Plasma lipids
Transported in bloodstream in form of macromolecular complexes of lipid and known as lipoproteins
Two major clinical importance/sequelae of high lipid
Acute pancreatitis
atherosclerosis

Hyperlipoproteinemia
Hyperlipidemia
Lipoprotein disorders
Primary hypertriglyceridemias
Primary chylomicronemia
Familial hypertriglyceridemia
Familial combined hyperlipoproteinemia
Familial dysbetalipoproteinemia
Primary hypercholesterolemias
Famimial hypercholesterolemia
Familial ligan-defective apolipoprotein B
Familial combine hyperlipoproteinemia
Lp(a) hyperlipoproteinemia
Secondary hyperlipoproteinemia

Lipid-lowering drugs
Several drugs are used
To decrease plasma LDL-cholesterol
Drug therapy is only one approach
Dietary measures are the first choice
Unless the patient has evident coronary or peripheral vascular disease
It is used in addition to
dietary management and
correction of other modifiable cardiovascular risk factors.
The selection of pts to be treated with drugs
Remains controversial.

Classes of lipid-lowering drugs
Statins
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase inhibitors
Fibrates
Bile acid-binding resins
Other –
nicotinic acid
Ezetimibe

Cholesterol synthesis:
HMG-CoA is the precursor for cholesterol synthesis. 
HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA.
The enzymes are located in the mitochondrial matrix.
HMG-CoA in cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
HMG-CoA is formed by condensation of acetyl-CoA and acetoacetyl-CoA, catalyzed by
HMG-CoA Synthase.

Statins - chemistry
Competitive inhibitors of HMG CoA reductase
Structural analogs of HMH-CoA
Lovastatin ) Inactive lactone
Simvastatin ) prodrugs
Atorvastatin )
Fluvastatin )
Mevastatin ) active as given
Pitavastatin )
Pravastatin )
Rosuvastatin )

Statins - pharmacokinetics
Absorption
40% to 75%
Exception of fluvastatin – almost completely absorbed
High first-pass extraction by the liver
Excretion
In the bile
5-20% in urine
Plasma half-lives
1 – 3 hrs
Exp
atorvastatin – 14 hrs
Rosuvastatin – 19 hrs

Statins - mechanism of action
HMG-Co A reductase mediates the first commited step in sterol biosynthesis
Statins cause partial inhibition /competitive inhibitors of HMG CoA reductase
induce an increase in high-affinity LDL receptors
Lead to increase
Fractional catabolic rate of LDL
Liver’s extraction of LDL precursors from the blood
Thus reducing LDL

Decrease in cholesterol concentration activates
a cellular signaling cascade culminating in the activation of sterol regulatory element binding protein (SREBP),

SREBP is a transcription factor
up-regulates expression of the gene encoding the LDL receptor.

Increased LDL receptor causes
increased uptake of plasma LDL, and
Leading to decreases plasma LDL-cholesterol concentration.

LDL receptors are expressed by
Approximately 70% are hepatocytes,
remaining expressed by a variety of cell types in the body.

Statin – therapeutic uses and dosage
One regime only
Combination regime
Resins
Niacin
Ezetimbie
Generally given at evening, cholesterol synthesis occurs at night
Except atorvastatin and rosuvastatin
Absorption is enhanced by food
Exception pravastatin
Dose: varies 5 – 80 mg/day

Adverse effects and contraindications
HMG-CoA inhibitors are contraindicated in pregnancy.
Liver disfunction:
Elevations of serum aminotransferase activity (up to three times normal)
intermittent and usually not associated with other evidence of hepatic toxicity.
Pt with underlying liver disease or a history of alcohol abuse, levels may exceed three times normal.
A relatively common side effect of the statins is myositis,
infammation of skeletal muscle accompanied by pain,weakness,and high levels of serum creatine kinase.
Rhabdomyolysis,
disintegration of muscle with urinary excretion of myoglobin and kidney damage

Fibric acid derivatives (Fibrates)
Several fibric acid derivatives
Gemfibrozil,
fenofibrate,
bezafibrate,
ciprofibrate and
clofibrate
Fibrates reduce plasma levels of triglycerides by 30-50% and typically increase levels of HDL-C by 5-15%

Fibrates - pharmacokinetics
Gembfibrozil
Absorption
From intestine and tightly bound to plasma proteins
Undergoes enterohepatic circulation and readily passes placenta
Half-life – 1.5 hrs
Elimination –
70% kidney (mostly unmodified)
Liver- modifies to hydroxymethyl, carboxyl or quinol derivatives
Fenofibrate
An isopropyl ester
Hydrolyzed completely in intestine
Half-life – 20 hrs
Elimination
60% Excreted in urine as glucuronide
25% excreted in feces

Mechanism of action
Act as ligands.

activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolise fatty acids, such as the liver, kidney, heart and muscle.

PPARα recognises and binds to specific PPARαresponse elements leading to modulation of expression of the target genes

Therapeutic uses and dosage
Hypertriglyceridemias
VLDL predominate
Dysbetalipoproteinemia

Gemfibrozil – 600 mg orally dly/ bd
Fenofibrate 48mg – 1-3 tab dly

Bile acid – binding resins (Bile Acid Sequestrants)
Example: Cholestyramine, Colestipol and colesevelam
Useful only for isolated increases in LDL
In hypertriglyceridemia, VLDL may increased during treatment with resins.

Resins - pharmacokinetics
Polymeric cationic exchangeresins
Insoluble in water
not absorbed from the GI tract
Bind to bile acids in the intestinal lumen and prevent reabsorption
will lower circulating levels of LDLs. 
A slight increase in VLDL may be seen early, but these levels will generally fall to pre-treatment levels soon (2-3 months) after the initiation of therapy. 
no effect on HDLs. 
if pre-treatment levels of VLDL and IDL TG is high, then they are generally NOT effective.

Resins - Mechanism of Action
bind to bile acids in the intestine. 
prevents the absorption of dietary fats
effectively removing the exogenous pathway of lipid transport. 
liver will detects in decreasing cholesterol and
up-regulates the LDL receptors, thus removing LDLs from the systemic circulation

Adverse Effects
GI in nature 
steatorrhoea (fatty diarrhoea, due to dietary fats remaining in the gut),
constipation, and nausea. 
decrease the absorption of drugs which will bind to the resin, including fat soluble vitamins (A, D, E, K), digoxin, phenobarbitone, and oral anticoagulants. 

Nicotinic Acid (Niacin)
reduce circulating levels of VLDL and LDL (slower response that VLDL) and Lp (a).
It will increase circulating levels of HDL.
It is converted to amide in body
Which is incorporated into niacinamide adenine dinucleotide (NAD)
Excreted in the urine (2 form)
Unmodified
Several metabolites

Niacin- Mechanism of Action
exact mechanism of action of niacin is not known. 
it may decrease synthesis of VLDL by either inhibition of lipolysis in adipose (reducing lipid mobilisation) or decreased esterification of TG. 

Therapeutic uses and dosage
In combination with
Resin
Reductase inhibitor
Used in
heterozygous familial hypercholesterolemia and
other form of hypercholesterolemia.
Severe mixed lipemia
Useful
Combined hyperlipidemia
dysbetalipoproteinemia
Effective agent
Increasing HDL
Only agent to reduce Lp(a)
Dose : 1.5 – 6 g daily

Inhibitors of intestinal sterol absorption
Ezetimibe (Zetia) is distinct from agents
it does not inhibit cholesterol synthesis in the liver or increase bile acid excretion.
selectively inhibits the intestinal absorption of cholesterol and related phytosterols.

Ezetimibe – pharmacokinetics
water insoluble,
absorbed and extensively conjugated to an active phenolic glucuronide (ezetimibe-glucuronide) after oral intake.
ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
metabolized mainly in the small intestine and liver via glucuronide conjugation,
Then biliary and renal excretion.
half-life of about 22 hours

Ezetimibe Mechanism of action
inhibits the absorption of cholesterol in the small intestine.
Unlike other cholesterol-reducing agents,
act at the brush border of the small intestine
leading to a decrease cholesterol absorption to the liver.
leads to a reduction of hepatic cholesterol stores and
an increase in clearance of cholesterol from the blood.
has no significant effect on the plasma concentrations of the fat-soluble vitamins A, D, and E

Therapeutic uses and dosage
Dose range- 5 –20 mg/d
Hypercholesterolemia
Phytosterolemia

Dose
Organ blood flow
Intrinsic function of the liver or kidneys

Volume of distribution per se has no effect on clearance or on average steady-state blood levels.

Diabetes drug
Generic name : metformin
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Chemical name:

Hypertension drug
Generic name : metoprolol
Brand name : Lopressor
Chemical name:

Erectile dysfunction drug
Generic name : sildenafil
Brand name : Viagra
Chemical name: 1-{[3-(6,7-dihydro…..)

Antidepression/seditive drug
Generic name : diazepam
Brand name : Valium
Chemical name:

Antipyretic drug
Generic name : Paracetamol
Brand name : Panadol / Uphamol
Chemical name: N-acetyl……

GENOMIC NAME: genomic is study of genetic

2. Indirect-acting cholinergic drugs is/are:
a. Edrohonium
b. Neostigmine
c. Physostigmine
d. Pyridostigmine
e. Parathion (Organophosphate)
(TTTTT)

3. Effects of parasympathetic stimulation:
a. Iris of eye (circular muscle) – contraction
b. Heart (SAN) – decreased conduction
c. Heart (muscle) – decreased contractility
d. Bronchiole of lung – relaxation
e. Smooth muscle of GIT – contraction
(TTTFT)

4. Effects of sympathetic stimulation:
a. Iris of eye (radial muscle, a receptor) – contraction
b. Ciliary muscle of eye (b2 receptor) – relaxation
c. Heart (muscle -b1 receptor) – decreased contractility
d. Bronchiole (b2 receptor) – contraction
e. Smooth muscle of GIT (b2 receptor) – relaxation
(TTFFT)

5. Muscarinic effects on Cardio vascular system (CVS)
a. Vagus nerve stimulation will cause increase HR and decrease BP
b. Vagus nerve stimulation will cause decrease HR and also decrease BP
c. Low to moderate dose of Ach will not alter the HR but decrease BP
d. High dose of Ach will decrease HR and also BP
e. High dose of Ach will increase HR and also BP
(FTTTF)

6. Acetylcholine (Ach) effects on CVS
a. Low to moderate doses of Ach will affect more on endothelial M3 receptor)
b. High dose of Ach will affect more on M2 receptor of the heart.
c. Low to moderate doses of Ach will cause vasoconstriction of peripheral vessels.
d. Low to moderate doses of Ach will cause decrease BP and subsequence lead to stimulation of Baroreceptor (reflex tachycardia).
e. High dose of Ach will decrease SAN activity and cause decrease HR(overrule reflex tachycardia) and decrease BP.
(TTFTT)

7. Nicotinic receptors are situated at
a. N1 receptors are present on ganglionic cells (sympathetic as well as parasympathetic)
b. N1 receptors are present on cells in adrenal medulla (embryologically derived from the same site as ganglionic cells)
c. N1 receptors are not selectively stimulated by Dimethyl phenyl piperazinium (DMPP).
d. N2 receptors are present at skeletal muscle end-plate.
e. N2 receptors are selectively stimulated by Phenyl trimethyl ammonium (PTMA) and selectively blocked by d-tubocurarine.
(TTFTT)

Thames
a) Bethanecol
b) Pilocarpine
c) Neostigmine
d) Edrophonium
e) Phenylephrine
f) Amphetamine
g) Tyramine

8. Act selectively on a1 receptors causes vasoconstrition and increase BP that lead to bradycardia reflex. It is used in nasal congestion. (e)

9. Its indication are urinary retention, gastroparesis and gastroesophageal reflux disease through Muscarinic receptors lead to smooth muscle contraction of bladder and stomach. (a)

10. Often abused drug. It is CNS stimulant by increasing Noradrenaline release. Indications are Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy.
(f)

11. It can be found in fermented foods eg. Cheese, yeast.
(g)

12. It is normally metabolized by monoamine oxidase (MAO) in gut and liver, however in patients treated with MAO inhibitor, it is not metabolized and causes release of catecholamines and lead to hypertensive crisis.
(g)

13. It is used as eyedrops that will decrease intraocular pressure in glaucoma.
(b)

14. Side effects of the drug is blurred vision or change in near or far vision, decreased night vision. Systemic absorption will lead to increased sweating, muscle tremors, nausea, vomiting, diarrhea, wheezing and salivation.
(b)

15. Anticholinesterase that temporary relief of the muscle weakness and fatigability in myasthenia gravis.
(c)

16. Pyridostigmine is
a. It is an anticholinestrase
b. It brand name is Mestinon
c. It has longer effects compared to neostigmine
d. It has shorter effects compared to Phytostigmine
e. It is the drug of choice for myasthenia gravis
(TTTFT)

17. Glaucoma
a. It is a condition where there is an increased in intraocular pressure leads to blindness of the eye.
b. Cholinergic drugs and anticholinesterase drugs will increase the intraocular pressure.
c. b blocker drugs will decreased secretion of aqueous humor from ciliary epithelium
d. There are two types of glaucoma, open-angle and closed angle.
e. Decreased intraocular pressure is due to increase outflow of aqueous humor and decrease secretion rate of aqueous humor.
(TFTTT)

18. Myasthenia gravis
a. It is an autoantibodies disorder against acetylcholine Muscarinic receptors
b. The number of nicotinic receptors is markedly reduced that lead to progressively reduced muscle strength with repeated use.
c. Tensilon (edrophonium) test is a screening test
d. The drug of choice for the treatment is Pyridostigmine
e. Pyridostigmine is short-acting anticholinesterase.
(FTFTF)

1. Below are the factors that are contributed for the route of drug administration:
i. Rate and extent of absorption of the drug from different routes
ii. Rapidity with which the response is desired.
iii. Condition of the patient
iv. Physical and chemical properties of the drug
v. Site of desired action for example local or generalized anesthesia

a. (i) only
b. (i) and (ii)
c. (i) and (iv)
d. (iii), (iv) and (v)
e. all the above
(TTTTT)

2. The following are true about intravenous injection except:
a. The drug directly reaches into the blood volume.
b. The effects are produced slowly.
c. The intima of veins is insensitive to drug.
d. It is the most hazardous route of administration.
e. The complications are thrombophlebitis and air embolism.
(TFTTT)

3. The statements are true about biological membrane except:
a. Bilayer of lipid molecules, the polar groups are oriented at the two surfaces and the nonpolar chains are embedded in the matrix.
b. The proteins are not able to freely float through the membrane.
c. Some of the intrinsic proteins surrounding the “fine aqueous pores” or “channels”.
d. Some proteins have enzymatic or carrier properties.
e. Drugs are transported across the membrane by passive diffusion and filtration and also specialized transport.
(TFTTT)

4. Absorption
i. Is the movement of drug from its site of administration into the circulation.
ii. All the fraction of the administered dose is absorbed into the circulation.
iii. Drugs given in solid form must dissolve in the aquesous biophase before they are absorbed.
iv. Drug in watery solution is absorbed slower than the same is given in solid form or as oily solution.
v. Concentrated solution drug is absorbed faster than from diluted solution.
a. (i) only
b. (i) and (ii)
c. (i) , (iii) and (v)
d. (i) , (ii) and (v)
e. non of the above.
(TFTFT)

5. Bioavailability
i. Is a measure of the fraction of administered dose of a drug that reaches the plasma circulation
ii. Incomplete bioavailability after s.c. or i.m. injection may occur due to local binding of the drug.
iii. Differences in bioavailability may arise due to variations in disintegration and dissolution rates.
iv. Oral bioavailability is less than 100% is due to incomplete drug absorption and drug undergo first pass metabolism in the intestinal wall/liver or excreted in bile.
v. Of drug injected intravenous is less than 100%.

a. (i) only
b. (i) and (ii)
c. (i), (ii) and (iii)
d. (i), (ii), (iii) and (iv)
e. all the above
(TTTTF)

6. Distribution is described as :
i. Once drug is absorbed in the blood circulation, it is not distributed to other tissue that initially does not have the drug.
ii. The absorbed drug is distributed from the plasma to tissue by means of concentration gradient.
iii. Movement of drug proceeds until equilibrium is established between unbound drug in plasma and tissue fluids.
iv. The extent of distribution of a drug is depends on its lipid solubility and ionization at physiological pH
v. The extend of distribution of a drug is not depends on the extent of the drug binding to plasma and tissue proteins.
vi. The extent of distribution of a drug is depends on the differences in regional blood flow.

a. (i) only
b. (i) and (ii)
c. (ii), (iii), (iv) and (vi)
d. (v) only
e. all the above
(FTTTFT)

7. The following statements are true about Brain and CSF except
a. The capillary endothelial cells in brain have tight junctions and lack large intercellular pores.
b. A sheet of glial cells lines the capillaries of the brain.
c. (a) and (b) forms blood brain barrier.
d. Only water-soluble drugs are able to penetrate and have action on the central nervous system.
e. Levodopa is the precursor of Dopamine that can cross the blood brain barier.
(TTTFT)

8. Plasma protein binding:
i. Most drugs possess physicochemical affinity for plasma proteins.
ii. Acidic drugs generally bind to alpha 1 acid glycoprotein
iii. Basic drugs generally bind to plasma albumin.
iv. Highly plasma protein bound drugs are largely restricted to vascular compartment and tend to have lower volumes of distribution.
v. The bound fraction is not available for action.
vi. The bound fraction is in equilibrium with the free drug in plasma and dissociates when the concentration of the latter is reduced due to elimination.

a. (i) only
b. (i) and (ii)
c. (ii) and (iii)
d. (i), (iv), (v) and (vi)
e. non of the above
(TFFTTT)

Question on Teratogenicity

a. Corticosteroids
b. Tetracyclines
c. Warfarin
d. Phenytoin
e. Thalidomide
f. Pilocarpine

9. Hypoplastic phalanges, cleft lip/palate, microcephaly
10. Nose, eye and hand defects, growth retardation.
11. Discoloured and deformed teeth, retarded bone growth
12. Phocomelia, multiple defects.
(9d, 10c, 11b, 12e)

13. Below are the sequence of neurohumoral transmission

i. Transmitter release – all the contents of ‘synaptic vesicles’ are extruded (exocytosis) in the junctional cleft.
ii. Postjunctional activity – A suprathreshold EPSP generates a propagated postjunctional AP which results in nerve impulse, contraction or secretion.
iii. Impulse conduction – stimulation or arrival of an electrical impulse causes a sudden increase in Na+ conductance – depolarization and overshoot.
iv. Transmitter action on postjuctional membrane – the released transmitter combines with specific receptors on the postjunctional membrane.
v. Termination of transmitter action – the transmitter is either locally degraded or is taken back into the prejunctional neurone by active uptake or diffuse away.
a. (i), (ii), (iii), (iv) and (v)
b. (ii), (iii), (iv), (i) and (v)
c. (iii), (iv), (ii), (i) and (v)
d. (iii), (i), (iv), (ii) and (v)
e. (v), (iv), (iii), (ii) and (i)
(d)

14. Drugs for which TDM is commonly used except:
a. Amikacin
b. Carbamazepine
c. Aminophylline
d. Atenolol
e. Phenytoin
(d)

15. Steps in drug development are
i. Postmarketing surveillance
ii. Phase I premarketing clinical studies
iii. Acute and subacute animal toxicity study
iv. Phase II and III clinical trial
v. Chronic safety testing in animal

a. (i), (ii), (iii), (iv) and (v)
b. (ii), (iv), (i), (iii) and (v)
c. (iii), (v), (ii), (iv) and (i)
d. (ii), (iii), (iv), (v) and (i)
e. (iii), (iv), (v), (ii) and (i)

(c)