retention and constipation.
o Disopyramide causes increased antimuscarinic side effects.
o They delay absorption of ketoconazole.
o Reduced sublingual nitrate tablets effect due to dry mouth.


***31-Antihistaine X : classifciation / comparisson….

1-H1 Antihistamines:

1st G anithistamineas
– ethanolamines (carbinoxamine)
– piperazine derivatives (hydroxyzine)
– alkylamines (brompheniramine)
– phenothiazine derivative (promethazine)

2nd Generation :

– piperidine (fexofenadine)
= 2nd generation of H1 blockers has less sedative effect because it is likely to cross the BBB
= H1 blockers are normally used in the treatment of allergic and inflammatory conditions, motion sickness and nausea.

= H2 receptor antagonists: these have little to no affinity for H1 receptors and are clinically used for treatment of gastric ulcers and heartburn (they have an effect on the gastric acid secretion). Eg ramitidine
= H3, H4 receptor antagonists 

2-H2 Receptor Antagonist G1
3-H3+H4 Receptro Antagonist!


G1 (sedating  antihistamines)
-High liquid soluble!..
-Cross BBB + antagonist H1 recpetor of CNS+ PNS!
-cause sedation/ comgitnive(-)
-used for sleep disutbance(due to utricaria/atopic dermatitis)
-Alimemzaeine+ promethzine=most sedating!

G2: (non sedating):
-large/lipophillic molecules ” 
-less lieky to cross BBB

4-anti- muscarinic effects such as urinary retention, dry mouth, blurred vision.
5- Rare: hypotension, palpitation, arrhythmias, extrapyramidal effects, 

– antimuscarinic and sedative effects are potentially enhanced by co-administration of antihistamines.
2 Co-administration of antifungal imidazoles (eg ketoconazole, itraconazole) and macrolide antibiotics (eg erythromycin, clarithromycin):
-is to be avoided, as these drugs interact and raise the plasma concentration of second-generation antihistamines.
-Lethal ventricular arrhythmias occurred in several patients taking G2 agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole, or macrolide antibiotics such as erythromycin.
– antimicrobial drugs (-) the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines. The mechanism of this toxicity involves blockade of the HERG (IKr) potassium channels in the heart that are responsible for repolarization of the action potential.

• For those H1 antagonists that cause significant sedation, concurrent use of other drugs that cause central nervous system depression produces additive effects and is contraindicated while driving or operating machinery.

***32 -Antideressants: classifcation , comparison….

-Indication : moderate to severe depression



SNRI(Serotoning reptuake inhi

-SSRI speicfic in inhibition of serotonin uptake in contract ot TCA
-SSRI and SNRI have little effect on alpha adregnergic, muscaridine H1 receptor
-TCA and SNRI  (-) both seoronin and NE

-GI effect
-Weight (+)
-Sleep disturbance
-Cardiotoxicity r
-Blurred vission
(constipation/dry mouth)

SSRI+ MOA- Serotonin Syndrome 
MOA _ Bupropin-Sezierure
•Combination with MOA  mutual enhancement leading to hypertension, hyperpyrexia, convulsions and coma
 Combination with ethanol or other CNS depressants toxic sedation

^^Rational management of depression:

The choice of an antidepressant depends first on the indication.
Not all conditions are equally responsive to all antidepressants. However, in the treatment of MDD ( major depressive disorder),
it is difficult to demonstrate that one antidepressant is 
consistently more effective than another. 
Thus, the choice of an antidepressant for the treatment of depression rests primarily on practical considerations such as:
A. Cost
B. Availability
C. adverse effects
D. potential drug interactions,
E. the patient’s history of response or lack thereof
F. patient preference
G. patient’s age
H. gender
I. medical status

For example, older patients are particularly sensitive to the anticholinergic effects of the TCAs.
-At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. 
-Their popularity comes from their ease of use, tolerability, and safety in overdose. The starting dose of the SSRIs is usually the same as the therapeutic dose for most patients, and so titration may not be required.
-Choice should be based on the individual patient’s require- ments, including the presence of concomitant disease, existing therapy, suicide risk, and previous response to antidepressant therapy.
-SSRIs are better tolerated and are safer in overdose than other classes of antidepressants and should be consid- ered first-line for treating depression. In patients with unstable angina or who have had a recent myocardial infarction, sertraline has been shown to be safe.
-TCAs have similar efficacy to SSRIs but are more likely to be discontinued because of side- effects; toxicity in overdosage is also a problem.
• Although anxiety is often present in depressive illness (and may be the presenting symptom), 
1- TCA : antimuscarinic+ sedatives !!
2-Co-adminsitration of ntigfundal imidazole and macrolide antibiotics!
(-) metabolism of Many x by CYP3A4 and ↑ blood [C] of antihistamines]

^^Monitoring of effectivenss:
-tx should continue t least 4 weeks
-X used at least 6 M
-post remiision Tx should be cont  for 6Months
-use depressent assement scale
-If there is Dep Hx maintaince Tx for 2 years
-use depressentman assesment scale

^^Duration of Tx:
At least 2 W to see side effects?


G1:(low potency)

G1( High potency) 





I-traditional antipsychotics:
1-Low potency(chjlorpormazine)
2-High potency (HAloperidol)-. greater dopamine (rcp affinity!

^^ADR (typical antipsychotics)
1-Antidopaminergic effect( extrapuyramicnal. Parkisnonism.,dystonia)
2-Anti-HAM effect
3-Weigh gain
4-Elevated lvier enzyme
7-Neruoleptic Maigannt syndrome

II-Atypical antipsychotic
-block dpamine+serotonin recptors
-Clozapine, Risperidone

– Also known as second generation antipsychotics
– They include colazapin, olanzapin
– Clozapin was less likely to produce extrapyramidal effects (physical symptoms such as tremors, paranoia, anxiety, dystonia, etc. as a result of improper doses or adverse reactions to this class of drug) in humans at clinically effective doses than some other types of antipsychotics.
– Block both dopamine and serotonin receptors (Clozapine, Risperidone)

Many atypical or second generation antipsychotics block serotonin(5-HT) receptors in the brain, particularly 5-HT2A receptors—the vital players in schizophrenia. In addition, atypical antipsychotics also act on adrenergic, cholinergic (muscarinic), and histamine receptors.

-Antidopaminergic effects: Extrapyramidal side effects – Parkinsonism, Akathisia, Dystonia, Hyperprolactinemialeading to decreased libido, galactorrhea, gynecomastia, impotence, amenorrhea, osteoporosis
-Anti-HAM effects
-Weight gain
– Elevated liver enzymes, jaundice
-Skin rashes, photosensitivity
-Tradive dyskinesia
-Neuroleptic malignant syndrome

1.In traditional high potency there is a higher incidence of anticholinergic and antihistaminic side effects than high-potency traditional antipsychotics. 
2.In traditional high potency they have a lower incidence of extrapyramidal side effects (EPSEs) and neuroleptic malignant syndrome(FALTER-fever, autonomic instability, leucocytosis, tremor, elevated CPK, Rigidity)
3.Atypical antipsychotic have fewer side effects than traditional antipsychotics -> start with atypical agents.


1. Acute and chronic psychosis 
2. schizophrenia
3. Acute agitation, anxiety
4. Nausea and vomiting (e.g haloperidol)
5. Tourette’s syndrome.

1.Antipsychotic scale (special questionnaire MMS, brief antipsychotic test) before and after therapy, clinical symptoms.
2.Clinics – extrapyramidal signs, hard to predict- depends on the dosage.
3.Plasma concentration of the drug ( better to do it when patient on monotherapy).

^^Safety – ECG (prolongation of QT interval), CBC, liver enzymes (all before starting Tx), BP+pulse+T0, 

^^Rational pharmacotherapy of psychosis
1.In case of 1st episode -> atypical
-> no response -> typical low potency -> no response -> typical high potency.
2.Monotherapy more effective then combination therapy. 
3.High doses should be given for a short duration. 
4.Before Tx needed to consider risk factors: obesity, age ( caution in elderly >70yrs)
5.ECG needed to be cheque before Tx and periodically during
– if QT is prolonged decrease dose. Other abnormalities needed to be monitored. 
6.High dosage of therapy – only for limited time -> need to be review regularly -> if no improvement after 3 months -> return to standart dose. 

Prescribing more than one drug of antipsychotic not recommended due to severe side effects. 

^^Conversion from oral therapy to long acting formulations
1.When making conversion from oral to long acting formulation it needed to be done in a safe manner.
2.The injection done in intervals of 1 to 4 weeks. 
3.When initiating therapy with sustained release preparations of conventional antipsychotics, patients should first be given a small test-dose as undesirable side-effects are prolonged.
4.Individual responses to neuroleptic drugs are very variable and to achieve optimum effect, dosage and dosage interval must be titrated according to the patient’s response 


^^Classification and comparison:
– classified ,According to Duration of Action!

Short Acting (3-8H)Intermediate acting 
(10-20 H)
Long acting (1-3D)


^^PK + PD:
-Liver metabolism by CYP450
-except : oxacpram/ lorazepamd /temazepam
-PD- Potentiate GABA by ↑ Frequnecy of CL- Channels opening + influex and hyperpolarization
-Antidote- Flumazenil
-Not Given ith Alcohol , Opoids or Barbiturates

1. Anxiety disorders : Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder, social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive-compulsive disorder, and the extreme anxiety sometimes encountered with specific phobias, such as fear of flying
2.Muscular disorders :
Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy
3. Amnesia :
The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty
4. Seizures :
Clonazepam is occasionally used in the treatment of certain types of epilepsy, whereas diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus
5. Hypnotics
6. Management of alcholo withdrawl symptoms
7. Centerally acting muscle relaxant

1. Drowsiness and confusion (most common)
2. Ataxia (high doses)
3. Cognitive impairment
4. most skills
5. anterograde amnesia
6. CV depression
 Benzodiazepines should be used cautiously in treating patients with liver disease. They should be avoided in patients with

^^Termintion therapy+ withdrawl sx:
-withdrawl from sedatives-hyponitic scan have life threaning manifestation:
4-orthostatic hypotension
5-Hpyperactive reflexe
6-Generalized seizures!

Sx more prominent with short Half life then in Long half life!
cross dpeendence  ability of 1 X to supperess basitence Sx from disontinous of another!~

They bind to GABA receptors causing an inhibitory effect. There are different types of GABA receptors and according to that, the action varies:
o GABA receptors contain a alpha 1 subunit, binding to this receptor causes sedation and possibly anticonvulsant actions.

•Short acting benzos like Midazolam (IM or IV) have a rapid onset of actionbut the drug is eliminated out really quickly.
•Long acting benzos have longer pharmacological action.
•They are all metabolized in the liver.

-Oral contraceptives
All enhance the systemic availability and decrease clearance.

^^Termination of therapy and withdrawal symptoms

With the long-term use of sedative-hypnotics, especially if doses are increased, a state of physiologic dependence can occur. 
Withdrawal from a sedative-hypnotic can have severe and life-threatening manifestations. 
Withdrawal symptoms range from:
-Orthostatic hypotension 
-Hyperactive reflexes and 
-Generalized seizures. 

SyX: of withdrawal are usually more severe following discontinuance of sedative-hypnotics with shorter half-lives. Symptoms are less pronounced with longer-acting drugs, which may partly accomplish their own “tapered” withdrawal by virtue of their slow elimination. Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked among sedative-hypnotics. This provides the rationale for therapeutic regimens in the management of withdrawal states: Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol.
Factors that make withdrawl hard:
-High daily dose
-Shorter half life
-Longer duration of prior benzodiazepine treatment
-Alcohol or substance abuse.

***35-Antiepilectic X:

Def: Chronic brain disoder of various etiologies!, Characterized by reccuent epileptic seizured!

^^Anti epiliectic X classification:
-According ot MOA  , Or by the classification of seizure to determine Tx!
-given as monotherapy you give combination in case :
1-Failure monotherapy!
2-2 Different  types of epilepsy!

-MOA: aim to prevent spread of Abnormal Electricl disacharge!
1-Block Na/Ca channel
2-↑ Inihibitory GABAergic impulses
3-interference with excitatory glutate transmission


valrpoic Acid

^^Na Channel Blocker:
(Alwas check for hyponitramia)
(↑ Liver enzyme!)

(Similar to carbazepine , they (+) hepatic enzyme)

^^Ca Channel Blocker:

^^GABA receptor Agonist:

^^GAMA reuptake (-):

^^GABA Transaminase (-):

^^AED with potential GABA MOA:

^^Glutamate blockers:

^^K Channel opener:

-Oxacrarpazapine+ valporic/phenotyn= (+)Fever
-carapamazapine+ Phenotyn/Phenovalposic= 
-Valporic Acids+ Phenoarbital=(+) effect of phenoarbital

-AED are made to modify the process to favor(-) of Excitation and stop seziure activity!
-Main action include : Na channel blocker/ CCB Gaba(+) Glutmate blocker/
Carbonic anhydrase(-) / Hormones /X


1-Partial Seizures:
-Simple Partial seizure
-Complex partieal seizure
2-Generalized Seizures:
-Generalized Tonix
-clonic Seizures
-Status epilepticus

-(+)Risk of Suicidal behavior
-Weight gain /weight loss

Toxicity may  (+) without icnreasing antiepletic effect!!
interaction by hepatic enzyme induction or inhibition

-Are compelx and may (+) toxicity without (+) in epileptic effect!
1-Carbamazepine—> ¯plasma concentration of lamotrigine
2-Ethosuximide—->­↑plasma concentration of phenytoin.
3-Lamotrigine——>↑­ plasma concentration of an active metabolite of carbamazepine.

^^Driving antiepletic use:
-patients cna drive if they been epilepsy free for 1 years
-patiwent with drowziness should not dive
-1st siezure must not drive for 6 M

^^Pregnancy women:
-Antieplectic X increase Teratogeneicity
-Valoprate associte with congenital malformation
,so should be avoided unless no safer alternative
-No (+) teratogencity with Phenytoin,primidone,phenoarobtal,lamotrigine!
-Foalte supplementsation to decrease Neural tube defects!
-Routin Vitamine K at bith minize risk of Neonatal hemorrhage!
   -Breast feeding is ok normal doses exception barbiturates!

^^Rational pharmacotherpy Epilepsy(C) Rest(PART 2):
1-Obbject of Tx is to prevent occurance of sieure by mainint an effecitve dose of X
2-when choosing X , The sieuzre type, cocominent medication
3-Dosagfe Frequnecy determined by plasma Half life [C]
4-when used in ussualt dose can be given 2x day!
5-Lamotgine,phenoribtal have long Half life cna be given at bedtime
6-Young children metabolize nati Epilesy X faster!
may need more frequent dose
7-change of X should be caution , by slow withdrawl
8-concurrent anti epilectic increase risk of ADR

^^STatus epilecpticus Therapy:

1-immeidate measure of epilectic status:
-Position thatpts to avoid injudr
-supprot respitation
-mainting BP
-Hypoglycemaia correction
2-PArantral thiamine should be be considered
3-Tx urgently with IC lorazepan , repeat once after 10 min
4-Clonazepan can be used as alt


1-Levodopa and Carbidopa
2-Monoamine oxidase inihibots (MAO)
4-Dopamine-receptor Agoniost:


6-Antimuscarinic agent:

-X Tx does Not Prevent diease progression 
-Pts with parkisnon disease need to be refered to a specilist to confirm the Dx!
-Reviews every 6-12 M
-Tx is not started until Sx cause significant Disruption of faily activities!
-Levodopa, non ergot Dopamine receptor agonist
-Tx with 2+3 anti parkisnon x maybe necessary!
-Eldely antiparkisonian X , low doses andto increase the dose gradually!

1-Vitamine pyriodoxine (B6)
—-> ↑peirpheral breakfown of Levoopsa+ ↓
2-Concomitat of Levodopa+ MAO (-) 
—–>Hypersenstivie Crises caused by (+) Catecholamine production!
3-In GLaucoma, The X can cause ↑ intraocular pressure
4-Cardiac pts—->can develop aRR
5-Antipsychotric x are counter CI in parkinon syndeome!

^^Levodopa and carbidopa:
-Levodopa—->Because parkisonim results in insuffience dopamine in brain
-Dopamine does nto cross BBB but levodopa(precursor) Does


Peripheral EffectsCNS Effects
-Adrenergic action on iris

-Visual And auditory hallucination

-postural hpoyesion
-hepatic necorsis
-sleep disorder

^^Dopamine-receptor agonists
– Sedation
– Hallucinations
– Confusion
– Anorexia, Nausea, vomiting
– Postural Hypotension
– Dyskinesia
^^Antimuscarinic agents:
-mood changes
-dry mouth
-visual problems
-pupillary dilation
-sinus tachycardia
-urinary retention


Non SpecificSpecific
-PAracetamol ,NSAID

II-Ergot alkaloid:

^^Choice for Migrain attacks:
1-Mild to moderate:
—->NSAID and other analgesics
(analgeics: Opoids/ caffeine/ Bulbalbital)
2-Severe Attack Migrgraine from onset= Triptance #1 chocie
(block release of Vasoactive neuropeptide that tigger migraine)
(If nausea is present use them with antiemetic)
(Ergotamien is also effective)

Considered in PTs 
->2-3 Attack/month
-↑Frequency attacks
-suffer despite suitable Tx
-Cant take Suitable Tx for Migraine!

x are taken daily although mechnism unkown:
2-Ca C blocker
4-Valproic acid
Doses shoudl be as low as possible!

Triptan—>Dizziness/muscle weakenss/neck pain!!

1-Triptan + ergot derivation
—>(+) Coronary artery vasocontriciton
—–>(+) DRisk of HBP
2- Propanolol —> icnrease Triptan [C]

Combination with ergot derivatives (_) risk of coronary artery vasoconstriction and hypertensive effect
-Concentration of triptan may be increased by concomitant administration of propranolol
2. Ergo-derivatives: all this drugs increase the risk of ergotism (vasoconstriction, convulsions, GI effects)

***DM Goals:
– Blood sugar Control :
-the goal to keep Blood sugar level at normal / Near normal levels!
-Control of blood ushar can prevent long -term effect
2-Postprandial Glucose <9mmol/L
-Home Blood  sugar testing can be done!

=Normal Fasting blood sugar is <100mg/dl (5.6mmol/L)
althought some people  have difference gols:

-Goal of A1C ofor most people is to keep AC <7% 
Most common Complication of DM II 
can lead to Heart atack , chest pain ,stroke ,death

(-) risk by :
1-Quitting smokng
2-BP <130/80
Choldrestol <5mmol/L
HDL >1.6
LSL <1.8

^^SMBG is helpful for DM :
1-To Detect High or Low gluvose level!+  adjust A1C
2-Folllowing pts for comfirmation of acute hypo or hyperglycemia!
3-Technology facilitates educations!
4-SMBG helps motivate people 

^^DM II Tx for Oral Hypoglycemia and incretins!

I-Insulin Secreagogue:
1. 1 st generation:older generation
-Tolbutamide 0.5-2g/d duration of action 6-12h
– Chlorpropamide 0.1-0.5g/d, duration of action &lt;60h
2. 2 nd generation  most commonly used because less A/E and drug interaction then 1 st generations
– glyburide &lt;20mg/d duration of action 10-24h
– glipizide &lt;40mg/d duration of action 10-24h

Main MOA is (+) Insulin Secretion from Pancreatic B cells  by closure ofPotassium channels
—->depolarization—->(+) insulin Realise (-) Glucagon!

—>Modulate B-cell insuline release by regulating K channel!

II-D-Phenylanine Derivative:
—–>newest x /(+) release by regulating K eflux.

2-Biguandies(500 mg-2.55g/d)
-MOA  ?? , but it slows Glucose absorption! from GIT!+↑ (+) of glycolysis!
-Metofrmine half life 1.5-3 H!

-Plotgitazone (15-45 mg/d) 
-Rosiglitazone (2-8 mg/d)

-↓ Insuline (R) .
-TZD are ligant of peroxisome !
-steriod and thyroid uperfamilt of nuclear receptor
-PPAR -gamam receptors module the expression of gene involved in lipid + glucose metabolism!
-TZD action is adipose tissue , modulate syntehsis of lipid hormone!

4-Alpha Glucosidas (-) :
-Acarbose 25-100 mg before meal
-M glittol 25-100 mg before meal

-acarose+ miglitil  are cumilative”(-) of intetinal glucosidas!
-↓post meal glucose exursion by delay abs+ digestion of stach!

Pramlintide 15-120mg-SC
—>Pramlinite  syntheitc analog of amylin!
—->is injectable antihyperglucemia aent
—>Modulate Postptandial glucose levels!
-Adminsitere with insulin
-for pts who cannto acheive post prnadial target 
glucose level!

-↓ Body weight
-Synthetic analog of glucagon -like-polypeptide!
-approved as injectable,adjuvent Tc for DMII with metformin!

↑ Body weight:
-(-) of DDP- enzyme that degrates incretic and GLP-1 lime molcules!
-Effect : (+) level og GLP-1 and GIP in blood!
-Decreaes Postprandial glucose excurtion!


I-Rapid Acting:
—->rapid onset and short duration
-insuline Lipro
-insulin Aspart
-.. Glilisine
-Human insuline Recombinant (inhaled)
Durection 3-5 H

II-Short acting Insulin:
-Soluble moledcule  
-Idnetical to human insuline
-appear withing 30 min and peask between 2-3 H
-Last 5-8 H

Regular insulin should be administed 30-45 min before meal to avoid postprandial hyperglycemia!

III-Intermediate Acting-Isophane:
-Insuline+ protamine
-After SC injection eunzme degrade
protamine to permit absrption of insulin
-NPH onset 2-5H ,
-Duration 4-12H

IV- Long acting:

-ulta long action
-onset 1-1.5H
-max effect 4-5 H
-durecton 11-24H 
-1-2 H
->24 H

^^NPH based concvnetional analgue:
-T FM to provide insulin in psychologioc manner
-Insulin replacement by giving preprandial insulin!
-Long acting( glargine or determir)
-Intermediate acting (NPH)

(NPH with rapid acting or regular) before breakdfast)
2-Split /ixed variant
(NPH with rapidacting or eular before breakdgast)
3-Multiple daily injection
(long acting once a day in morning or evening)
(Rapid actng insulin Before Meals or snacks)
4-continous subcutanous insulin infusion:
(rapid acting insulin infused continously 24 hours a day , via insuline pump)

***Antithyroid X:

^^Clinical Pharmacologgy :

-Action to ito prevent hormone synthesis —>(-) Thyroid peroxidas enzyme!
1-blocks  iodone oxidartion
2-(-) incorporation of indion to tyrosne
3-Stops coupling of T3+T4 compouds
DO Not stop iodine uptake by glands!

–>used to lower thyroid hormone levels , but do not block target organ!
–>TY (-) converstion of T4 to T3  since the synthesis rather then
realease hormone is affecte the onset of afent is slow

ADR  3-12%
1-Heptitis and choelstatic jaundice( Methimazole) —>Need ot moniter transaminase level(AST, ALT)
2-Agranulocytosis—> infreuqnecty but fatal (tiomides)

Efficacy :
-Perchlar/pertecnetate. thiocyanate—> block uptake of Iodine by gland!
-competitive (-) of iodine trnasprot mechanism !

^^Efficacy :
(-) organification and hormone release and decrease the size of vasculairy of hyerplastic gland!

-Iodine increase intraglandular sotreage, delay onset of thiomade therapy!
-should be used alone, because glad will escae from iodide block in 2-8 W
leading to thyrotoxicosis exacerbationb!
-Acoid in preganacy

IV-adioactive iodine:
-in few weks can destroy Thyroid parenchhyma  visible by epithlial sweeling and necrosis!

-NMot for nursing mother ( crosses lacenta and destroy fetal thyroid gland)
-may lead to hypothyroidism—>moniter TH4+ TSH level
( in case of hypothyrdosim give 50-150 mcg of levothyroxine)

-NMot for nursing mother ( crosses lacenta and destroy fetal thyroid gland)
-may lead to hypothyroidism—>moniter TH4+ TSH level
( in case of hypothyrdosim give 50-150 mcg of levothyroxine)

V-Adenorecpeotre Blocking agents:
^^Efficacy :
-Beta blockers—->(metorolol/propranlo/atenolol) are effective theraputic adjuvents in Thyrodixcodsis manafement!
-beta blockers can cause clinical improvement of hyperthyroid Sx!
-At big dose ropanolol reduce T3 levels!

^^Rational Tx of Thyrotoxicosis:
Goal is to Decrease synthesis or release of additional hormone , This may be accomlished by:
1-remvoing art of gland!
2-(-) synthesis of hormone bby blocking release of horone from follicle!

***cliniccal aspects of hypothyrodism:

Congenital Acquired
-Early Dx is very important!!
– New born needed to be screened on his 2 nd week of life.
– Tx with L-thyroxine(for life)
– In infants a&children with congenital hypothyroidism and juvenile myxedema, the dose of levothyroxine should be titrated
according to clinical response, growth assessment, and measurements of plasma thyroxine and TSH.

– The target – TSH slightly elevated then the lower limit
#1 Most often due to autoimmune Hashimoto&#39;s thyroiditis.

#2 It is require long-term replacement therapy for thyroid hormone (levothyroxine=T 4 , Triiodothyronine = T 3 ).

#3Baseline ECG  because changes induced by hypothyroidism can be confused with ischemia.

#4 The dosage needed to be small -&gt; if improvement -&gt; slowly increasing dosage.
5) The optimal dose in the treatment of hypothyroidism is determined by the patient&#39;s well-being and TSH level (within the normal
limit=0.5-5.7mu/L) and T4 (the upper limit of normal=70-140nmol/L) in

uncomplicated Adult1.61.7mcg/kg/d averge replacement dose
Onset of action:
2-3 Weeks

Max Effect:

-Reversal of skin and hair changes , may take several mnth
-Th4 and TSH should be checked 6-8 W after inititation of Tx!
– doses before steady state are mislading
Elderly<1/6mcg/ kg/d
-initiate Th4 cautiona,ly
-Eldely may require less then young
– prs >60 ,  need <50 mcg/d
Cardiovascur isease(
Angina , CAD)
-Start with 12.5-25 mcg/d
-(+) by 25 mcg/day every 4-6 W
-sensitive to Cardiovascular effecto f T4 
-Steady state may be delayed becayse of ↓clearance

Preganancy Most ↑ in dose to ensure eurothyrodiasm
-Evaluate TSH/ TTH
ediatric (0-3M)10-15 mcg/kg/dayHypothyroid kids  can exihibi skin mottlets, lethary

***Inefficacy of Ax:

-When ts has inadwequate (WBC/CRP/ fever) clinical or microbiological response ot Ax , 
—>Systemic invetigation shouldbe done

^^Causes may include:
1-errors in suspectiblity test( repeat the test)
2-X doses and absorption( test serum emasurments)
3-Abnormalities in immune system!
4-Developmen t of infection and superinfection!
(follow up culture)

——>after Test AAx therapy muyst be adjusted!

***Pharmacotherpay of Diarrhea+conspitation

-Tx the Cause: Ax/ antiparasites!
-Diahrea is a Sx it can be managed non X
-Loperamide 2.4mg4x/day
-Coedine phosphate 15-330 mg2/d
-Correct electrolyte disutbance
-Blood idahrreea=C difficil
-Antidiahrea X  ↑ Risk of Hemolytic urenmic syndrome

-OP huydration
-Underlying disease
Underlying disease TX
-Anticholenrgic agents1

Replacement Tx(mainly lipasE)
-pancreatic enzyme used in exocrine ancreatic enzyme deficient!
-Fat absprtion of protien, madigestion occuyr when pancreaseloss >90%
Goal: prevent malabsrption+ pallaiation of Pain1

II-Conspitaption (phamacotherpy)
Osmatoic Laxatives:
-Sorbital OP 
-Lactulose 10-20mg/d
-Sodiumphophate 10hg/day
-Polyethelem glycol 17g/day


Glycerin 2-3g suppositories 1/d
Mineral oil 15-45mL 1/d
Docusate Na 100mg 2-3x/d

Bisacodyl 10mg suppositories up to x3/week
Tegaserod 6mg x2/d

***Clinical Pharmacology  of antimicrobial X :speicific aspects of rational use:
-Ax are veyr improtant for Tx! of infection 
-also help in complciation as Cancer/chemotx/ surgery!
-they are hwoever ovepescribed! a
– Due ot overprescibrition,over or underuse there is a Resistance develpment!
-Resistance limits our option for Txcx lfie htratinign ifnection which evolved!

Quesiton to ASk for Ax therpay:
-is Ax indicated on basis of Clinical finding?
-have appropirate microbiolgoical test been made?
-what are leiky etiolgoical agents?
-how to protect the indicual exsoed to the index case to prevent 2nd cases!?
-how ot prevent further exposure
-is there any clincial evidence that suggest Ax will not be beneficial

One you establish the cause , further test must be done!:
-can wer substitue narrow spectured for empireical?
-is it 1 Ax of cominbation neded?
-what is optimal ,dose, Routes. duration?
-what adjuvent therapy must be added to eradicate thei nfection
(fex surgery to remvoe forieng body ,/drainage of abscess/ infusion of aAx into an area)
( is it ossible to reduce mrotality by reducing the host immunolgical response to the infeciton)

***Risk of Bacteiral (R) to Ax and its managment:
-(r) may be inherent to a specifis or maybe acquired ivia genesfor Ax (R)!
-resisance genes between 2 bacteiral cell follow this:
1- Transformation (uptake of naked DNA from another organism)
2- Transduction (infection by a bacteriophage)
3- Conjugation (exchange of genetic material in the form of either plasmids, which are pieces of independently replicatingextrachromosomal DNA,)

-Ax elimiante non(R) vbacteira, but increases proortion of (R) bacteria that remains !
-Ax has effectn ot only on pathogens but also on Normal Flora!
-To prevent (R) has to be used onle where is it required!
-spectrum should be as narrow ass possible!

***Eradication of H pylori:
-Single Ax is ineffective!
-Combinination of 2-3 Ax+ ACid suppresion therpay!
-PPI or H2 BLocker+ (amoxicillin or carlithromycin)
-10-14 Days  not less

– triple Theray (14 days) : PPI + clarithromycin  600mg + metronidazole 500mg/amoxillin 1g 2x/day

-Quaterary therapy(14 days: PPI 2/dat+ nmetronidazole 500mg x3/day+ bismuth 535mg+tetracyline 500 mg x4/day!

-change lfiestyle: Lose Kg/HEad of bed elevation/ small infrequent meals!
-Phamacological = PPI, omerpazole,H2 lbockers(cimetidine,ranititne), antacid!!